Exam 2: Oncogenesis

Question 1

Virus Association to Cancer (5)

Answer 1

o HPV, cervical
o Epstein-Barr Virus (EBV), mono, lymphoma, nasopharyngeal carcinoma
o Kaposi sarcoma herpesvirus
o Hepatitis B and C, hepatocellular carcinoma (liver)
o HIV, leukemias

Question 2

what are all forms of cancer related to?

Answer 2

all forms of cancer are related to inherited or acquired genetic mutations

Question 3

the pattern of cancer occurrences

Answer 3

may be inherited, familial, or sporadic

Question 4

what are inherited forms of cancers due to?

Answer 4

due to germ line mutations and may account for about 5 to 10 percent of all cancers

 Example: women with heredity breast and ovarian cancer have a germ-line mutation in either BRCA 1 or BRCA 2. Most common in people of Ashkenazi Jewish decent, HNPCC or heredity nonpolyposis colorectal cancer, has a hereditary link and is also known as Lynch syndrome

Question 5

95% of the time, cancer are sporadical in nature and they are somatic, what does somatic mean?

Answer 5

they are acquired, usually something in the environment. toxic to DNA

Question 6

hallmarks of hereditary cancers (4)

Answer 6

o Early age onset: less than 40-50 years for adult onset cancers
o Multiple primary cancers in a single individual
o Bilateral cancers in paired organs
o Uncommon presentations of cancer

Question 7

environmental factors for cancer

Answer 7

o Diet, lifestyle sun exposure up to 90% of cancers are linked to environmental factors
o Breast, colon, prostate cancers may be modulated by hormonal systems including estrogens, androgens, insulin
o Increased fasting insulin levels are associated with cancer, heart disease, stroke, DM, and cognitive dysfunction

Question 8

Epidemiological Risk Factors for cancer

Answer 8

o Tobacco
o Alcohol
o Lack of fruit and vegetables
o Meat
o Lack of fiber
o Overweight
 Chronic inflammation + increased lipids and other macromolecules + insulin signaling + adipokines can lead to cancer
 A lot of Leptin is present, which causes chronic inflammation
o Lack of physical exercise
o Post-menopause
o Infections
o Ionizing radiation
o Occupational hazard
o Reproduction
o Sun exposure and sunbeds
o Life style + Carcinogen exposures + Occupational Exposures  leads to altered epigenomic marks  abnormal expression of tumor-suppressor genes and oncogenes  increased susceptibility to cancer

Question 9

what are the three phases that occur in carcinogenesis process?

Answer 9

• initiation
• promotion
• progression

Question 10

what is the initiation phase of the carcinogenesis process?

Answer 10

Initiation involves the alteration change, or mutation of genes arising spontaneously or induced by exposure to a carcinogenic agent

 Still reversible, Single event mutates the DNA
* Exposure to a known carcinogen- UV light

Question 11

what is the promotion phase of the carcinogenesis process?

Answer 11

The promotion stage is considered to be a relatively lengthy and reversible process in which actively proliferating pre-neoplastic cells accumulate.
- Within this period the process can be altered by a chemo preventative agents and affect growth rates

 clonal expansion of the initiated cell
* constant exposure to that carcinogen substance
 can be interrupted and reversed
* smoking

Question 12

what is the progression phase of the carcinogenesis process?

Answer 12

Progression is the final stage of neoplastic transformation, where genetic and phenotypic changes and cell proliferation occur.
- This involves a fast increase in the tumor size where the cells may undergo further mutation with invasive and metastatic potential

 irreversibles

Question 13

characteristics of benign tumors

Answer 13

• Grow slowly
• Have a well-defined capsule- Encapsulated
• Are not invasive
• Are well differentiated, look like the tissue from which they arose
• low mitotic index, diving cells are rare
• Do NOT metastasize
• NOT cancer
• -oma
  o Lipoma, organ hypertrophy
   Can be life threatening if enlarged in critical locations
• Uniform shape
• Cell cohesiveness
• Controlled growth
• Well-differentiated
• Mortal (apoptosis)
  o Programmed cell death if mistakes are found

Question 14

characteristics of malignant tumors

Answer 14

• Grow rapidly
• Are not encapsulated
• Invade local structures and tissues
• Are poorly differentiated, may not be able to determine tissue of origin
• High mitotic index; many diving cells!!
• Can spread distantly, often through blood vessels and lymphatics (metastasis)
• *Hallmark is anaplasia
  o the loss of cellular differentiation, irregularities of the size and shape of the nucleus and the loss of normal tissue structure
• Abnormal appearance
• Lack of cohesiveness
• Rapid, disorderly division
• Immortal (lack apoptosis)

Question 15

what are the two main characteristics that make cancer cells deadly?

