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MFM > Hallmarks of Cancer > Flashcards

Hallmarks of Cancer Flashcards

1
Q

6 hallmarks of cancer

A
  1. immortality
  2. persistent proliferative signal
  3. inactivation of anti-proliferative signals
  4. resistance to cell death
  5. angiogenesis
  6. metastasis
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2
Q

what is immortality in relation to cancer

A

continuous cell division and limitless replication

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3
Q

what is replicative capacity?

A

the predetermined number of divisions in somatic cells

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4
Q

what governs replicative capacity?

A
  1. senescence

2. telomere length

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5
Q

what is senescence

A

a cell irreversibly exits the cell cycle but is still metabolically active

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6
Q

what causes a cell to go into senescence

A

cells measure cumulative physiologic stress that they experience over extended periods of time and stop proliferating once the damage exceeds threshold, such as accumulation of ROS

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7
Q

why is telomere length used for replative capacity?

A

telomere length is how the cell measures how many replicative generations it has passed through

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8
Q

how does a cell respond to ROS?

A

ROS causes DNA damage, but the cell repairs this by activating p53, which regulates p21 to inactivate Cdk

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9
Q

what sends a cell into senescence?

A

accumulated p21 (Cdk inhibitor)

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10
Q

happens during telomere shortening

A

a section of a telomere is lost during each cycle of replication at the 5’ end of the lagging strand due to lack of DNA upstream to ligate to

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11
Q

what occurs when there is insufficient telomerase activity?

A

prevention of addition of nucleotide repeats at the end of the chromosome

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12
Q

what occurs in the normal aging process of telomerase shortening and what happens in cancer cells?

A

telomeres in (somatic) cells become progressively shorter as we age, but some cancer cells can upregulate telomerase and increase or prevent the shortening of telomeres, 90% of human tumors are telomerase positive

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13
Q

what is a proto-oncogene

A

genes that encode proteins that function to receive or transmit cellular growth promoting signals, cause cell proliferation and survival in normal cells

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14
Q

what is an oncogene

A

GAIN OF FUNCTION MUTATIONS, when proto-oncogenes undergo a mutation that causes them to be ALWAYS ON (constitutive activation, inappropriate activation), leading to excessive cell survival and proliferation, most are dominant (only one allele has to be affected)

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15
Q

what are the main 3 proto-oncogenes?

A

growth factor receptors, Ras protein, Src kinase (could be anti-apoptotic proteins also)

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16
Q

what is the mitogenic pathway that is the most important in cancer pathogenesis?

A

Ras-MAPK, where the GF binds to RTK, RTK phosphorylates tyrosines attracting the adaptor protein Grb2, which recruits Sos (the Ras activating protein), which activates Ras, which phosphorylates Raf (MAPKKK), which phosphorylates MEK (MAPKK), which phosphorylates ERK (MAPK)

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17
Q

what is the prevalence of Ras mutation in cancers?

A

more than 20% of human tumors contain activating Ras mutations where Ras is always on

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18
Q

what is the prevalence of Raf mutation in cancers?

A

67% of melanomas contain activating Beta-Raf mutations, beta Raf always on to phosphorylate MEK and ERK for increased gene expression

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19
Q

what mutations can turn a proto-oncogene into an oncogene?

A
  1. mutation in coding sequence, causing a hyperactive protein made in normal amounts
  2. gene amplification causing a normal protein to be greatly overproduced
  3. chromosome rearrangement causing nearby regulatory DNA sequence to cause a normal protein to be over produced OR the chromosome fusion to actively transcribed gene produces a hyperactive fusion protein
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20
Q

what are the tumor suppressor genes?

A

Rb protein and p53 protein and Cdk inhibitors like p21 or p16^ink4a - loss of function

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21
Q

what allele combination do tumor suppressors have?

A

tumor suppressors are recessive, meaning both alleles have to be affected to cause abnormalities

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22
Q

difference between oncogene and tumor suppressor function?

A

oncogene is a gain of function mutation and tumor suppressor is a loss of function mutation

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23
Q

what is the two hit model?

A
  1. a mutation event (point mutation) inactivates one allele of a tumor suppressor, but unaffected allele can still function
  2. a second mutation event occurs that inactivates the unaffected allele, resulting in the complete functional elimination of the tumor suppressor gene (usually caused by a loss of heterozygosity)
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24
Q

what is the end result of inactivating the tumor suppressor genes?

A

excessive cell survival and proliferation

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25
Q

what is “loss of heterozygosity”

A

loss of normal function of one allele in a gene in which the the other allele was already inactivated, aka second hit in the two hit model of tumor suppressor gene inactivation, more likely to occur than a random mutation

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26
Q

what genetic events can eliminate tumor suppressor gene activity?

