Ch 7

Question 1

New growth is called a ___, and a more specific definition is a disorder of cell growth that is triggered by a series of acquired mutations affecting a single cell and its clonal progeny

___ is the generic term for all malignant neoplasms

A ___ is what the swelling caused by inflammation was originally called, but now it is synonymous with a neoplasm

Answer 1

Neoplasm

Cancer

Tumor

Question 2

All tumors have two basic components, the Parenchyma and the Stroma

The ___ cells are the tumor cells themselves since they make up the functional tissue of the organ (usually referring to epithelial cells of the organ)

The ___ cells are connective tissues cells that support the parenchymal cells (not actually the tumor cells themselves, but are stimulated to grow by the tumor secreting growth factors) and generally consist of connective tissue for the supporting framework or blood vessels for nutrition

^** In cases where the parenchymal cells stimulate the formation of an abundant collagenous stroma, it is called a ____ (if they are stony and hard, as seen in breast cancers, they are called ____)

^**Classification of tumor cells is based on their parenchymal component but their growth and spread is based on their stromal component

Answer 2

Parnchyma

Stroma

Desmoplasia (desmoplastic tumors), scirrhous

Question 3

___ tumors will remain localized, not spread, and able to be removed by surgical procedures

Attaching the suffix ___ to the end of the cell type from which the tumor originates is used to show that the tumor is benign (works well for mesenchymal cells, but not so much for epithelial cells)

___ is applied to benign epithelial neoplasms derived from glands (all glands are derived from epithelial cells are glands are an organ that synthesizes a substance such as hormones)

___ is applied to benign epithelial neoplasms that produce micro and macroscopically visible fingerlike or warty projections from the epithelial surface

A large cystic mass such as those seen in the ovaries is called a ____

___ is applied to fibrous benign epithelial neoplasms that produce large cystic masses

___ is applied to EITHER benign or malignant macroscopically visible projections above a mucosal surface

^** So for example, if a polyp has glandular tissue it is called a ___

**So realize polyps extend from the mucosa into the lumen of a hallow organ and papillomas are epithelial tissues that project outward

Answer 3

Benign

-Oma

Adenoma

Papilloma

Cystadenomas

Cystadenofibroma

Polyp

Adenomatous polyp (since adenomas are derived from glands)

Question 4

___ tumors can invade and destroy structures and spread to distant sites (metastasize) to cause death and malignant tumors are also collectively called Cancers

____ is the name for malignant tumors arising from solid mesenchymal tissues (fat, muscle, bone, connective tissue, etc) AKA STROMA****

___ or ___ is the name for malignant tumors arising from blood-forming cells

___ is the name for malignant tumors arising from epithelial cell origin, derived from any of the three germ layers (mesoderm, endoderm, ectoderm)

^***Carcinomas can be further broken down for their naming including ___ where the tumor cells resemble stratified squamous epithelium, ___ is a lesion in which the neoplastic epithelial cells grow in a glandular pattern (also note that for either of these, if the tissue or organ of origin is known, it can be added in front of the name)

Answer 4

Malignant

Sarcomas

Leukemia (from white cells) or Lymphoma (from lymphocytes)

Carcinomas

Squamous cell carcinoma, Adenocarcinoma

Question 5

In most benign or malignant tumors, the parenchymal cells that have undergone their excessive growth are similar in nature

However, sometimes there can be a divergent differentiation of a single neoplastic clone that creates a ___ tumor such as those seen in the salivary glands and all of these elements arising from a single clone are capable of producing both epithelial and myoepithelial cells and therefore this tumor is called a ____

^** These are also almost NEVER ____ (benign or malignant?)

^** Realize that even though these are called mixed, they arise from a SINGLE germ layer (along with most other neoplasms), however, a ____ is when there is a tumor that contains cells from more than one germ layer and an immature teratoma is ____ (benign or malignant?)

^** These come from totipotent germ cells present in the ovaries or testes and a common example is the ovarian cystic teratoma aka ___ cyst and often are ____ (benign or malignant?)

Answer 5

Mixed, pleomorphic adenoma

Malignant

Teratoma, malignant

Dermoid, Benign

Question 6

____ is the degree to which a neoplasm resembles the tissue from which it arises or is derived (both morphologically and functionally)

A lack of differentiation is called ___, which is the hallmark of malignancy

___ tumors are well-differentiated (in other words, they look almost identical to the normal parenchymal cells) and in well-differentiated benign tumors, the mitoses are usually rare and are of normal configuration

___ tumors are most commonly less-differentiated and therefore exhibit morphological alterations that betray their malignant nature (in other words, the malignant cells don’t look like the normal parenchymal cells)

^** However, sometimes malignant cells CAN look well-differentiated like in squamous cell carcinomas of the thyroid and therefore, sometimes it is hard to tell the difference between a benign tumor and a well-differentiated malignant tumor

Realize that malignant tumors can be graded as…

1) Closely resembles parent tissues
2) Features of original tissue type identifiable, but not dominant pattern. With additional atypia
3) Small minority of cellular constituents allow identification of the parent tissue (associated with cellular anaplasia)
4) Tissue of origin cannot be discerned by histopathologic appearance of the neoplasm (associated with anaplasia ALWAYS)

If you see a keratin pearl in a squamous cell carcinoma, it is a ___ differentiated malignant tumor

Answer 6

Differentiation

Anaplasia

Benign

Malignant

1) Well
2) Moderately
3) Poorly
4) Undifferentiated

Well

Question 7

The lack of differentiation (undifferenetiation), which we said was called anaplasia, is often associated with many other morphological changes including

1) Pleomorphism (variation in cell size and shape) like tumor giant cells
2) Abnormal nuclear morphology (nuclei are disproportionately large, chromatin clumped, and can stain darker than normal aka hyperchromatic)
3) Many cells are in ___ which represents the high proliferative activity of the parenchymal cells
4) Atypical, bizarre mitotic figures and some have tri/quad/multi polar spindles
5) Loss of polarity
6) Many rapidly growing malignant tumors develop large central areas of ischemic necrosis

^** So if you see these types of changes, think anaplasia and therefore a malignant tumor

Answer 7

3) Mitosis

Question 8

____ means disordered growth and is characterized by changes that include a loss of uniformity of the individual cells as wells as a loss in their architectural orientation

The new architecture of the tissues can be disruptive and cause changes to the normal tissue

Often, mitotic figures are abundant and not only contained in the basal layer, considerable pleomorphisms and hyperchormatic nuclei are also often seen

When dysplasitc changes are marked and involve the full thickness of the epithelium, however the lesion does NOT penetrate the basement membrane, then it is called a pre-invasive neoplasm aka ___ and once they breach the basement membrane, it is now said to be ____

^** Therefore, dysplasia is a precursor to malignant transformation, but realize that it does NOT always progress to cancer and also not all metaplastic epithelium is dysplastic

Answer 8

Dysplasia

Carcinoma in situ, invasive

Question 9

Cancers occur via progressive infiltration, invasion, and destruction of surrounding tissues

___ is the spread of a tumor to sites that are physically discontinuous with the primary tumor and ALWAYS marks a tumor as ___ because benign neoplasms DO NOT metastasize

^** Realize that some malignant neoplasms don’t metastisize (even though all malignant tumors CAN) like malignant neoplasms of the glial cells in the CNS called gliomas or ___ cell carcinomas of the skin

Also realize that sometimes we can’t tell if a tumor is capable of metastasis or not, such as in _____ (a tumor commonly of the adrenal glands) aka 10% tumors… Which are neuroendocrine tumors and only 10% are malignant and the only way we can call it malignant is when it metastisizes

Also realize that invasion and metastasis are two separate entities

Since benign tumors grow and expand slowly, they usually develop a rim of compressed fibrous tissue called a ___ that separates them from host tissue and often consists of ECM deposited by stromal cells (like fibroblasts)

^** There are some examples of unencapsulated benign tumors like ___ which are neoplasms composed of tangled blood vessels

In contrast, malignant tumors have no capsulation and therefore poorly demarcated from the surrounding tissue (some exceptions like slowly growing malignant tumors do develop a capsule and called psuedoencapsulated)

**** 100% a question will be asked on what determines if a tumor is malignant and the answer will be Metastasis, but invasion will also be listed as a choice so don’t pick it!!*******

Answer 9

Metastasis, malignant

Basal

Pheochromocytomas

Capsule

Hemangiomas

Question 10

Dissemination (spreading) of cancers can occur via 3 pathways

1) Direct seeding of body cavities or surfaces

^** Occurs when a malignant neoplasm penetrates into a natural “open field” lacking physical barriers such as the peritoneal cavity and sometimes if the neoplasm secretes mucus into the cavity, the gelatinous neoplastic mass is called a pseudomyxoma peritonei

2) Lymphatic spread

^** Most common for carcinomas, but sarcomas can also use this pathway

Important for breast cancer spreading and instead of completely removing the axillary lymph nodes, often a ___ lymph node (the first node in a regional lymphatic basin that receives lymph flow from the primary tumor) is biopsied to assess the presence or absence of metastatic lesion in the lymph nodes

3) Hematogenous spread

^** Most common for sarcomas, but also seen in carcinomas

In venous invasion, the blood-borne cells follow the venous flow and tumor cells often come to rest in the first capillary bed they encounter

Most common in the liver (because all portal area drainage flows to the liver) and lungs (because all caval blood flows to the lungs)

Answer 10

2) Sentinel

Question 11

The most common tumors in men arise in the prostate, lung, and colon/rectum

In females, it’s the breast, lung, and colon/rectum

In women, breast carcinomas are 2.5 times more frequent than those in the lungs, but lung cancers cause more deaths in women