Answer 15

1) dont exhibit contact inhibition
2) not anchorage indepedent—>they do not need agar to stick to, they can grow freely

Question 16

describe cancer cell growth

Answer 16

o abnormal appearance, lack of cohesiveness, rapid disorderly division, poorly differentiated, immortal (lack apoptosis)

Question 17

describe dysregulated growth

Answer 17

o factor alone does not cause malignancy
o Ability to invade and metastasize are of equal importance

Question 18

describe anaplasia

Answer 18

o Microscopic hallmark to cancer cells
o Loss of cellular differentiation
**Loss of structural and functional differentiation of normal cells

Question 19

describe tumor invasion

Answer 19

o capacity for local invasion/spread
 Prereq for metastasis
 The first step in the metastatic process
 Direct tumor extension and then cells migrate way from the primary tumor and invade the surrounding tissues
 Mechanisms important to Local Invasion
* Recruitment of macrophages and other cell types to the primary tumor
o There they promote digestion of connective tissue capsules and other structural barriers by secreted proteases
 Causes changes in cell to cell adhesion making the cancer cells more slippery and mobile
* changes in the expression of cell adhesion molecules such as cadherins and integrins
o Can be extensive, but may not always involve the vascular and lymphatic entry
 Basal cell carcinoma of the skin is an example  superficial spread is common and often diagnosed early and treated successfully
o Some tissues are easily invaded, whereas others often resistant to invasion
 Difficult to invade include cartilage, tendons, sclera, arterial walls, muscles.
* It is important to consider contractility, density, and antimitotic properties of these tissues

Question 20

describe tumor metastasis

Answer 20

o Major cause of death from cancer
 Cancer that has NOT metastasized, can be cured.
* Steroids are used to reduce the ability of cancer cells to metastasize (inflammation again)
o Ability of malignant tumors (most deadly characteristic) ability to spread far beyond the tissue of origin
o To transition from LOCAL to METASTASIS; The cancer cell must be able to invade local blood and lymphatic vessels
 That metastatic cell must be able to survive in the circulation, attach in an appropriate new microenvironment and multiply to produce an entire new tumor
o Complex multistep process
 involves the capacity of neoplastic cells to detach from the primary tumor and disseminate to other parts of the body
o Many tumors have begun to metastasize at the time of detection. It is estimated that 60% of patients with solid tumors have microscopic or macroscopic metastasis at diagnosis

Question 21

what is the seed and soil theory?

Answer 21

 Cancer cells (the seed) must overcome multiple physical and physiologic barriers in order to spread, survive, and proliferate in distant locations
 The destination (the soil) must be receptive to the growth of the cancer
 ONLY certain cancer cells will grow in certain structures
* Must survive 10 diff steps, must win all of them
o There may be many opportunities to interrupt the potential lethal pathway

look on page 4 of objectives for the 10 steps

Question 22

what does cancer cell secrete in order to spread?

Answer 22

proteases and protease activators

Question 23

what does active proteases do?

Answer 23

they digest the ECM and basement membranes-> creating pathways which cells can move

Question 24

define proto-oncogene

Answer 24

o Regulates normal cellular proliferation
o They control cells in the cell cycle!
 They basically say get into that cell cycle, and they say get out
 Example; growth factor/receptor, RAS

Question 25

what is RAS

Answer 25

a normal protein that is essential for the cells to go in and out of the cell cycle

Question 26

what happens when theres a mutation in the RAS gene?

Answer 26

it becomes an oncogene and strong driver to become cancer

Question 27

define oncogene

Answer 27

o When there is a mutation in a proto-oncogene, they become oncogene  It only takes one mutation to make that transition!  Independent function, acts in a dominant manner o Oncogene are mutant genes that in their normal non-mutant state direct synthesis of proteins that positively accelerate proliferation  they are GENES THAT CAUSE CANCER o Drives cells into an unregulated expression of proliferation/uncontrolled cell growth

Question 28

what is driver mutations? give examples

Answer 28

* They drive the progression to cancer * Mutations in a coding region o Example- mutations in p53 or RAS

Question 29

what is passenger mutations?