A
  1. a whole (normal) chromosome is lost
  2. a region containing the normal gene is deleted
  3. there is a loss of function mutation in the normal gene (LOH)
  4. normal gene activity is silenced by epigenetic changes (via methylation)
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27
Q

what is promoter methylation?

A

methylases covalently attach a methyl group to cytosine bases in promoter region of DNA, repressing the transcription of that gene, upregulation of methylases usually used in cancer to turn off tumor suppressor genes

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28
Q

how are cancer cells resistant to apoptosis?

A
  1. mutations in growth factor receptors make them constitutively active, never turning off even in absence of mitogens
  2. DNA damage response is not active, allowing for accumulation of genetic mutations - aka tumor suppressors (LOF) of pro-apoptotic proteins and p53 activating (oncogenes)(gain of function) anti-apoptotics
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29
Q

1/3 ways activated p53 evokes apoptotic response

A

induce expression of gene encoding FasR, causing display of Fas receptor on cell surface, sensitizing cell to any FasL in extracellular space

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30
Q

2/3 ways activated p53 evokes apoptotic response

A

induce expression of IGF-binding protein-3 (IGFBP-3) which is released into extracellular space, where it sequesters IGF-1 and IGF-2, which are prosurvival/anti-apoptotic signaling molecules

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31
Q

3/3 ways activated p53 evokes apoptotic response

A

induce expression of Bax, a pro-apoptotic protein that causes cytochrome C release from mitochondria (channel protein)

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32
Q

how would the loss of function (tumor suppressor) of p53 affect the cancer cell?

A

FasR would not be expressed on the cells, IGF-1 and IGF-2 would NOT be sequestered by IGFBP-3 and therefore would promote cancer cell survival and anti-apoptosis, Bax would not be expressed and NO mitochondrial channel pore would be formed

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33
Q

what is angiogenesis

A

new blood vessel formation

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34
Q

why is the cancer cell motivated to connect to circulatory system?

A

while the tumor grows, the inner cells are oxygen deprived and exposed to low nutrient levels, high levels of CO2, and high levels of metabolic waste, so cancer cell needs to find oxygen and nutrient source, and find a way to rid of waste and CO2

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35
Q

what is the angiogenic switch

A

when the cancer cells acquire the ability to induce growth of new blood vessels

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36
Q

how do cancer cells induce angiogenesis and what does that indicate?

A

cancer cells secrete VEGF (vascular endothelial growth factor), and the connection to blood vessels allow cancer cells to metastasize through the blood stream

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37
Q

what are the 2 phases of metastasis?

A
  1. invasion of ECM

2. vascular dissemination, homing of tumor cells, and colonization

38
Q

4 steps of invading the ECM

A
  1. dissociate from each other
  2. degrading basement membrane
  3. change in attachment of tumor cells to ECM proteins
  4. locomotion
39
Q

how do cells dissociate from each other

A

tumor cells downregulate cadherins, cause cells to bind weakly to each other

40
Q

how do cells degrade basement membrane

A

tumor cells secrete collagenases and MMP that degrade components of the basement membrane (clearing a path)

41
Q

how do cells change attachment to ECM proteins & start moving

A

cleavage of collagen in the basement membrane generates new sites that bind to receptors on tumor cells, stimulating migration and locomotion

42
Q

what do tumor cells do in blood vessels?

A

tumor cells tend to aggregate and form clumps which interact with T-lymphocytes

43
Q

what is “homing”

A

when T-lymphocytes express gycoproteins in their surface that are needed for extraversion

44
Q

how is the secondary site of tumor formation determined?

A

site of metastatic tumor is determined by the anatomic location of the primary tumor, usually at the first capillary bed available

45
Q

what causes cancer?

A

10% cases are genetic, 90% are from environment, diet/lifestyle, infectious agents (virus)

46
Q

what mutations cause hereditary breast and ovarian cancer syndromes?

A

BRCA1 and BRCA2

47
Q

what mutations cause familial adenomatous polyposis? (FAP)

A

APC or MUTYH

48
Q

what causes lynch syndrome? (hereditary non-polyposis colorectal cancer syndrome)

A

MSH2 and MLH1 (mismatch repair proteins)

49
Q

what causes Li-Fraumeni Syndrome

A

TP53 (p53) mutations

50
Q

what mutations cause VonHippel Lindau Syndrome

A

VHL

51
Q

what mutations cause cowden syndrome

A

PTEN

52
Q

what mutations cause retinoblastoma

A

Rb

53
Q

what does tobacco use increase risk of?

A

lung, bladder, kidney cancer

54
Q

a diet low in vegetables, high in nitrates and high in salts could cause ?

A

stomach and esophageal cancer

55
Q

a diet high in fat, low in fiber, and high in broiled/fried foods could cause?