The most dominant risk factor for cancer is ____ factors even though genetic factors do play a role

The most common tumor of men in the united states and most of the developed world is ___ cancer

The most common tumor of men that causes death is ____

The most common tumor of women in the united states and most of the developed world is ___ cancer

The most common tumor of women that causes death is ____

The major environmental factors that can lead to cancer include

1) Infectious agents (liked HPV causing cervical cancer)
2) Smoking is a huge contributor to lung cancer deaths
3) Alcohol
4) Diet
5) Reproductive history
6) Environmental carcinogens
^** ___ is found in old construction, ___ is found in paint or dry cleaning, ___ in mining, ___ in drinking wells, vinyl chloride in aerosol propellants, etc…
7) Age
^** Most occur after 55 and the types of tumors also are different based on age… For adults, the most common general category of tumors are ___, but among children these are VERY rare… Instead ____ or distinctive neoplasms of the ___ are the most common and are sometimes referred to the “small round blue cell tumors”
8) Acquired predisposing conditions (discussed on next notecard)

Answer 11

Environmental

Prostate

Lung

Breast

Lung

6) Abestos, Benzene, radon, arsenic
7) Carcinomas, Acute leukemia, CNS

Question 12

GO OVER TABLE 7-4 ONCE YOU FINISH THE CHAPTER

Acquired conditions that predisposes someone to cancer include chronic inflammation, precursor lesions (can be detected via pap smears), and immunodeficiency

Chronic inflammation and precursor lesions span a diverse set of conditions that are all associated with increased cellular ___ and the proliferating cells are the MOST at risk for accumulating the genetic lesions that lead to carcinogenesis

1) Chronic inflammation

^** These are mostly ___, but can also be mesotheliomas (mesothelium is the epithelium that lines the pleura) and several kinds of lymphomas

Here, tissue damage occurs and in order to repair the damage there is a inflammatory response leading to a compensatory proliferation of cells which are the replicating cells we said are susceptible to mutations (including a possible increase in tissue stem cells susceptible to transformation)

Along with the increased cell proliferation that increases the risk of accumulating genetic lesions that lead to carcinogenesis, the activated immune response also produces ROS and mediators than can promote bystander cell survival even if these have damaged genomes

Chronic epithelial injury often leads to ____, which can be adaptive and simply help the organism survive but if the alterations occur for long periods of time, cells with potentially oncogenic mutations can survive and cause cancer

2) Precursor lesions

^** These are localized morphological changes that are associated with the high risk of cancer and ALL precursor lesions arise in ___ surfaces (Carcinomas in situ is an example)

Many precursor lesions arise in the setting of chronic inflammation and can be recognized by the presence of ____ including Barrett’s esophagus, squamous metaplasia of bronchial mucosa (from smoking) or bladder mucosa (from schistosomiasis infection), or colonic metaplasia

Although most occur in the setting of chronic inflammation, some precursor lesions are noninflammatory ____ such as endometrial hyperplasia (occurs in the uterus) which is caused by a sustained estrogenic stimulation of the endometrium

Another frequent precursor lesion is the thickening of squamous epithelium that may occur in the oral cavity or on the penis or uvula called leukoplakia and this can give rise to squamous carcinomas

The final group of precursor lesions with the classic example being villous adenoma is from ___ neoplasms that are at risk for malignant transformation
^** But realize most benign tumors are NOT at risk for malignant transformation

3) Immunodeficiency states

^** These predispose a patient to ___-induced cancers

These cancers are mainly ___, but can also be some carcinomas and even some sarcomas

Answer 12

replication

1) Carcinomas

Metaplasia

2) Epithelial

Metaplasia

Hyperplasias

Benign

3) Virus

Lymphomas

Question 13

Realize that although cancers are genetic in origin (aka sometime in the genes is abnormal, that is different from the fact that MOST cancers are not actually inherited)… So realize there is a difference in those statements (inherited vs sporadic neoplasms -95%)

But like we said, SOME cancers can be genetically passed down and often come from a germline mutation in a ___ gene

One example is the genes that code ____, where if a polymorphism occurs in one of the loci there is increased susceptibility to lung cancers in cigarette smokers

___ malignant neoplasms make up 95% of cancers in the united states****

Realize that genetic and environmental factors interact such as in breast cancer where females with a defect in BRCA1 or BRCA2 tumor suppressor gene have a 3x higher chance of breast cancer if born after 1940 compared to before 1940 due to the environmental factor changes in ___ history (such as the timing or number of pregnancies)

Answer 13

Tumor suppressor

Cytochrome P-450

Sporadic

Reproductive

Question 14

Nonlethal genetic damage (or mutations) lies at the heart of carcinogenesis and can be caused from environmental exposures (acquired mutation via exogenous agents or endogenous agents), inherited in the germline, or sporadic (bad luck)

Once a mutation or DNA damage has occurred, a tumor can be formed by the ____ expansion of a single precursor cell

Name the most common genes that undergo mutations that lead to cancer

^** Also note, these are all oncogenes since they are related to cancer development

1) Proto-oncogenes (growth promoting)

^** Mutations that activate proto-oncogenes lead to a ___ of function and therefore can increase the normal functions of a gene or create a completely new function and therefore even if the cells have a normal copy of the same gene, they can still be transformed

2) Tumor suppressor genes (growth inhibiting)

^** Mutations that activate tumor suppressor genes lead to a ___ of function And often both alleles must be damaged before transformation can occur (behave in recessive fashion unless haploinsufficiency occurs aka only one mutated TSG leads to transformation)

3) Genes that regulate apoptosis

^** Mutations lead to less apoptosis and more cell survival like in a gain-of-function mutation for anti-apoptotic factors or loss of function in pro-apoptotic factors

4) Genes involved in DNA repair

^** A ___ -of-function would cause cells to not be able to repair nonlethal genetic damage and can therefore cause the cells to gain mutations at an accelerated rate called a mutator phenotype marked by genomic instability

A single mutation however won’t cause cancer, carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time (discussed on next notecard)

Answer 14

Clonal

Growth promoting proto-oncogenes, Growth inhibiting proto-oncogenes, apoptotic oncogenes, DNA-repair oncogenes

1) Gain
2) Loss
4) Loss

Question 15

A single mutation won’t cause cancer, instead carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time and the mutations that contribute to the development of a malignant phenotype are called ___ mutations

The first driver mutation that starts a cell on its path to malignancy is called the ___ mutation

Once the initiation mutation occurs, the normal cell is now a initiated precursor cell that has stem cell like properties. Next, a ___-of function mutation in genes that maintain genomic ____ causes the cell to turn into a precursor with a mutator phenotype (at the same time driver mutations are accumulating, passenger mutations aka those that cause no phenotypic changes are also accumulating)

As the drive mutations continue to develop, the cancer hallmarks finally occur which include excessive growth, local invasiveness, and the ability to form distant metastases and now a founding cancer cell has developed

Once the founder cells have developed, they continue to undergo additional mutations and subclones start to be made and via Darwinian selection and further genetic evolution, genetically heterogeneous cancers are born, which is called ____, and a diagnosis can now be made (tumor has gone through at least 30 cell doublings)

^** So realize even though malignant tumors are ____ in origin (aka they arise from a SINGLE cell that acquired a mutation), they become heterogenous genetically (especially tumors with a mutator phenotype) aka a cell originally from the first cancer cell can acquire its own new mutation and diverge as a new clone

^** So the mutation can vary from the original site and even varies between metastatic sites or locales

Like we said, selection of the fittest is important for tumor progression so it is important to realize that if one receives chemo and the tumor comes back, that most likely means the tumor cells that weren’t killed are selected against chemo (the therapy selected for preexisting subclones that had a genotype resistant to the therapy) and therefore resistant to it so if you tried the same chemo approach it would no longer word

Answer 15

Driver

Initiation

Loss, integrity

Tumor progression

Clonal

Question 16

In addition to mutations that cause DNA damage leading to cancer cells, epigenetic (changes in gene expression not caused by alterations in the DNA sequence) aberrations can also contribute to malignancy

These include DNA methylation, which is important in silencing ___ genes or Histone modification, which is important in having effects on gene expression

^** These can actually be reversed via inhibiting DNA methylation or histone modification via drugs

Answer 16

Tumor suppressor genes

Question 17

All cancer cells have eight fundamental changes in cell physiology

1) Self sufficiency in growth signals aka they can proliferate without external stimuli
2) Insensitivity to growth-inhibitor signals usually due to the fact that ___ genes are inactive
3) Altered cellular metabolism where the cancer cells undergo a switch to ___ and this is called the ___ effect
4) Evasion of apoptosis
5) Unlimited replication potential
6) Sustained angiogenesis
7) Ability to invade and metastasize
8) Ability to evade host immune response

^** Genomic ___ and cancer-promoting ____ can accelerate the transformation and subsequent tumor progression (aka the features “hallmarks” of cancer”

Answer 17

2) Tumor suppressor genes
3) Aerobic glycolysis, Warburg effect

Instability, inflammation

Question 18

Genes that promote autonomous cell growth in cancer cells are called ___ and they are created by mutations in ____ that encode proteins called ___ which have the ability to promote cell growth in the absence of normal growth-promoting signals

^** Oncoproteins resemble the normal products of proto-oncogenes, but bear mutations that often inactive internal regulator elements and therefore cells that express oncoproteins are freed from normal checkpoints and controls that limit growth

Proto-oncogenes all participate at some level in signaling pathways that drive proliferation and onogenes that encode oncoproteins generally encode signals similar to their normal function, however the main difference here is that they are constantly ____ and therefore pro-growth oncoproteins endow cells with self-sufficiency in growth

