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Small Animal Medicine II > Cancer Biology > Flashcards

Cancer Biology Flashcards

1
Q

What is the incidence of cancer in companion animals? What makes it seem like the incidence has been increasing?

A

UNKNOWN - leading cause of death in dogs and cats

  • longer life spans due to improved care
  • willingness to diagnose and treat
  • ability to diagnose and treat
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2
Q

What is the longest phase of the cell cycle?

A

interphase —> G1, G2, S phases

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3
Q

What are the 4 phases of mitosis?

A
  1. PROPHASE - first appearance of chromosomes as 2 identical sister chromatids
  2. METAPHASE - chromosomes line up in the middle of the spindle
  3. ANAPHASE - centromeres split and chromatids are pulled apart by the spindle contraction
  4. TELOPHASE - formation of nuclear membrane around each group of chromosomes and separation of cytoplasm into 2 diploid cells (cytokinesis)
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4
Q

What are the active and inactive phases of the cell cycle?

A

ACTIVE - M, S, G1, G2

INACTIVE - G0, majority of normal cells that are not dividing (not sensitive to chemotherapy or radiation)

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5
Q

What induces cells to enter the cell cycle?

A

in response to external factors, like growth factors and cell/matrix adhesion

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6
Q

What is a restriction point?

A

point in G1 phase where once it is passed a certain threshold, the cell cycle becomes autonomous

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7
Q

What mediated progression through the cell cycle? What 3 things are they regulated by?

A

cyclin-dependent kinases (CDKs)

  • cyclins
  • CAKs
  • CDK inhibitors - INK4a, CIP/KIP
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8
Q

How do CDKs induce progression through the cell cycle? What does this play a critical role in?

A

cyclin D-CDK complexes, which causes phosphorylation of the retinoblastoma protein (Rb), resulting in dissociation of the transcription factor E2F from the Rb

G1 progression / R point

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9
Q

What is the point of checkpoints in the cell cycle? What 3 are seen?

A

allow recognition and response to DNA damage, ultimately leading to cell cycle arrest or apoptosis

  1. G1 - DNA damage
  2. S - quality of DNA replication, DNA damage
  3. G2/M - status of spindle
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10
Q

What is the most important tumor suppressor gene? How does it work?

A

p53 - genomic guardian

  • in normal cells, it is short-lived
  • when phosphorylated in response to stress, it is stabilized and can act as a transcription regulator by binding to sequences and trans-activating genes
  • this leads to G1 arrest, allowing for DNA repair prior to replication or apoptosis
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11
Q

What is a negative regulator of p53 function?

A

MDM2 —> upregulated in some cancers

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12
Q

What kind of disease is cancer?

A

genetic, not always inheritable —> tumors arise from the accumulation of mutations that eliminate the normal constraints or proliferation and genetic integrity

  • heritable cancers seen in younger patients
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13
Q

What are the 2 types of mutagens that cause the development of cancer?

A
  1. EXTRINSIC - UV light, cigarette smoke (GI lymphoma)
  2. INTRINSIC - inherent error of DNA replication enzymes causes daughter cells to carry a few hundred mutations (most are silent, other can disable tumor suppressor genes)
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14
Q

What are oncogenes? Tumor suppressor genes?

A

mutated proto-oncogenes that promote cell growth and proliferation

genes that creat stop signals for cell growth and proliferation

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15
Q

What is Knudson’s “two hit” hypothesis?

A

individuals at risk for developing heritable cancers are heterozygous, where one mutation is found in all cells in the body and a spontaneous mutation can arise in normal/wild-type alleles and inactivate it —> loss of heterozygosity

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16
Q

What heritable cancer has been seen in dog breeds?

A

renal carcinoma and nodular dermatofibrosis of GSDs caused by the folliculin gene

  • Birt-Hogg-Dube syndrome
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17
Q

What are the 3 steps in the cancer development model?

A
  1. INITIATION - initial genetic event (can be a series of mutations that alter cell function and phenotype) results in a somatic cell with limitless replicative potential or growth/survival advantage - not enough to result in cancer alone as it is constrained by environmental factors
  2. PROMOTION - second event adds to the cell’s ability to outcompete its neighbors, leading to expansion to a tumor mass
  3. PROGRESSION - third event reinforces the malignant potential leading to clinical disease

(happens over years!)

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18
Q

What are oncogenes? Where were they first identified?

A

abnormal functioning proto-oncogenes that are usually responsible for normal cell growth and proliferation

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19
Q

What are the 5 types of oncogenes?

A
  1. growth factors - excessive production or abnormal expression causes uncontrolled growth
  2. growth factor receptors - initiate the delivery of mitogenic signals
  3. protein kinases - signal transduction and receptor-ligand binding
  4. signal transducers - send mitogenic signals to the nucleus (G protein secondary messengers)
  5. nuclear proteins/transcription factors - control gene expression and proliferation —> malignant transformation
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20
Q

What are 4 causes of dominant gain of function of oncogenes?