A

bowel, pancreas, prostate, breast cancers

56
Q

exposure to what could cause acute leukemias

A

benzenes

57
Q

exposure to benzenes could cause what

A

acute leukemias

58
Q

exposure to arsenic could cause what

A

skin carcinoma

59
Q

exposure to what could cause skin carcinoma

A

arsenic

60
Q

what is the danger of cooking meat at high temps and burning it

A

generates heterocyclic amines, which are potent mutagens, and are carcinogens identified by Ames test

61
Q

process of Ames test

A
  1. test compound activated by liver homogenate
  2. activated compound is added to bacterial strain that is histidine dependent
  3. ,if bacteria are ABLE to grow in a histidine-independent manner, indicates a random mutation has occurred in the gene responsible for histidine independence
  4. compound is mutagenic
62
Q

what if a bacteria can grow in the histidine dependent medium without histidine being added?

A

indicates random mutation has occurred in gene responsible for histidine independence , indicates mutagenic potential

63
Q

problem with Ames test

A

a lot of false positives for mutagens

64
Q

problem with rodent carcinogenicity tests

A

the doses that the rats are exposed to are 10,000x or more higher than the doses experienced by humans, and the delivery may not correspond to that experienced by humans, therefore, there is a potential for false positives and false negatives

65
Q

example of false positive encountered in the rodent carcinogenicity test

A

saccharin was found to be positive, but not really

66
Q

example of false negative encountered in rodent carcinogenicity test

A

tobacco smoke was found to NOT cause cancer in rats, but DOES in humans

67
Q

what virus is known to cause cervical carcinoma in humans

A

HPV

68
Q

what virus is known to cause non-hodgkins lymphoma

A

HTLV-1

69
Q

how does HPV have carcinogenic potential

A

2 viral genes: E6 and E7

70
Q

what does E6 do in HPV

A

binds to p53, causing ubiquitination and degradation of p53 (causes cancer cells to not die)

71
Q

what does E7 do in HPV

A

binds to Rb, prevents Rb inhibition of E2F, allowing E2F to induce expression of S phase genes (continuous cell cycling)

72
Q

what does parenchyma?

A

neoplastic cells making up tumor

73
Q

what is stroma?

A

connective tissue, blood vessels, innate immune system helping the growth and spread of cancer parenchyma

74
Q

describe benign tumors

A

well differentiated and resemble normal cells, remain localized, named by the tissue of origin, usually form capsule around mass, readily palpable, movable, discrete

75
Q

describe malignant tumors

A

derangement of differentiation, invasive, named from tissue of origin, pattern, or microscopic view, poorly demarcated, does not recognize normal anatomic boundaries, may have mitotic figures

76
Q

what is a mixed tumor?

A

divergent differentiation of a single neoplastic clone capable of producing both epithelial and nonepithelial cells, epithelial components scattered within myxoid stroma
ex. teratoma

77
Q

hallmark of malignancy

A

pleomorphism, abnormal nuclear morphology, mitoses, loss of polarity, vascular stroma

78
Q

what is metaplasia

A

replacement of one cell with another cell type in association with tissue damage, repair or regeneration

79
Q

what cells are replaced with GERD?

A

squamous cells are replaced with glandular cuboidal

80
Q

what cells are replaced with smoking?

A

pseudocolumnar replaced with squamous

81
Q

what is dysplasia

A

disordered growth and loss of uniformity in individual cells and architectural organization, is a precursor to cancer

82
Q

what is carcinoma in situ?

A

pre-invasive neoplasm, dysplastic changes that involve the full thickness of the epithelium but the lesion does not penetrate the basement membrane

83
Q

what predicts likelihood of metastasis?

A
  1. lack of differentiation
  2. aggresssive local invasion
  3. rapid growth
  4. large size
  5. large # of cells in replicative pool
84
Q

what is the pathway of cancer spreading?

A
  1. direct seeding of body cavities and surfaces
  2. lymphatic spread
  3. hematogenous spread
85
Q

what is direct seeding?

A

wherever the neoplasm penetrates into an open field lacking physical boundaries

86
Q

what is lymphatic spread

A

travel of cancer through normal lymphatic drainage

87
Q

what is a sentinel node

A

the first node in the regional lymph basin that receives lymph flow from the primary tumor, cancer cells may be destroyed here by tumor specific immune response

88
Q

what causes enlargement of lymph nodes in cancer?

A

spread and growth of cancer cells, or reactive hyperplasia

89
Q

what is hematogenous spread

A

tumor cells invade arteries or more likely veins by following venous flow and come to rest at the first capillary bed encountered

90
Q

what is cancer cachexia?

A

equal loss of both fat and lean muscle from humoral factors released from tumor cells (proteolysis) or elevated TGFbeta released from immune cells, elevated BMR, weakness, anemia, anorexia

91
Q

what is paraneoplastic syndrome

A

signs and sx that cannot be explained by the anatomic distribution of tumor or elaboration of hormones indigenous to tissue where tumor is

MFM (39 decks)

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