Answer 18

Oncogenes, Proto-oncogenes, oncoproteins

Active

Question 19

1) Growth factors can lead to cancer development such as glioblastomas (brain tumors) aka astrocytes to be more specific that over-express ____ and the PDGF RTK, many sarcomas that over-express ____ and the EGFR… And the autocrine signaling loop causes cancers to develop…

^**So note that the growth factor gene itself is not mutated, just that the GFs are over-expressed

2) Growth factor receptors can also lead to cancer development such as when a oncogene causes RTKs to be constantly active even in the absence of growth factors to deliver continuous mitogenic signals

^** Examples include the ____ proto-oncogene that encodes EGFRs and from a point mutation, ____ often occurs due to excess EGFR stimulation

The ____ proto-oncogene encodes for HER2 and from an over-amplification, ___ often occurs due to excess HER2 stimulation

Along with point mutations and gene amplifications, gene rearrangements can occur such as a deletion on chromosome 5 fusing part of the ___ gene with part of the ____ gene via a translocation causing the ELM4-ALK protein to be made that leads to excess ALKR activity and often occurs in ____

^** Inhibiting the receptors in these liked HER2, or ALKR can inhibit and regress the tumors

Answer 19

1) PDGF, TGF-alpha
2) ERBB1, lung adenocarcinomas

ERBB2, Breast carcinomas

ALK, ELM4, lung adenocarcinomas

Question 20

3) Proteins involved in signal transduction can lead to cancer development and the most common mutations in signaling transduction pathways include a ___ mutation in RAS genes including HRAS, KRAS, or NRAS

Remember, RAS is a small g-protein that is active when bound to GTP and quiescent when bound to GDP and it has GTPase activity called ___ that controls its activity in order to prevent excessive activation by turning GTP back into GDP

^** Therefore, if there is a mutation in the GTPase activity of the RAS protein, it won’t be turned off and excess signaling will occur which causes downstream signaling leading to the turn on of genes that support rapid cell growth (pro-growth)

So realize that a ___ of function mutation in RAS, or a ___ of function mutation in GAP, causes pro-growth

One example of the GAP mutation is the ___ gene that encodes a GAP, so if this tumor suppressor gene is mutated then no GAP is made and excess growth occurs leading to familial neurofibromatosis type 1

RAS mutations are commonly found in pancreatic adenocarcinomas and cholangiocarcinomas (bile duct cancer)

Continuing with the section of proteins involved in signal transduction that can lead to cancer development, downstream factors from RAS can also occur such as mutations in ____, which is a serine/threonine protein kinase at the top of the RAS/MAPK cascade and a gain of function mutation leads to excess TF activation and pro-growth signals

^** BRAF mutations often lead to hair cell leukemias or melanomas

_____ is another serine/threonine protein kinase at the top of the PI3K/Akt pathway and when Akt is activated, it causes protein and lipid synthesis via inactivating the pro-apoptotic protein BAD or FOXO and Akt can also activated ___ (a sensor of cellular nutrition status), which is important for increased protein synthesis

^** PI3K is regulated via ___ in order to turn off its signaling

Therefore, a ___ of function in PI3K or a ___ of function in PTEN, causes increased enzyme activity leading to pro-growth

Answer 20

Point, GAP (GTPase activating proteins)

Gain, loss

NF1

BRAF

PI3K, mTOR

PTEN

Gain, loss

Question 21

4) Proteins involved in signal transduction can lead to cancer development and the most common mutations in signaling transduction pathways include the RTK signaling pathways…

However, there can also be mutations in nonreceptor tyrosine kinases such as the ___ tyrosine kinase that is translocated from chromosome 9 to chromosome 22 and fuses with the ____ gene; and often seen in ___ cancers or acute lymphoblastic leukemia

^** Note that the BCR moiety promotes self association with the ABL gene and this often occurs in cancer where a NRTKs partner (BCR in this case) drives the self-association… And once these associate, the tyrosine kinase activity of ABL is able to be unleashed and activation of growth factor signaling pathways and pro-growth occurs

BCR-ABL inhibitors can treat CMLs and is an example of an oncogene addiction in which tumor cells are highly dependent on the activity of one or more oncogenes

Along with translocations in NRTKs, point mutations can also cause pro-growth such as in the JAK/STAT pathway that has a gain-of-function point mutation in the NRTK ___ causing pro-growth; and can lead to myeloproliferative disorders aka disorders where to many RBCs, WBCs, platelets, etc are made in the bone marrow (most commonly polycythemia vera aka a problem where the bone marrow makes to many RBCs)

Answer 21

ABL, BCR, CMLs (Chronic myelogenous leukemia)

JAK2

Question 22

******5) Nuclear regulatory proteins can lead to cancer development (aka transcription factors) and the most common in the ___ gene (the prototypical nuclear regulatory protein)

^** MYC is induced by the ___ signaling pathway following growth factor stimulation of quiescent cells and genetic variants alter the function of enhancer elements that regulate MYC expression, leading to excess MYC RNA expression and therefore excess pro-growth signaling

MYC activates the expression of many genes involved in cell growth like D cyclins which cause cell cycle progression, up-regulates rRNA genes and processing to enhance ribosomes for protein synthesis, and increases metabolic reprogramming (Warburg effect) via upregulating multiple glycolytic enzymes and factors needed for glutamine metabolism

^** The fastest growing tumors like ____s always bear a chromosomal ___ involving the MYC gene (MYC ongocene and IG gene from 8 and 14), but realize the MYC gene itself can have mutations or be amplified to lead to other types of cancers

MYC can also up-regulate ___ to give the cells endless replicative capacity

NMYC is a functionally identical gene that can cause neuroblastomas (cancer commonly in the adrenal glands) via ____ of the gene and LMYC another functionally identical gene can cause small cell cancers of the lungs

MYC can also reprogram somatic cells into pluripotent stem cells

So realize that along with defects towards the MYC gene itself, various up-strean signaling pathway defects also act through up-regulation of MYC itself

Answer 22

MYC

RAS/MAPK

Burkitt lymphoma, Translocation

Telomerase

Amplification

Question 23

6) Cell cycle regulators can lead to cancer development such as a ___-of-function mutation leading to the amplification of cyclin___-CDK___ which forms a complex that phosphorylates RB and allows the cell to progress through the G1 checkpoint aka G1/S progression (if mutated, it allows to many cells to pass through this checkpoint)

Since CDKIs inhibit G1/S progression via exerting negative control over the cell cycle, if there is a ___ of function mutation in the CDKIs it can lead to excessive growth and cancer and a common germline mutation involving P16 (CDKN2A), part of the INK4/ARF family is often involved in various cancers (P16 binds to D-CDK4 to promote the inhibitory effects of RB)

Also tumor suppressor genes that control the cell cycle including ___ (binds E2F transcription factors to prevent G1/S transition) or ___ (acts through P21 to cause cell cycle arrest and needed for G1/S and G2/M checkpoints) can be mutated leading to excessive cell cycle progression and cancer

Answer 23

5) Gain, Cyclin D - CDK 4

Loss

RB, TP53

Question 24

Expression of oncogenes in normal cells with intact tumor suppressor genes leads to quiescence or permanent cell cycle arrest, so it seems like even if a mutation were to occur causing a proto-oncogene to mutate into a oncogene that codes an oncoprotein, if tumor supressor genes are still intact then no cancer cells will proliferate

^* NOT SURE IF THIS IS TRUE, SO RECHECK***

The RB gene (referred to as the governor or proliferation) is important for inhibiting the ___/___ cell cycle progression and it encodes for the ___ protein

RB is active (hyp__phosphorylated) in quiescent cells and inactive (hyp___phosphorylated) in cells going through the G1/S cell cycle transition

^** The “two hit” hypothesis of oncogenesis came from studying this gene which states there must be 2 mutations (hits) involving both alleles at chromosome locus 13q14 to produce retinoblastoma

In the familial cases, the child inherits 1 defective copy of the RB gene in the ___ (1st hit) and 1 normal copy of the RB gene. Then sometime during the childs life a 2nd hit occurs due to a spontaneous ___ mutation causing the normal RB in the retinoblasts to become mutated and therefore the child develops retinoblastoma

^** This is an autosomal dominant inheritance

In the sporadic cases, a person must have both RB alleles undergo ___ mutations in the same retinoblast (2 hits)

So realize that RB function can be compromised via either a ___-of function mutation involving both RB alleles or a shift from the hypO (active) to hypER (inactive) phosphorylated state via a ___ of function mutation that increases CyclinD-CDK activity or a ___ of function mutation in CDKIs

^** So when Cyclin-CDK is high, it causes the RB gene to be hypERphosphorylated (inactive) and this causes the RB gene which normally binds to the ___ transcription factor when active to release the E2F transcription factor since now RB is inactive and the E2F TF can go on to progress the cells from G1 to S

So realize that normal cell cycle control is central to malignant transformations and that at least one of four key regulators of the cell cycle including P16/INK4a, Cyclin-D, CDK4, or RB is dysregulated in the vast majority of human cancers

Finally, realize that human DNA viruses can also neutralize the growth-inhibitory activities of RB via the binding of viral proteins and one important example of this is the ___ protein binding to the ___ viral type which bind to the hypOphosphorylated state of RB causing it to not be able to bind to the E2F TF and therefore rendered inactive and the E2F can now cause cell cycle progression