Answer 29

* Not all mutations cause cancer, these are random mutations, they don’t mean anything * A mutation in a “non-coding” region

Question 30

Mechanisms of Action for Activation of Oncogenes (7)

Answer 30

 Point mutations; driver vs passenger  Gene Amplification * Duplication of a small piece of a chromosome over and over  Chromosomal translocations * Large changes in chromosome structure in which a piece of one chromosome is connected to another * *these are more significant, codes for oncogenes  Subtle alterations * Insertions or deletions  Inversions  Gene silencing  Exogenous sequences (from tumor viruses)

Question 31

what are tumor suppressor genes?

Answer 31

o regulates the cell cycle, inhibits proliferation, resulting from growth signals, stop cell division when cells are damaged, and prevent mutations  they put the brakes on, PREVENT CANCER in cells!!! o Also referred as “anti-oncogenes” o Need TWO mutations before you can get cancer  cancer cells learn to suppress that second allele without needing a mutation  the first one can be turned off by inheritance/environment driven * tumor suppressor must be inactivated to allow cancer to occur

Question 32

what are the two main categories of tumor suppressor genes?

Answer 32

-gatekeepers -caretakers

Question 33

what are the gatekeepers of TSG? Give an example

Answer 33

* prevent cells from going through cell cycle, REGULATE cell cycle * these are checkpoints for errors, prior to going into the cell cycle o one mutation in a gatekeeper predisposes an individual to cancer, two mutations leads to a neoplasia (excess growth)  example- Rb gene

Question 34

what are the caretakers of TSG?

Answer 34

* maintain the integrity of cell genetic material * these protect DNA, maintain the integrity and fix them, help prevent accumulation of mutations o example- p53

Question 35

ID chromosomal alterations found in malignancies (4)

Answer 35

-translocation -deletions -inversions -change in chromosome number

Question 36

what is the key cell that promote tumor survival?

Answer 36

tumor-associated macrophage (TAM)

Question 37

function of macrophages M1

Answer 37

produces an acute inflammatory response and is responsible for removal and destruction of infectious agents

Question 38

function of macrophages M2

Answer 38

produces inflammatory mediators to suppress ongoing inflammation and induce cellular proliferation, angiogenesis, and wound healing TAM mimic M2

Question 39

how does TAM evades/avoids immune destruction?

Answer 39

o TAMs have diminished cytotoxic response, and develop the capacity to block T-cytotoxic cell and NK-cell functions and produce cytokines that are advantageous for tumor growth and spread. o TAMs secrete cellular growth factors, that favor tumor cell proliferation, angiogenesis, and tissue remodeling, similar to their activities in wound healing

Question 40

Mechanisms by Which Tumor Cells Evade the Immune System

Answer 40

o Tumors may evade the immune response by losing expression of antigens or major histocompatibility complex (MHC) molecules or by producing immunosuppressive cytokines or ligands for inhibitory receptors on T cells - Restricting antigen recognition, inhibiting immune system, and reducing T cell exhaustion o Viral and tumor antigens are processed by the tumor cells and presented on the cell surface by MHC class I molecules and are targets of CD8+ T-cytotoxic cells o the theory of inflammation suggests that a variety of infectious mediators and their relationships with inflammatory cells are a major cause of cancer.

Question 41

Define carcinoma in situ (CIS)

Answer 41

o Pre-invasive epithelial tumors of glandular or squamous cell origin o Early stage cancers are localized to the epithelium and have NOT penetrated the local basement membrane or invaded surrounding stroma  changes are occurring but has not invaded basement membrane o Not malignant therefore they are called CIS  Steps to prevent; SCREENING AND SURVEILLANCE!!

Question 42

what three fates do CIS lesions have?

Answer 42

 Can remain stable for a long time  Can progress to invasive and metastatic cancers  Can regress and disappear

Question 43

treatment for CIS

Answer 43

 Challenging due to unknown if it will progress to cancer  Some people prefer “removal” vs watchful waiting

Question 44

SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: Angiogenesis/Neovascularization

Answer 44

o When we have a cut or a wound, healing is the process of establishing new blood vessels within the tissue to undergo repair.  Once the tumor begins to grow larger than a mm in diameter, they NEED their own blood supply to deliver oxygen and nutrients o Normally- angiogenetic factors/angiogenic inhibitors  Control development of new vessels o In Cancer  Several mechanisms increase and maintain secretion of angiogenetic factors * Vascular endothelial growth factor (VEGF) * Platelet derived growth factor (PDGF) * Basic fibroblast growth factor (bFGF)  All three ^^ recruit new vascular endothelial cells and initiate the proliferation of existing blood vessels in cells, ALLOWING SMALL CANCERS TO BECOME LARGE ONES- feeding the tumor

Question 45

SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: Energy Metabolism

Answer 45

o Cancer cells often grow in a hypoxic/acidic environment o Alteration in a number of cancer genes promote the activity of glycolytic (breaking down sugar to generate energy) pathways that support growth of cancers – in other words they uptake sugar!!!  ^This is why with PET scans, cancer can be detected!