A
  1. chromosomal translocation - BCR/ABL
  2. gene amplification - increase number of gene copies (Myc)
  3. point mutations - single base change that can result in homeostasis disruption due to sustained proliferation signals or failure to respond to negative feedback
  4. viral insertions - acute transforming virus (not natural, occur in a single animal)
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21
Q

What is retinoblastoma gene?

A

tumor suppressor gene that controls cell cycle progression at restriction points

  • disruption is a common feature of many cancers
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22
Q

What is p53? What 3 functions does it have?

A

tumor suppressor gene (guardian of the genome)

  1. push cells into arrest or apoptosis based on degree of DNA damage
  2. prevents accumulation of potentially oncogenic mutations and genomic instability
  3. regulates gene expression and cellular response to DNA damage, which plays a role in cell cycle progression

(most frequently inactivated gene in human cancers)

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23
Q

What are 6 hallmarks of cancer?

A
  1. self-sufficiency of growth signals
  2. insensitivity to antigrowth signals
  3. ability to evade apoptosis
  4. limitless replicative potential
  5. sustained angiogenesis
  6. invasion and metastasis
24
Q

What 2 new enabling and emerging hallmarks of cancer have been observed?

A

NEW - genome instability, tumor-promoting inflammation

EMERGING - deregulating cellular energetics, avoiding immune destruction

25
Q

What is thought to be the most important event in neoplastic transformation?

A

self-sufficiency of growth signals to sustain chronic proliferation

normal cells require mitogenic stimuli for growth and proliferation

26
Q

What 4 stimuli are used by cells for growth and proliferation? How does this compare in neoplastic cells?

A
  1. binding of signaling molecules to receptors
  2. diffusion of growth factor into the cell
  3. extracellular matric components
  4. cell to cell adhesions and interactions

oncogenes allow cells to gain self-sufficiency from environmental stimuli and NOT external mitogenic stimuli (not all growth-promoting genes have the capacity to become oncogenes!)

27
Q

What is the most common result of oncogene activation?

A

senescence or apoptosis unless there are additional events that promote transformation and survival

28
Q

What are some causes of cancer cells acquiring self-sufficiency of growth signals?

A
  • production of growth factors themselves
  • induce stromal production of growth factor ligands
  • increase receptor concentration
  • structural alterations in growth factor receptors which results in ligand-independent signaling
  • constitutive activation of the signaling pathway downstream of receptor
  • disruptions of negative-feedback mechanisms that attenuate proliferative signaling
  • cell to cell growth signaling derived from tumor stromal elements
29
Q

What are 2 ways the normal cells maintain cellular quiescence and homeostasis?

A

antiproliferative signals!

  1. soluble growth inhibitors via surface receptors
  2. immobilized inhibitors embedded in extracellular matrix or adjacent cells

pushes cells into G0 or postmitotic state

30
Q

What are antigrowth factors controlled by? How does this compare in neoplastic cells?

A

tumor suppressor genes - Rb*, p53

  • loss of function of tumor suppressor genes
  • evade contact inhibition
31
Q

What are 4 ways that neoplastic cells avoid apoptosis?

A
  1. loss of proapoptotic tumor suppressor genes - p53, pTEN
  2. gain of function of antiapoptotic genes - BCL2 (indolent, follicular lymphoma)
  3. anioikis - loss of integral cell-to-cell or cell-to-matrix contact
  4. avoid caspases that normally chop up DNA
32
Q

What is the Hayflick limit?

A

normal number of times a cell is able to replicate before cell senescence is induced

33
Q

What are telomeres?

A

caps at the ends of chromosomes made up of repetitive DNA that protect coding DNA from attrition

  • after 50 cell divisions, cells enter an irreversible state of cellular senescence (arrest of proliferation without loss of biochemical function)
34
Q

How do tumors acquire immortalization?

A

telomerase - keeps added onto telomeres on the caps of DNA strands

35
Q

What is angiogenesis? How are neoplastic cells able to do this?

A

endothelial cells or endothelial progenitors are activated by tumor-derived growth factors and result in the production of new capillaries at the tumor site

produce signals that result in endothelial cell survival, motility, invasion, differentiation, and organization via VEGF, PDGF, and angiopoietins

36
Q

When is angiogenesis normal? How does the angiogenesis created by neoplastic cells compare?

A

surgical repair, menstruation, pregnancy —> not common in companion animals (spayed!)

vasulature is aberrant, leaky, tortuous, and poorly organized —> leaky and centers of necrosis commonly seen in tumors (makes tx difficult!)

37
Q

What takes place during the metastatic cascade?