^** HPV-E7 has a high risk for developing cervical carcinomas

Answer 24

G1/S, Retinoblastoma (RB) protein

HypO, HypER

Germline, somatic

Somatic

Loss, Gain, Loss

E2F

E7, HPV

Question 25

TP53 is referred to as the “guardian of the genome” because it regulates cell cycle progression, DNA repair, cellular senescence (permanent cell cycle arrest) and apoptosis and is the most frequently mutated gene in human cancers

___ of function mutations in TP53 is the most common and also most of the time these are present in both TP53 alleles acquired in somatic cells aka not inherited in the germline… Aka sporadic cancers

^** However, sometimes one can inherit a defective TP53 in the germline and are said to have ___ syndrome that increases the risk of a malignant tumor by the age of 50 more than 25x and can lead to many different disorders (unlike RB that leads mostly to retinoblastoma)

If a tumor is not due to a defective TP53, it can often be due to mutations in other proteins that regulate TP53 like ___ and other related proteins that stimulate the degredation on P53 and therefore overepxression of MDM2 is often found in tumors or DNA viruses like HPV and ___ protein that lead to the degredation on P53

^** So in healthy cells, MDM2 degrades P53 via ubiquitinylates causing no P53 to be expressed and therefore healthy cells can divide. However if a cellular stress is noticed (most commonly DNA damage) then P53 is released from MDM2s inhibitory effects and P53 can act on the stressed cells and this disengagement of P53 and MDM2 occurs via 2 mechanisms

1) DNA damage or hypoxia activates ATM (Ataxia-telangiectasia) or ATR (Rad3) to phosphorylate P53 and MDM2 disrupting their binding
2) Oncogenic stress (like RAS oncoproteins being excessively activated) leading to increased p14/ARF, which encodes the ____ tumor suppressor gene (a CDKI) that binds to MDM2 to displace P53 and therefore this is why it is considered a cell cycle inhibitor

^** Realize that CDKN2A encodes for p14/ARF that activates the p53 pathway by inhibiting MDM2 and preventing P53 destruction to inhibit cell cycle progression, and also CDKN2A encodes for p16/INK4a which blocks CDK4/CyclinD mediated phosphorylation of RB and therefore reinforcing the RB checkpoint to inhibit cell cycle progression and germline mutations in CDKN2A are associated with familial forms of ___ and sporadic forms with pancreatic, breast, esophageal, etc carcinomas

Answer 25

Loss,

Li-Fraumeni syndrome

MDM2

HPV-E6

CDKN2A

Melanomas (skin cancer)

Question 26

P53s main mode of action is through its ability to act as a transcription factor, so one enough P53 accumulates various outcomes occur including

1) Transient cell cycle arrest

^** This is a primordial response to DNA damage acting via p53-dependent transcription of the CDKN1A gene that encodes to CDKI p___, and p21 inhibits CyclinD-CDK4 to arrest the cell in the ___ phase

GADD45 is also induced by p53 which is a gene needed for DNA repair and if cell DNA damage is repaired successfully, p53 decreases and cells can continue back into the cycle

2) Senescence (permanent cell cycle arrest)

^** Blocks DNA damaged cells from developing into tumors

3) Apoptosis

^** p53 can activate the pro-apoptotic genes ___ or ___ to cause death via the intrinsic mitochondrial pathway

4) Some studies suggest P53 can inhibit angiogenesis

If p53 function is loss, DNA damage goes unrepaired and driver mutations accumulate in oncogenes and other genes causing a path towards malignant transformation

To treat these cancers, one can use chemotherapy or radiation to ___ (induce or reduce?) DNA damage in order to lead to subsequent apoptosis

*** Tumors with ___ (wild or mutated?) type TP53 alleles are MUCH more likely to be killed by such therapies compared to tumors with ____ (wild or mutated?) type TP53 alleles… So in other words if the p53 itself is mutated it’s harder to cure, but if other proteins that affect p53 are mutated (therefore the p53 has a wildtype allele) it is easier to cure

Name if the type of cancer has a wildtype or mutant p53 allel

1) Testicular teratocarcinomas
2) Lung cancers
3) Colorectal cancers
4) Childhood acute lymphoblastic leukemia

Also note that p53 defects are more prone to mutator phenotypes (aka acquire additional mutations at a higher rate) and this is another reason why defects in the p53 gene itself is hard to cure, because tumors will most likely produce lots of subclones that are resistant to most forms of therapy

Answer 26

1) p21, G1
3) BAX or PUMA

Induce

Wild, mutated

1) Wild type
2) Mutated
3) Mutated
4) Wild type

Question 27

Other tumor suppressor genes exist and often their location is suspected by the detection of recurrent sites of chromosomal deletions

1) ___s are the gatekeepers for colonic neoplasias that function via down regulating growth-promoting signaling pathways

Germline loss of function mutations result in ___ (a disorder where a child develops thousands of polyps in the colon) and one of the polyps often undergoes malignant transformation leading to colon cancer

^** In this germline defect, along with nonfamilial and sporadic cases, both copies of the APC gene must be lost for an ___ to arise (A benign epithelial neoplasm derived from glands) but must undergo several more mutations to become malignant

APC is a component of the ___ signaling pathway with a major role in controlling cell fate, adhesion, and cell polarity during embryonic development

^** This occurs via APC holding in check ____, because remember when WNT/FRZ (frizzled) is activated it releases B-catenin to translocate to the nucleus where a B-catenin/TCF (DNA binding factor) complex is formed and activates signaling for cell proliferation via increasing MYC, Cyclin D1, and others genes… so APC makes sure B-catenin does not accumulate when WNT is not active

^** So in other words, a cell that loses APC seems like it is constantly being stimulated by WNT (since B-catenin continues to translocate to the nucleus for cell proliferation)… Also realize that a B-catenin mutation not allowing it to bind with APC and become inactivated can also lead to excess B-catenin

Answer 27

1) APCs (Adenomatous polyposis coli)

Familial adenomatous polyposis

Adenoma

WNT

B-Catenin

Question 28

Along with the APC/B-catenin complex that decreases active B-catenin levels, the B-catenin/___ complex also maintains B-catenin activity levels aka “contact inhibition” and is involved in intracellular adhesiveness so if the epithelium becomes injured for example, the B-catenin is released and can translocate to the nucleus for cell proliferation (important for responses to injury), however if contact inhibition is lost, B-catenin is in excess and cell proliferation and cancers can develop

Along with maintaining the E-cadherin/B-catenin complex to prevent excessive activation and accumulation of B-catenin, the E-cadherin molecules are also important for preventing cells from diaggregating and moving to other sites so if E-cadherin was mutated, it can contribute to the malignant phenotype by allowing easy access to disaggregation of cells allowing them to invade locally or metastisize

Germline loss of functions in the E-cadherin gene called ___, can cause familial ___ carcinomas and also sporadic mutations can lead to gastric carcinomas, or lobular breast carcinomas

^** E-cadherin an also be downregulated by the transcription repressor SNAIL (involved in epithelial to mesenchymal transition and metastasis)

Answer 28

E-cadherin

CDH1, gastric

Question 29

TGF-Beta is another potent inhibitor of cell proliferation due to binding of TGF-B to TGF-B receptors 1 and 2 and once bound, the receptors involve the signaling proteins ___, which turn on antiproliferative genes (like CDKIs) and turn off proliferative genes (like MYC, cyclins, CDKs, etc) in order to inhibit cell proliferation

Loss of function mutations in TGF-B are common in colon cancers and loss of function mutations in SMAD4 are common in ___ cancers

___ is another tumor suppressor gene (encoding for the protein Phophatase and Tensin homologue) that is found mutated in the familial Cowden syndrome (frequent benign growths) and remember this gene is important for inhibiting the ___ arm of the RTK pathway

Patients that inherit one mutant allele of ___ develop benign neurofibromas and if 3 alleles are mutated optic nerve gliomas occur and this condition is called familial neruofibromatosis type 1

^** Remember, NF1 gene produces neurofibromin-1 which acts as a GAP to inhibit and control RAS signaling so a mutation causes excess RAS activation

NF2 is another gene that codes for the neurofibromin-2 aka ___ protein and if mutated, cells do not establish cell-to-cell junctions and are insensitive to normal growth arrest signals generated by the cell-to-cell contact leading to excess proliferation

^** If a patient has a single germline mutation they develop familial neurofribomatosis type 2 and somatic mutations can cause schwannomas of the acoustic nerve or meningiomas

Answer 29

SMAD

Pancreatic

PTEN, PI3K/AKT

NF1

Merlin

Question 30

Loss of function mutations in the ___ gene lead to a pediatric kidney cancer called ___ tumor

^** The protein is a transcriptional activator of genes involved in the renal and gonadal differentiation and regulates the mesenchymal to epithelial transition in kidney development

Another tumor suppressor gene is ___, which codes a protein that is a negative regulator of the Hedge-Hog signaling pathway (PATCHED 1 protein)

^** If PTCH1 is mutated, excess Hedge-Hog signaling occurs leading to pro-growth genes like NMYC or Cyclin D and germline loss of function mutations lead to ___ syndrome (an increased risk of basal cell carcinomas or medulloblastomas) and somatic mutations also can lead to basal cell carcinomas of the skin or medulloblastomas (aggressive cerebellar tumor)

Germline loss of function mutations of the __ gene on chromosome 3p can lead to renal cell carcinomas, pheochromocytomas, hemangioblastomas of the CNS, retinal angiomas, and renal cysts

^** The VHL protein is a component of a ubiquitin ligase that promotes the degradation of certain proteins via proteasomes and an important substrate for the VHL ubiquitin ligase is the ____ transcription factor that VHL needs to bind in order to prevent excess angiogenesis and pro-growth….