Question 46

SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: resting apoptosis

Answer 46

o Normally- apoptosis, a programmed cell death that is triggered by either intrinsic pathway (mitochondrial) or the extrinsic pathway o Cancer- turned off  P53 gene mutations

Question 47

describe warburg effect

Answer 47

 4 ATP/glucose is produced  Cancer cells utilize glucose and pyruvate to generate lactate  Cancers Have Altered Metabolism  Normal tissues use oxidative phosphorylation (OXPHOS) to turn glucose into CO2 and energy (in the form of ATP)  Cancers take a different approach; even in the presence of oxygen, usually they do not use OXPHOS. Instead, they consume large quantities of glucose to make cellular building blocks, supporting rapid proliferation.

Question 48

what are tumor markers and why is it important?

Answer 48

* Substances produced by both benign and malignant cells, are either present in or on tumor cells or are found in blood, spinal fluid, urine o Tumor markers- Include hormones, enzymes, genes, antigens, and antibodies * Tumor markers are important because a lot of cancer cells can produce a lot of substances that mimics normal biologic substances

Question 49

how are tumor markers used? (3)

Answer 49

o Screen and identify individuals at high risk for cancer o Help diagnose the specific type of tumor in patients with clinical manifestations relating to their tumor  Adrenal tumor, enlarged liver, or prostate o Follow the course of a tumor

Question 50

T-N-M staging classification

Answer 50

it is a classification staging system for cancers-solid organ o T: the size and/or extent (reach) of the primary tumor  Indicates tumor size o N: amount of nearby lymph nodes  Indicates node involvement o M: presence of metastasis or secondary tumors formed by the spread of cancer cells to other parts of the body  Indicates the presence of distant metastasis

Question 51

staging cancers

Answer 51

o Stage 1- cancer confine to the organ of origin (cancer in situ) o Stage 2- cancer that is locally invasive o Stage 3- cancer that has spread to regional structures, such as lymph nodes o Stage 4- cancer that has spread to the distant sites  Liver spreading to lung or prostate spreading to bone

Question 52

Ann Arbor Staging System for NHL- liquid tumor staging

Answer 52

o Stage 1- single lymph node/extralymphatic site o Stage 2- two or more lymph node regions on the SAME side of diaphragm o Stage 3- lymph node involvement to BOTH sides of the diaphragm o Stage 4- diffuse extralymphatic disease

Question 53

discuss tumor grading in relation to cell differentiation

Answer 53

* Grade VERY different than staging! o Grading is- how differentiated cells are o Used to target treatment * Tumor grade describes a tumor based on how abnormal the cells and tissue look to indicate how quickly a tumor is likely to grow and spread * Tumor grading determines how responsive the disease will be to therapy

Question 54

Grading System for tumors that are NOT SPECIFIED

Answer 54

o 1-4 depending on abnormality  G1- well differentiated (low grade)  G 2- moderately differentiated (intermediate grade)  G 3- poorly differentiated (high grade)  G 4- undifferentiated (high grade) o Grade 1- Tumor cells and the organization of the tumor tissue appear close to normal o Grade 3 and 4- tumors do not look like normal cells.  Grade 3 and 4 grow rapidly and spread faster

Question 55

IDENTIFY PARANEOPLASTIC SYNDROMES AND LINK THEM TO PATHOPHYSIOLOGIC MECHANISMS OF CANCER

Answer 55

o Symptom developments that are triggered by a cancer but are not caused by direct local effects of the tumor mass o Mostly caused by biologic substances that are released from the tumor or by the immune response triggered by the tumor, hormones!  Example- carcinoid tumors release serotonin into the bloodstream, causing flushing, diarrhea, wheezing, rapid heartrate  Usually occur at distant sites of primary tumor * Endocrine, neuromuscular, renal, hematologic, cardiovascular, musculoskeletal, GI, rheumatologic systems autoimmune triggered o These syndromes are significant because they may be the earliest symptom of an unknown cancer**

Question 56

what is Rb protein (pRB) responsible for?

Answer 56

its responsible for a major G1 checkpoint, blocking S- phase entry and cell growth - it is also a tumor suppressor gene -plays a important role in the negative control of the cell cycle and in tumor progression