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Advanced Patho Exam 2 > Exam 2: Oncogenesis > Flashcards

Exam 2: Oncogenesis Flashcards

1
Q

Virus Association to Cancer (5)

A

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

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2
Q

what are all forms of cancer related to?

A

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

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3
Q

the pattern of cancer occurrences

A

may be inherited, familial, or sporadic

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4
Q

what are inherited forms of cancers due to?

A

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

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5
Q

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

A

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

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6
Q

hallmarks of hereditary cancers (4)

A

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

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7
Q

environmental factors for cancer

A

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

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8
Q

Epidemiological Risk Factors for cancer

A

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

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9
Q

what are the three phases that occur in carcinogenesis process?

A
  • initiation
  • promotion
  • progression
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10
Q

what is the initiation phase of the carcinogenesis process?

A

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

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11
Q

what is the promotion phase of the carcinogenesis process?

A

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

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12
Q

what is the progression phase of the carcinogenesis process?

A

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

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13
Q

characteristics of benign tumors

A
  • 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
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14
Q

characteristics of malignant tumors

A
  • 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)
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15
Q

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

A

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

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16
Q

describe cancer cell growth

A

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

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17
Q

describe dysregulated growth

A

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

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18
Q

describe anaplasia

A

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

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19
Q

describe tumor invasion

A

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

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20
Q

describe tumor metastasis

A

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

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21
Q

what is the seed and soil theory?

A

 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

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22
Q

what does cancer cell secrete in order to spread?

A

proteases and protease activators

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23
Q

what does active proteases do?

A

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

24
Q

define proto-oncogene

A

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

25
Q

what is RAS

A

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

26
Q

what happens when theres a mutation in the RAS gene?

A

it becomes an oncogene and strong driver to become cancer

27
Q

define oncogene

A

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

28
Q

what is driver mutations? give examples

A
  • They drive the progression to cancer
  • Mutations in a coding region
    o Example- mutations in p53 or RAS
29
Q

what is passenger mutations?

A
  • Not all mutations cause cancer, these are random mutations, they don’t mean anything
  • A mutation in a “non-coding” region
30
Q

Mechanisms of Action for Activation of Oncogenes (7)

A

 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)

31
Q

what are tumor suppressor genes?

A

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

32
Q

what are the two main categories of tumor suppressor genes?

A

-gatekeepers
-caretakers

33
Q

what are the gatekeepers of TSG?
Give an example

A
  • 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
34
Q

what are the caretakers of TSG?

A
  • maintain the integrity of cell genetic material
  • these protect DNA, maintain the integrity and fix them, help prevent accumulation of mutations
    o example- p53
35
Q

ID chromosomal alterations found in malignancies (4)

A

-translocation
-deletions
-inversions
-change in chromosome number

36
Q

what is the key cell that promote tumor survival?

A

tumor-associated macrophage (TAM)

37
Q

function of macrophages M1

A

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

38
Q

function of macrophages M2

A

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

TAM mimic M2

39
Q

how does TAM evades/avoids immune destruction?

A

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

40
Q

Mechanisms by Which Tumor Cells Evade the Immune System

A

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.

41
Q

Define carcinoma in situ (CIS)

A

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!!

42
Q

what three fates do CIS lesions have?

A

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

43
Q

treatment for CIS

A

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

44
Q

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

A

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

45
Q

SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: Energy Metabolism

A

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!

46
Q

SYNTHESIZE THE FACTORS WHICH SUPPORT CANCER CELL SURVIVAL: resting apoptosis

A

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

47
Q

describe warburg effect

A

 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.

48
Q

what are tumor markers and why is it important?

A
  • 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
49
Q

how are tumor markers used? (3)

A

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

50
Q

T-N-M staging classification

A

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

51
Q

staging cancers

A

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

52
Q

Ann Arbor Staging System for NHL- liquid tumor staging

A

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

53
Q

discuss tumor grading in relation to cell differentiation

A
  • 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
54
Q

Grading System for tumors that are NOT SPECIFIED

A

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

55
Q

IDENTIFY PARANEOPLASTIC SYNDROMES AND LINK THEM TO PATHOPHYSIOLOGIC MECHANISMS OF CANCER

A

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**

56
Q

what is Rb protein (pRB) responsible for?

A

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

Advanced Patho Exam 2 (4 decks)

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