^** Under ___ conditions, the VHL does not bind the HIF1alpha and the HIF1alpha accumulates in the nuclei and activates pro-growth/angiogenic signaling… Also if a ___ of function mutation occurs in the VHL gene, the HIF1alpha transcription factor also won’t bind leading to once again pro-growth/angiogenesis

Last but not least, the ___ aka the ____ protein encodes a serine/theronine kinase that is important for regulating cellular metabolism (glucose uptake, gluconeogenesis, protein synthesis, etc) and germline loss of function mutations lead to Peutz-Jeghers syndrome (benign polyps of the GI tract at risk for mutliple epithelial cancers) or sporadic loss of function mutations found in various carcinomas

Answer 30

WT1, Wilms

PTCH1

Gorlin

VHL (von Hippel-Lindau)

HIF1alpha

Hypoxic, loss

STK11, LKB1

Question 31

Even in the presence of normal oxygen amounts, cancer cells demonstrate a distinctive form of cellular metabolism characterized by high levels of ___ uptake and increased conversion of glucose to ___ aka fermentation via the glycolytic pathway

^** This is called the Warburg effect aka ____ aka aerobic fermentation… and also realize that this type of metabolism is not cancer specific, it also occurs in embryonic tissues that are undergoing rapid cell growth, however it is better to look at it as a general property of growing cells that become “fixed” cancer cells

The reason why cancer cells use aerobic fermentation (which only makes 2 ATP) rather than oxidative phosphorylation (which makes 36 ATPs) is because aerobic glycolysis provides metabolic intermediates that are needed for the synthesis of cellular components whereas OP does not

So cancer cells have a strong biased towards AF (aerobic fermentation is what we will abbreviate it as) with only a slight use of OP to produce 4 ATPs (remember, normal AF produces only 2 ATPs) and carbon moieties that can be used to build cellular components like nucleotides, proteins, and lipids

In a normal growing or tumor cell, the PI3K/AKT pathway can

1) Up-regulate the activity of ___ transporters and multiple glycolytic enzymes to increase glycolysis
2) Promote shunting of mitochondrial intermediates to pathways leading to lipid biosynthesis
3) Stimulate factors needed for protein synthesis

RTKs also influence metabolism in addition to sending signals to the nucleus since rapidly dividing cells (normal or tumor) express the ___ isoform of pyruvate kinase (the enzyme for the last step in t he glycolytic pathway) and when RTKs are activated, they increase the M2 isofrom of Pyruvate Kinase leading to the buildup of upstream glycolytic intermediates that can be used for RNA, DNA, or protein synthesis

^** Post-mitotic tissues that needs lots of ATP in contrast express the M1 isoform

____ is also up regulated and causes multiple glycolytic enzymes and glutaminase (which is required for mitochondrial glutamine utilization) to be up regulated

Answer 31

Glucose, lactose

Aerobic glycolysis

Glucose

M2

MYC

Question 32

For the intrinsic (mitochondrial) pathway

2 pro-apoptotic proteins are ___ and ___

3 anti-apoptotic proteins are ___, ___, and ____

3 BCH3-only proteins are ___, ____, and ___

^** Remember, BCH3-only proteins sense death inducing stimuli (like the removal of survival factors, stress, or injury) and inhibit the anti-apoptotic proteins (like BCL2 or MCL1) allowing pro-apoptotic proteins to exert their actions (BAX and BAK)… Then cytochrome C leaks out where it binds to ___, which activates caspase 9 and then caspase 3 is activated leading to apoptosis

^** Caspases are held in check in normal cells via IAP (Inhibitors of apoptosis protein)

For the extrinsic death receptor pathway

Remember, FAS (CD95) binds to FASL -> FADD recruited -> Procaspase 8 cleaved to caspase 8 -> downstream executioner caspases activated -> apoptosis

^** Realize that caspase 8 can also cleave a BH3-only protein called BID, that activates BAX and BAK and eventually apoptosis

The most common mutation that cancer cell use to mess with the apoptotic pathway in order to prevent their apoptosis is in malignant lymphoid cells (follicular Beta cell lymphomas) that over-express ____ due to a translocation at (14;18)(q32;q31)

Also realize the chemotherapy and radiation kill cells mainly via apoptosis, so if BCL2 family is over-expressed, resistance will occur

Finally, remember p53 can cause apoptosis and does so normally via BAX and PUMA activation, so apoptosis can be evaded by either a defect in the proteins directly affecting the pathway, or defects causing a loss of sensors of genomic integrity (like a mutation in p53)

Answer 32

BAX and BAK

BCL2, BC-XL, and MCL1

BAD, BIM, and PUMA

APAF1

BCL2

Question 33

All cancer cells are immortal and have limitless replication potential due to

1) Evasion of senescence

^** Due to upregulation of p53 and INK4a/p16

2) Evasion of mitotic crisis

^** As we know, somatic cells don’t express ___ (maintains telomeres) so with each replication, the telomeres shorten and eventually p53 causes senescence or apoptosis…. However, if p53 is absent, the cells still aren’t immortal because a non-homologous end joining pathway (bridge-fusion breakage cycles aka ___) is activated and mitotic catastrophe and cell death eventually occurs

3) Self-renewal

^** Tissue stem cells and germ cells express telomerase to evade mitotic crisis, can evade senescence by an unknown mechanism, and posses the capacity for self renewal (each time a stem cell divides, one remains a stem cell)

Symmetric division = both daughter cells remain stem cells

Asymmetric division = one daughter cell remains a stem cell

Some tumors arise from the transformation of already existing stem cells, like CML with the ___ translocation that comes from an already normal hematopoietic stem cell that was mutated

In contrast, sometimes a somatic cell (or a more differentiated cell) can acquire a mutation that allows them to gain stem-cell like properties such as in ____ that occurs from the transcription factor fusion of PML-RARA

^** Low amounts of TFs expressed can lead to somatic -> pluripotent stem cell so if MYC for example is low, it can cause cells to turn into stem cells

Answer 33

2) NHEJ (Non-homologous end-joining)
3) Telomerase

BCR-ABL

Acute myeloid lukemia

Question 34

Even if a solid tumor possesses all of the genetic aberrations required for malignant transformation, it can’t enlarge beyond 1-2mm in diameter unless it has the capacity for ___

^** Neovascularization allows for the perfusion of needed nutrients and oxygen, along with the fact that newly forming endothelial cells secrete PDGF and IGFs needed for the growth of adjacent tumor cells

Angiogenesis also contributes to metastasis since it allows tumor cells to access these abnormal vessels

Tumor cells are able to stimulate angiogenesis due to the fact that angiogenic tumors have increased expression of promotors (___ and ___) over angiogenesis inhibitors (angiostatin produced via cleavage of plasminogen and endostatin via cleavage of collagen)

^**(induced by either the tumor cells themselves, stromal cells, or inflammation factors)

So when hypoxia is present, the ___ transcription factor is stabilized and causes VEGF and bFGF to increase angiogenesis

Mutations aka loss of ___ causes no more inhibition of the pro-angiogenic factors like VEGF or thrombospondin-1 and therefore this also increases angiogenesis

Gain-of function mutations in RAS or MYC up regulates the expression of VEGF

Proteases can also be involved in angiogenesis via secreting bFGF

Therefore, if one were to stop angiogenesis it could cause tumor cells to not be able to grow and one example is bevacizumab, which blocks VEGF

Answer 34

Angiogenesis

VEGF and bFGF

HIF1alpha

P53

Question 35

For tumor cells to emerge from a primary mass, enter blood vessels or lymphatics and produce a secondary growth at a distant site, they must go through a series of steps broken down into 2 major cascades

1) Invasion of the ECM

^** Remember the ECM is made up of the basement membrane and intracellular matrix…

2) Vascular dissemination, homing of the tumor cells, and colonization

First, a transformed cell undergoes clonal expansion, growth, diversification, and angiogenesis -> A metastatic subclone is produced (one that can metastisize) -> Adhesion and invasion of the basement membrane then occurs -> Passage through the intracellular matrix ->

^** For the adhesion and invasion of the basement membrane and ICM this also has multiple steps including

A) “loosening up” of tumor cell-tumor cell interactions via the loss of ____ function, decreasing the ability for the cells to adhere to each other and allowing them to detach from the primary tumor and advance into the surrounding tissue

B) Once cells detach, they can attract inflammatory cells and the tumor cells themselves and the inflammatory cells release ____ which cause the ECM (BM and ICM) to be degraded

^** Proteases include MMPs, cathepsin D, and urokinase plasminogen activator, type 4 collegenease, etc…

Also realize MMPs not only destroy the BM and ICM, but also release growth factors

C) Chances int attachment of the tumor cells to the ECM proteins

D) Migration and invasion of tumor cells due to ____ factors (cytokines released by the tumor cells acting on their own cytoskeleton to allow movement through the ECM)

^** In addition, some cleavage products from the ECM and growth factors have chemotactic activity for tumor cells and stromal cells also produce paracrine effectors of cell motitlity like hepatocyte growth factor/scatter factor

-> passage through the vascular basement membrane (aka intravasation) -> Interaction with host lymphoid cells -> Tumor cells embolus (tumor cells clump along with platelets clumping to them, and also coagulation factors activated to form the emboli) -> Adhesion to endothelium via tumor cells expressing ___ adhesion molecule that binds to hyaluronate on high endothelial venules -> adhesion to basement membrane -> Extravasation -> Metastatic deposit (secondary deposit) -> Angiogenesis -> Growth

^** Colonization most likely occurs from tumor cells secreting growth factors, cytokines, and ECM molecules that act on the resident stromal cells to make the metastatic site habitable for the cancer cells