A
  • primary tumor formation
  • angiogenesis
  • intravasation
  • embolization (resisting anoikis)
  • arrest in target tissues
  • early survival in distant sites (significant hurdle of cancer cells)
  • extravasation
  • tumor cell proliferation
  • angiogenesis
  • repeat

+ evasion of the immune system

38
Q

What is the first step in the metastatic cascade following primary tumor growth? What does it require?

A

intravasation into vascular and lymphatic circulation

motility of tumor cells that the ability to digest, modulate, or escape the extracellular matrix —> enzymatic degradation (MMPs), amoeboid invasion

39
Q

What is responsible for tumor survival in circulation? How do normal cells usually prevent this?

A

resistant anoikis - induction of apoptosis after disruption of the interaction between epithelial cells and ECM

  • cell-matrix anchorage: integrins
  • cell-cell interactions: cadherins
  • loss of these interactions results in the activation of caspases and apoptosis*
40
Q

What are the 3 mechanisms that neoplastic cells use to avoid anoikis?

A
  1. homotypic interactions - interact with other tumor cells (bind to themselves
  2. heterotypic interactions - interact with host cells, like platelets and WBCs
  3. overexpression of proteins that inhibit anoikis - integrins, TrkB, FAK, TGF-b, galectin-3
41
Q

What 2 mechanisms do neoplastic cells use to arrest in target tissue?

A
  1. size-dependent trapping - tumor cell lodges in first capillary bed encountered (why lungs are common sites of metastasis)
  2. receptor-mediated interaction between tumor cell and host vasculature
42
Q

What 2 things occur once a cancer cell or embolus has arrested at a distant site? What does both require?

A
  1. immediately move out of circulation into target organ
  2. stay within circulation

survival in the new environment (significant hurdle!)

43
Q

What is the seed and soil hypothesis?

A

success of cancer metastasis is defined by interactions between the seed (tumor cell) and soil (micoenvironment)

44
Q

Is metastasis commonly efficient in cancer cells? What are 5 factors that contribute to successful metastasis?

A

NO —> less than 1% of cancer cells that enter circulation are able to survive at distant sites

  1. oxygen tension
  2. pH
  3. growth factor availability
  4. cellular binding partners
  5. modulation of microenvironment
45
Q

What happens after cancer cells arrest in distant locations? What is this based on?

A

extravasation - proliferate and modulate the new environment

tumor-induced changes to the stroma, which leads to production of growth factors —> proliferation, angiogenesis

46
Q

What are the 2 models of metastasis?

A
  1. LATE/PROGRESSION - genetic changes that resulted in the primary tumor are distinct and precede the changes that result in metastasis (phenotype acquired within a small number of cells within a heterogenous tumor)
  2. EARLY ONCOGENIC - genetic events that lead to primary tumor developed at the same time as events that contribute to metastasis (bad cancer born bad)
47
Q

What can cause a dormancy in metastatic ability?

A

metastatic cells reside in transient sites (BM) before they are recruited into the metastatic cascade

48
Q

Maintenance mechanisms of the normal cell monitor DNA damage and regulate repair enzymes. How does this affect the genome?

A

requires it to attain increased mutability (instability) in order to overcome redundant homeostatic mechanisms that prevent cancer emergence

49
Q

What is the minimum number of mutations required for clinical onset of solid tumors?

A

15-25

(smaller in cytogenically stable leukemia)

50
Q

What 3 effects does tumor-producing inflammation have?

A
  1. supply growth factors, which promote angiogenesis, proliferation, and invasion of neoplastic cells
  2. production of signals that promote EMT
  3. production of mutagenic reactive oxygen species

(used to have been thought this was an attempted immune response to eradicate the tumor)

51
Q

What is the Warburg effect? What advantage does this give neoplastic cells?

A

observation that most cancer cells release energy predominantly not through the ‘usual’ citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through less efficient anaerobic glycolysis

deregulates cellular energy and avoidance of immune destruction —> T cells, myeloid-derived suppressor cells, TGF-B, Igs

52
Q

What is the cancer stem cell theory?

A

tumors are hierarchically organized into a subpopulation of cells that retain or acquire the capacity for self renewal and can initiate and maintain a tumor —> only a small portion of cells care clonogenic and CSC progeny can undergo differentiation and lose capacity to support the tumor

53
Q

What is the competing hypothesis about cancer stem cells?

A

stochastic model - all cells in a tumor posses an equal capacity for self renewal

54
Q

What is the prevailing theory about cancer stem cells? What support does this have?

A

CSC have peculiar phenotypes and mutations in a small number of genes

the metastatic pathway shows that only a small number of cells are capable of producing metastatic lesions

55
Q

What are the 2 theories of cancer stem cell origin?

A
  1. arise from stem cells
  2. de-differentiation of somatic cells
56
Q

CSC:

A

Small Animal Medicine II (57 decks)

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