Dormancy refers to prolonged survival of micrometastases without progression

Answer 35

A) E-cadherins

B) Proteases

D) Autocrine motility

CD44

Question 36

Not much is confirmed for the molecular genetics of metastasis development, however some propose that to much of SNAIL or TWIST (which are required for ___ expression downregulation) cause loss of E-cadherin and therefore EMT (epithelial to mesenchymal transition), which might favor development of metastasis

Answer 36

E-cadherin

Question 37

The site at which circulating tumor cells leave the capillaries to form secondary deposits is related to the anatomic location and vascular drainage of the primary tumor and the tropism of particular tumors for specific tissues

^** In other words, even though most metastases occur in the first ____ available for the tumor, some tissues might express ligands for tumor cells to migrate to their specific organ (like the fact that prostatic carcinomas spread to the bone), certain tissues might express chemokines that attract certain tumors, and some tissues might just not have the proper environemnt for tumors so the tumors don’t grow there…. and this is the idea behind tropism

Answer 37

Capillary bed

Question 38

Tumor cells can be recognized as “foreign” and eliminated by the immune system

Tumor antigens include

1) Products of mutated genes

^** Genetic alterations in proto-oncogenes and tumor suppressor genes (driver mutations), along with passenger mutations that are normally unrelated to the transformed phenotype, but can sometimes fall into the coding sequences of genes giving rise to protein variants that serve as tumor antigens

2) Over-expressed or abnormally expressed cellular proteins

^** Aka normal cellular proteins that are abnormally expressed such as the over-expression of tyrosinase (a normal protein but usually it is at extremely low levels) or abnormal expression of cancer-testis antigens (which is encoded by genes silent in all adult tissues, except germ cells but even then they are not antigens, so if these become expressed no matter what tissue they are in including the testis, they are taken as foreign)

^** one common cancer-testis antigen is of the ___ family that is seen commonly in melanomas

3) Tumor antigens produced by oncogenic virsuses like HPV or EBV that are recognized by CTLs and killed
4) Oncogetal antigens

^** Expressed at high levels on cancer cells and in normal developing fetal tissue and can be used as markers that id in tumor diagnosis and clinical management with the two most common being ___ or ___

5) Altered cell surface glycolipids and glycoproteins including gangliosides, blood group antigens, and mucins

^** MUC-1 is abnormally expressed in ductal carcinomas of the breast

6) Cell type-specific differentiation antigens

^** Tumors express molecules that are normally present on the cells of origin called differentiation Ags

Answer 38

MAGE

CEA (Carcinoembryonic antigen) or AFP (alpha-fetoprotein)

Question 39

____-mediated immunity is the major anti-tumor mechanism in vivo and includes CTLs, NK cells, and macropahges

However, cancers have developed ways to evade cell-mediated immunity via various ways including

1) Selective outgrowth of antigen negative variants aka sub-clones that are easily recognizable (immunogenic) don’t survive
2) Decreased MHC expression
3) Activation of immunoregulatory pathways

^** This includes tumor cells down-regulating CD28 costimulators and up-regulating CTLA4 on effector T cells; activating PD-1L which binds to effector T cells PD1 causing effector cell death and inhibiting T cell function

^** Treatment with antibodies against CTLA4 or PD-1 can be used to cure some cancers possibly

4) Secretion of immunosuppressive factors like TGF-Beta
5) Induction of T regulatory cells that favor immunosupression

Answer 39

Cell

Question 40

Defects in 3 types of DNA repair systems can lead to genomic instability and therefore cancer including

1) DNA mismatch repair

^** One common syndrome resulting from defective mismatch repair is ____ syndrome characterized by familial carcinomas of the colon affecting mainly the cecum and proximal colon

One of the hallmarks of patients with mismatch repair defects is ___ which are tandem repeats of one to six nucleotides found throughout the genome that become unstable and increase or decrease in length

2) Nucleotide excision repair

^** One common syndrome resulting from defective nucleotide excision repair is ___ syndrome who are at an increased risk for skin cancer development after UV exposure from the sun since they can’t repair pyrimidine dimers

3) Recombination repair

^** Defects in homologous recombination can lead to Bloom syndrome (developmental defects) with a defective helicase gene, Faconi anemia (bone marrow aplasia) with a defective BRCA2 gene and others, and Ataxia-telangiectasia (neural symptoms) with a defective ATM gene; which are characterized by hypersensitivity to DNA damaging agents like ionizing radiation or DNA cross-linking agents

___ and ___, which are mutated in familial breast cancers are involved in DNA repair and if defective chromosomal breaks and severe aneuploidy will develop

4) Defective genes for somatic recombination, class switching, and somatic hypermutation

Remember, RAG1 and RAG2 allow somatic recombination so antigen receptors can be made functional, and once a Ag encounters a B cell it can undergo class switching or somatic hypermutation via the activation of the AID enzyme; however if any of these are defective (RAG1, RAG2, or AID) then Ag gene assembly and diversification won’t occur and ___ neoplasms often develop from this

Answer 40

1) HNPCC (Hereditary nonpolyposis colon cancer0

Microsatellite instability

2) Xeroderma Pigmentosum
3) BRCA1 and BRCA2
4) Lymphoid

Question 41

Infiltrating cancers provoke a chronic inflammatory reaction and in patients with advanced cancers, the reactions can lead to ____ due to inflammation induced sequestration of iron and down-regulation of erythropoietin (a hormone that increases RBCs in response to low oxygen), fatigue, and ___ (weakness and wasting of the body due to severe chronic illness)

Inflammatory cells can modify the local tumor micro-environment to enable many of the hallmarks of cancer to develop and it can do so by acting directly on tumor cells themselves or acting on resident stromal cells indirectly

1) Leukocytes and stromal cells can release factors that promote proliferation
2) Inflammatory cells can release proteases to destroy cell to cell interactions (via adhesion molecules) causing a removal of growth suppressors (because remember, E-cadherin made it so cells can excessively grow aka a growth suppressor)
3) Tumor macrophage cells prevent ___ (the death of cells that were detached from either the ECM or other cell-cell interactions)
4) Induce angiogenesis
5) Activating invasion and metastasis via macrophages that release proteases which cause ECM remodeling, TNF and EGF tumor motility; and stromal cells can release TGF-B involved in EMT (Epithelial-mesenchymal transition)
6) Evading immune destruction via macropahges and stromal cells releasing TGF-B and other cytokines causing immunosupression via T-reg cell recruitment, CTL destruction, or excess M2 macrophage activation

___ inhibitors can be used as an inhibitor to decrease inflammation and has shown to decrease colonic adenomas and can be used in patients with familial adenomatous polyposois

Answer 41

Anemia, cachexia

3) Anoikis

COX2 inhibitors

Question 42

We already discussed mutations leading to dysregulation of cancer via activation of oncogenes or inactivation of TSGs… However chromosomal changes can also contribute to cancer

KNOW TABLE 7-8**

Any chromosomal rearrangement can activate proto-oncogenes, but chromosomal translocations are the most common rearrangements and cause cancer via either

1) Promoter or enhancer substitution due to swapping of a proto-oncogenes regulatory elements with that of a gene that has higher expressed regulatory elements

^** The most common translocation leading to overexpression of a proto-oncogene is Burkitts lymphoma which has a translocation of ____ and ____ which has the MYC gene translocated to chromosome 14q32 which puts it next to the immunoglobulin heave chain IGH gene and this causes excess expression of MYC leading to oncogenic activity

^** Note since this involves the Ig chain, it must be from a B-cell origin (if a translocation involves the TCR gene, it obviously is T-cell origin)

2) Formation of a fusion gene (coding sequences fused) leading to the expression of a novel chimeric protein with oncogenic properties

^** The most common formation of a fusion gene encoding a chimeric protein is CML (chronic myelogenous leukemia) and sometimes subset of B-cell acute lymphoblastic leukemia (B-ALL)

^** This chromosome that is fused is called the ___ chromosome (which is on chromosome 22) and the breaks occur between the ___ gene on chromosome ___ and the ___ gene on chromosome ___ and the genes are fused via non-homologous end-joining and this causes excess tyrosine kinase activity

The example above like we mentioned, causes excess tyrosine kinase activity, however sometimes fusion genes can encode nuclear factors that regulate transcription or chromatin structure and the best known example of this is the fusion of chromosomes 15 and 17 leading to a ___-___ fusion gene which is seen in a form of leukemia called ____

^** Normally, RARalpha binds to DNA and when RA (retinoic acid) binds it causes RARalpha to induce transcription allowing myeloid progenitors to differentiate into ___

However, when RARalpha is fused with PML, the complex does not bind RA and transcription is inhibited since now transcriptional repressors are recruited instead and this leads to a pileup of progenitors that replace the bone marrow elements

In order to treat this, give the patient ____ and this will bind to PML-RARA and displace the repressor complexes allowing transcription to occur and progenitor cells to differentiate (an example of differentiation therapy)

Other than translocations, deletions are also common including the chromosomal deletion 13q14 which is the site of the ___ gene leading to retinoblastoma, or deletion of chromosome 3p which is the site of the ___ tumor suppressor gene leading to renal cell carcinomas

^** So realize deletions cause loss of tumor suppressor gene function and also can sometimes activate proto-oncogenes instead

Gene amplification can also lead to the overexpression and function of oncogenes such as ___ found in neuroblastomas or ___ found in breast cancers (which can be treated via Ab therapy directed at the HER2 receptor)

Finally, chromothrypsis is the name for a chromosomal catastrophe where hundreds of breaks occur in a chromosome and the DNA repairs it in a haphazard way resulting in many chromosome rearrangements and loss of segments and this is often seen in osteosarcomas and other bone cancers, along with gliomas

Answer 42

1) MYC 8q24 and IGH 14q32 -> aka t(8:14)(q24;q32)*
2) Philadelphia, ABL on 9 and BCR on 22 -> t(9;22)(q34;q11)

PML-RARA, APML (Acute promyelocytic leukemia)

Neutrophils

All-trans RA (ATRA)

RB, VHL

NMYC, ERBB2

Question 43

Remember, epigenetics is the heritable changes in gene expression that are not caused by alterations in DNA sequences

Also remember the nuclei of cancer cells are abnormal such as hyperchromasia, chromatin clumping, or chomatin clearing (vesicular nuclear chromtin) and this is due to mutations involving genes that encode epigenetic regulatory proteins and examples include

1) Silencing of tumor suppressor genes via LOCAL hyper-methylation of DNA and one commonly hypermethylated gene in cancers is the CDKN2A gene
2) Along with local hyper-methylation, GLOBAL changes in DNA methylation can also have effects (both hyper and hypo methylation) such as the gene DNMT3A that is involved in DNA methylation leading to acute myeloid leukemia

^** So realize a DNA-methylation inhibitor can be used to treat myeloid tumors

3) Changes in histones due to mutations that either affect the activity of protein complexes to “write” “read” and “erase” histone marks or mutations that affect the positions of nucleosomes on DNA

^** Drugs that target to inhibit histone deacetylases can be used as a therapy for cancers

Also note that just as genomic instability giving rise to genetic heterogenity made it possible for cancers to be drug resistant, epigenetic heterogenity also occurs making cancers drug resistant as well

****Note the MOST COMMON epigenetic modification disease in infants (90%), is due to ____ in the ___ gene causes _____ and histone methylation in the MML2 gene causes ____ (90%)

Also when the ____ gene has nucleosome positioning/chromatin remodeling there is a 100% chance of ____ tumor (which is a skeletal muscle tumor)********

Along with methylation and histone modification, remember miRNAs can have a epigenetic component and therefore also affect cancer

^** Remember, miRNAs (non-coding RNAs) cause post-transcriptional silencing via pre-miRNA being cleaved by DICER and associates with RISC and the RISC complex cleaves mRNA or represses the mRNA to prevent translation

miRNAs can either have tumor suppressor activity themselves (tumor suppressor miRNAs), OR they can inhibit tumor suppressor genes (onco-miRNAs)… so if one were to have a decreased tumor suppressor miRNA activity, or an increased onco-miRNA activity, it can lead to cancer

Common Onco-miRNAs include miR-200 (promotes EMT) or miR-155 (promotes MYC up-regulation leading to B cell lymphomas)

Common tumor suppressive miRNAs Include miR-15/miR-16 (promotes up-regulation of BCL-2 leading to chronic lymphocytic leukemia)

Answer 43

Histone methylation, MLL1, ALL - (Acute lymphoblastic leukemia), Follicular lymphoma

SNF5, Malignant Rhabdoid tumor

Increase

Question 44

Cancers result from a stepwise accumulation of multiple mutations that act in complementary ways to produce a fully malignant tumor (aka incremental acquisition of a malignant phenotype) and a great example of this is seen in colon carcinomas

^** Colon epithelial hyperplasia occurs first, then formation of ___ (benign epithelial neoplasms derived from glands) next, and these progressively enlarge and eventually undergo malignant transformation leading to ___ (malignant neoplasms of epithelial cell origin derived from any of the three germ layers)

So in other words it is an adenoma->carcinoma sequence and this goes as follows…

1) Early on, there is a “first hit” due to the inactivation of the ____ tumor supressor gene at 5q21 (germline or somatic)

^**This causes the mucosa to be at an increased risk for turning into a tumor

2) A “second hit” occurs either from methylation abnormalities or inactivation of the second normal allele involving APC and B-catenin
3) Now the adenoma begins to form and the activation of ___ at 12p12 causes full adenomal development
4) If the ____ gene is intact, the cells will go into oncogene-induced senescence, however, if the gene is inactivated at 17p13 and loss of other tumor suppressor gene like those on 18q21 leading to loss of heterozygosisty (LOH) such as SMAD2 and SMAD4, then a carcinoma will finally develop and additional mutations and gross chromosomal alterations will lead to the continuing development and growth of the carcinoma

** So realize APC loss occurs early and TP53 loss occurs late in the process and the other steps vary in different cancers

Answer 44

Adenomas, carcinomas

1) APC
3) K-RAS
4) TP53

Question 45

Carcinogenesis is a multistep process and the steps involved in chemical carcinogenesis include

1) Initiation due to exposure altering the cells making them potentially capable of giving rise to a tumor but this alone is NOT sufficient for tumor formation
2) Cells that are exposed to a carcinogen can be directly detoxified and excreted by the kidney, or if they produce electrophilic intermediates they can also be detoxified and excreted by the kidneys…. If the carcinogens or their electrophilic intermediates are not detoxified, they can bind to DNA and in order to prevent tumor formation the DNA must be repaired or the DNA damaged cells must undergo apoptosis….

^** If none of this occurs (detoxification or destruction of the DNA damaged cells), then permanent DNA lesions occur that is rapid and has “memory” and now the cell is referred to as an initiated cell

3) Now for the tumors to occur, there MUST be a ___ to induce the tumors to arise from the initiated cells and this can occur soon after initiator cell formation or a long time after (promotors can be provided by the initiating agent themselves or administered such as hormones, phenols, drugs, chronic inflammation, etc)… Promotors cause the proliferation and clonal expansion of the initiated cells and subclones suffer additional mutations

^** Realize that the effects of initiators affect the DNA directly, but effects of promotors don’t, they simply enhance to proliferation of initiated cells (therefore promotor affects can be reversed)

** Promoters or agents cause pathologic hyperplasias of the endometrium or regenerative activity in the liver

**So initiators alone ___ cause tumors, Promoters alone ___ cause tumors, initiators follow by promoters instantaneously ___ cause tumors, initiators followed by promoters after months ___ cause tumors, and promoters followed by initiators ___ cause tumors

Answer 45

3) Promoter

Don’t, Don’t, Do, Do, Don’t

Question 46

Carcinogens can be either

1) ___-acting aka require no metabolic conversion (like alkylating agents)
2) ___-acting aka require metabolic conversion to become active carcinogens

^** Include ___ which are present in fossil fuels such as benzo(a)pyrene which can be found in cigarettes due to tobacco combustion leading to lung cancer or aromatic amines and azo dyes that used to be used in the rubber industries

** So realize that chemical carcinogens most often need to be actively metabolized into ultimate carcinogens (procarcinogens aka indirect-acting carcinogens) and this occurs most commonly via the enzyme ____ and depending on a patients polymorphic variants that they inherit can determine if they are at an increased risk to get a cancer

So for example, lets say a patient inherited a highly inducible form of the P-450 gene product ___… This makes it more likely for the enzyme to convert benzo(a)pyrene (a polycyclic aromatic hydrocarbon) to a ultimate carcinogen and this causes a much higher risk of developing lung cancer

Another example of a Procarcinogen is Aflatoxin B1 and this is produced by some strains of mold called Aspergillus; this is interesting because these carcinogens target specific DNA sequences and bases called “hotspots” leading to a mutation in the TP53 gene that leads to hepatocellular carcinomas

^** realize that other carcinogens cause mutations in a more random fashion rather than affecting “hotspots”

Answer 46

1) Direct
2) Indirect (aka procarcinogens)

Polycyclic hydrocarbons

Cytochrome P-450-dependent mono-oxygenase

CYP1A1

Question 47

Exposure to UV rays can lead to increased risk of squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin

___ skin cancers (basal and squamous) are associated with total cumulative exposure to UV radiation and ___ are associated with intense intermittent exposure to UV radiation (like sun-bathing or severe sun burns during childhood) ****

UV__ light (280-320nm) causes most cutaneous cancers due to the causation of ___ dimers in DNA and these dimers are repaired via nucleotide excision repair, but to much UV exposure overwhelms this repair pathway and causes error-prone non-template DNA repair mechanisms that provide the survival of the cell at the cost of genomic mutations

^** Remember, the importance of the nucleotide excision repair pathway is best seen in ____ (where patients have hereditary disorders in this repair pathway)

Radiation can also cause cancers and humans have a hierarchy of vulnerability to different tissues with the most common tissues transformed to cancers via radiation being ___, with thyroid cancers in children following closely… Breast, lung, and salivary gland cancers are intermediates and skin, bone, and GI tract are the most resistant to radiation induced cancers

Answer 47

Nonmelanoma, melanomas

UVB, pyrimidine

Xeroderma pigmentosum

Myeloid leukemias (CML or AML aka chronic or acute)

Question 48

____ is an oncogenic RNA virus (the only human retrovirus known to cause caner) that causes ATLL (Adult T-cell Leukemia/lymphoma) and often, patients with ATLL have FoxP3 expression (T-reg cells) which remember, act to suppress immune responses and therefore these patients are susceptible to opportunistic infections and often can die from this

^** Like all other retroviruses, the HTLV-1 genome contains gag, pol, and env… But something it contains that others don’t is ___ which stimulates transcription of viral RNA and alters transcription of host genes and host signaling processes including

1) Increased pro-growth signaling and cell survival via interacting with PI3K and activating AKT, up-regulating Cyclin D2, inhibiting CDKIs, and activating NF-KB
2) Increased genomic instability due to causing defective DNA repair functions and defective cell cycle checkpoints

Answer 48

HTLV-1 (Human T-cell Leukemia Virus Type 1)

Tax

Question 49

Other than oncogenic RNA virus HTLV-1, multiple oncogenic DNA viruses can also cause cancer including

1) HPV

^** Can be low risk (HPV-6/HPV-11) commonly causing benign squamous papillomas in humans aka genital warts or high risk (HPV-16/HPV-18) causing squamous cell carcinomas of the cervix, anogenital region, and head/neck

Only once the HPV is integrated into the genome will the tumor go from benign -> malignant and the integration interupts the viral DNA within the E1/E2 open reading frame, causing the loss of the ___ viral repressor and the over-expression of ___ and ___ leading to caner

^** E6 represses ___ and stimulates ___ (the catalytic subunit of telomerase leading to its expression)

^** E7 is involved with speeding cells through the G1-S checkpoint and does so by binding to RB-E2F complex and displacing E2F so it can cause cell cycle progression (remember, E2F is only active when unbound from RB) and it also inactivates ____ causing cell cycle progression and it can bind and activate Cyclins E and A to cause cell cycle progression

*** So to summarize, High-risk HPV express oncogenic proteins that inactivate tumor suppressors, activate cyclins, inhibit apoptosis, and combat cellular senescence

Obviously, HPV leads to cervical cancer and also realize HPV alone will not cause carcinogenesis, it must act with another co-factor like co-transfection with mutated RAS genes, environmental co-factors, etc

Answer 49

E2, E6 and E7

TP53, TERT

CDKIs (p21 and p27 specifically)

Question 50

Other than oncogenic RNA virus HTLV-1, multiple oncogenic DNA viruses can also cause cancer including

2) EBV

^** Involved in an African form of ___ (the most common african childhood tumor), B-cell lymphomas, a subset of Hodgkin lymphomas, etc…

This occurs via EBV infecting B-lymphocytes and possibly epithelial cells of the oropharynx

^** EBV infects B-lymphocytes by using the CD___ receptor to attach to the B-cells and this infection of B-cells is a ___ infection aka no viral replication occurs. However B-cell infected with latent EBV express viral proteins that hijack normal signaling pathways such as the EBV gene ___, which acts as an oncogene to cause excess B-cell polyclonal proliferation by acting like a CD40 receptor (co-stimulator) to activate NF-KB and JAK/STAT signaling and it also activated BCL-2 to inhibit apoptosis

Another EBV gene called EBNA2 acts like a Notch receptor and the gene vIL-10 inhibits macrophages and monocytes from activating T cells that kill the virus and all of these EBV genes help in polyclonal B-cell expansion

So to summarize, EBV is not directly oncogenic, but instead acts as a polyclonal B-cell mitogen

EBV subsets in immunologically normal people are recognized by the immune system via EBV-specific CTLs that kill the virus and control the growth

In Africa, often patients have a concomitant infection like malaria, which destroys immune competence and allows B-cell proliferation to continue… This sets the stage for MYC translocations to occur that can lead to full blown cancer and in B-cells that have the MYC translocation and low expression of LMP-1 and EBNA2, Burkitt lymphomas develop

^** So realize that Burkitt lymphomas are occurring in patients with NORMAL immune systems, its just that LMP-1 and EBNA2 are down regulated in the proliferating B-cells so they are able to evade the immune system and these cells continue to proliferate until a MYC mutation occurs that acts as an oncogene (maybe due to the concamitant malarial infection that causes the B-cells to become prone to an MYC translocation)

** So to summarize, EBV is not directly oncogenic, instead it acts as a polyclonal B-cell mitogen to aid in polyclonal B-cell expansion and sets the stage for acquisition of the MYC translocation t(8;14) and other mutations that can lead to full-blow cancer.

In immunosuppressed patients, EBV has a more direct affect in causing B-cell lymphomas since LMP-1 and EBNA2 is expressed and no MYC translocation occurs, the EBV-infected B-cells simply grow out as aggressive B-cell tumors

In contrast to Burkitts lymphoma, there is another type of cancer called ___ which has 100% of the cancer cells containing EBV and once again, unlike Burkitt lymphoma, LMP-1 is expressed

** Also, Hodgkin lymphomas are another EBV associated cancer

Answer 50

Burkitt lymphoma

CD21, latent

LMP-1

Nasopharyngeal carcinomas

Question 51

3) HBV (and HCV)

^** This cancer causes ___ cancer

The oncogenic effects of HBV and HCV are multi-factorial, with the dominant effect being ____ and hepatocyte death leading to the regeneration of the cells and over time, genomic damage so in other words the immune response that was suppose to help this problem actually becomes maladaptive (promoting rather than preventing tumorigenesis)

During the regeneration of the liver cells, one key pathway the becomes dysregulated is the excess activation of the ____ pathway, which prevents apoptosis so the regenerating hepatocytes that are accumulating mutations and ROS don’t die

Along with this, genes like ___ in the HBV gene or ___ in the HCV gene; and viral integration in the HBV virus can also cause tumorigenesis via activating signal transduction pathways

HBV is a DNA virus and HCV is not

4) Merkel cell polyoma virus
5) Kaposi sarcoma hyerpesvirus aka human herpesvirus 8 aka HHV-8

Answer 51

3) Liver (hepatocellular carcinomas)

Chronic inflammation

NF-KB

HBx, HCV core protein

Question 52

6) H. Pylori is the first bacterial carcinogen classified and causes ___ adenocarcinomas and gastric lymphomas (also called ___ lymphomas)

^** Similar to the HBV and HCV pathway of tumors, gastric adenocarcinomas involve increased ___ cell proliferation (liver cells in HBV/HCV) in a background of chronic inflammation

Also similar to the HBV/HCV viruses, H. Pylori in gastric adenocarcinomas also has genes that act directly in oncogenesis like the ____ gene which penetrates into the gastric epithelium and initiates a signaling cascade that leads to unregulated growth factor stimulation

In MALTomas, the lymphomas are of __ cell origin

^** It starts from a chronic H. pylori infection and the infection leads to the appearance of H.pylori-reactive T cells, which stimulates polyclonal B cell proliferation via NF-KB activation so at the early stages if you use antibiotics to clear the Ags presented by the T cells it can cure the disease, but after a while additional mutations can develop causing nonstop NF-KB activation and antibiotics will no longer work

Once polyclonal B-cell proliferation occurs, it can give rise to a monoclonal B cell tumor aka a MALT lymphoma of the stomach

Answer 52

6) Gastric, MALT (aka MALTomas)

Epithelial

CagA (Cytotoxin associated A)

B-cell

Question 53

Location is a critical determinant of the clinical effects of both benign and malignant tumors

Benign and malignant neoplasms arising in the endocrine glands can cause the production of hormones and is more common in ___ tumors

Answer 53

Benign

Question 54

Cancer ___ is weakness and wasting of the body associated with loss of fat and lean muscle, elevated BMR, and evidence of systemic inflammation (like an increased acute phase reactants) and ___ is the most probable mediator contributing to this

_____ syndromes are seen in patients who develop signs and symptoms that can’t readily be explained by the anatomic distribution of the tumor or by the elaboration of hormones indigenous to the tissues from which the tumor arose

These syndromes include

1) Endocrinopathies

^** These are cancers with no endocrine origin, but have secretory activity of hormones called ectopic hormone production

The most common endocrinopathies is found in small-cell carcinomas of the lung, called ____ syndrome which has increased levels of pro-opiomelanocortin AND ___ aka the precursor for ACTH (in patients with excess CRH not from a tumor, they DON’T have increased pro-opiomelanocortin as well…

Another common paraneoplastic syndrome endocrinopathy is Hypercalcemia due to ___ induced by cancer AND production of ____ substances

^** The most important and common humoral factor associated with paraneoplasitc hypercalcemia is ____ (TGFalpha, IL1 and TNF are also sometimes seen) and is often seen in tumors associated with the breast, lung (squamous cell carcinomas), kidneys, and ovaries

Answer 54

Cachexia, TNFalpha

Paraneoplastic

1) Cushings, corticotropin (CRH)

Osteolysis (destruction of bone tissue)m calcemic humoral

PTHRP (Parathyroid hormone related protein)

Question 55

Other Paraneoplasitc syndromes include

2) Neuromyopathic syndromes

^** These include peripheral neuropathies, cortical cerebellar degeneration, a polymyopathy resembling polymyositis and a myasthenic syndrome (similar to myasthenia gravis) which is due to an ____ response

4) Acanthosis nigricans is a dermatologic disorder characterized by gray-black patches of thickened, hyperkeratotic skin with a velvety appearance and is due to an immunological response or secretion of EGF
5) Hypertrophic osteoarthropathy is a skeleton and joint abnormality that is most commonly seen in ___ carcinomas and is characterized by new bone formation at distal ends of long bones/metatarsals/metacarpals/proximal phalanges, arthritis of the adjacent joints, and ___ of the digits
6) Migratory thrombophlebitis (aka Trousseau syndrome) is seen in carcinomas of the pancreas or lungs and is due to tumor products like mucins that activate clotting
7) DIC (Disseminated intravascular coagulation) can be seen in acute promyelocytic leukemia or prostatic carcinomas and also caused by tumor products that activate clotting

Answer 55

2) Immunologic

5) Lung, clubbing

Question 56

The level of differentiation of a tumor is called it’s ___

^** Poorly differentiated tumors have more aggressive behavior

The size of the primary lesion, the extent of spread to regional lymph nodes, and the presence or absence of blood borne metastases is called its ___

^** The classification system is based on TNM (T = primary Tumor, N = regional lymph Nodes, M = Metastases)

____gists do the grading, ___gists do the staging

Answer 56

Grade

Stage

Pathologists, Oncologists