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BMS 100 Test 2 > Carcinogenesis > Flashcards

Carcinogenesis Flashcards

1
Q

New growth (aka tumour)

A

Neoplasia:
Neoplasm is an abnormal mass of tissue
-Uncoordinated & excessive growth
-Continues beyond cessation of growth
stimuli.
Tumours can be classified as malignant or benign.

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2
Q

Benign

A

remain localized at their site of origin

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3
Q

Malignant

A

invade and destroy adjacent structures and spread to distant sites.

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4
Q

-oma

A

Often denotes a benign tumour
ex) Lipoma, osteochondroma, adenoma

Some notable exceptions: lymphoma, melanoma, mesothelioma (all malignant)

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5
Q

Carcinoma

A

Malignant tumour of epithelial cell origin

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6
Q

Sarcoma

A

Malignant tumour of mesodermal/mesenchymal origin

ex) muscle, cartilage, bone

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7
Q

Differentiation

A

Extent to which neoplastic parenchymal cells resemble corresponding normal parenchymal cells both morphologically and functionally.

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8
Q

tumour cells resemble normal cells

A

Well-differentiated
Characteristic of benign tumors

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9
Q

tumor cells do not resemble normal cells

A

Poorly-differentiated (aka anaplastic)
Characteristic of malignant tumor

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10
Q

Pleomorphism: cells vary in size and shape
-may include the presence of tumor giant
cells.
Abnormal nuclear morphology
-Nuclei containing abundant chromatic will
stain darker than normal (aka
hyperchromatic)
-Disproportionally large nuclei & nucleoli
-Presence of large numbers and abnormal
mitosis.
ex) Tripolar or quadripolar
Loss of cell polarity

A

Anaplasia (poorly differentiated)

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11
Q

In addition to anaplasia, malignant tumors will often show:

A

Ischemic necrosis
Areas of hemorrhage
Local invasion:
-Benign tumors are frequently encapsulated and do not demonstrate local invasion.
-Malignant tumors typically lack a capsule and do extend into adjacent normal tissue

Metastasis:
-migration to distant tissues via lymphatics or blood vessels

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12
Q

Chart of tumor characteristics:

A

visual:

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13
Q

What are the two factors that can contribute to cancer risk?

A

genetic and environmental

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14
Q

Best established environmental risk factors include:

A

-Infectious agent
-Smoking
-Alcohol
-Diet
-Obesity
-Reproductive history
-Environmental carcinogens

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15
Q

Cancer can occur at any age, but most carcinomas occur in adults older than ______

A

55

-Likely explained by accumulations of somatic mutations that accompany the aging of cells.
-A decline in immune competence may also play a role.

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16
Q

Some acquired conditions increase the risk of cancer:

A

-Chronic inflammatory disorders
-Precursor lesions
-Immunodeficiency states

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17
Q

Cancer risk is increased in individuals with a wide variety of chronic inflammatory diseases. Why?

A

Chronic inflammatory diseases is accompanied by tissue damage.
-Cell proliferation must occur to repair the
damage.

Activated immune cells produce reactive oxygen species that can damage DNA.

Inflammatory mediators produced can promote cell survival.

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18
Q

Localized morphologic changes in epithelial tissue that increase the risk of malignant transformation.

ex) could be hyperplasia, metaplasia, or dysplasia

A

Precursor lesions

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19
Q

Increase in number of normal cells
ex) endometrial hyperplasia increases risk of endometrial cancer.

A

Hyperplasia

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20
Q

Metaplasia

A

replacement of one differentiated somatic cells with another

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21
Q

Presence of abnormal cells

ex) cervical dysplasia increases risk of cervical cancer

A

Dysplasia

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22
Q

Metaplasia is the ________ of one differentiated somatic cells with another.

A

Replacement

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23
Q

When does metaplasia occur?

A

In response to chronic irritation so that cells can better withstand the stress.
-Occurs due to the reprogramming of stem
cells
or undifferentiated mesenchymal cells
found in connective tissue.
ex) Transformation of columnar epithelium of squamous epithelium in trachea of cigarette smokers.

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24
Q

Immunodeficient patients are at an increased risk for cancer. Why?

A

They have a higher than-normal incidence of chronic infection from viruses.

Thus, higher risk of getting oncogenic virus.

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25
Q

Increased cellular replication creates a “fertile ground” for the development of malignant tumors:

A

Repeated rounds of cell division-> higher likelihood of accumulating mutations resulting in malignancy

(Mutations frequently involve dysregulation of start transition)

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26
Q

__________ a multistep process resulting from the accumulation of multiple mutations.

A

Carcinogenesis

Mutations that results in the attributes of malignant cells-excessive growth, local invasion, distant metastasis

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27
Q

Found in all progeny, begins the process towards malignant transformation.

-Essentially the first driver mutation
-Often include loss-of-function mutations in genes that maintain genomic integrity.
-leading to genomic instability

A

Initiating Mutation

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28
Q

mutation that increases malignant potential of the cell.

A

Driver Mutation

29
Q

Mutation with low malignant effect

A

Passenger Mutation

30
Q

What are the 4 main categories of mutated genes:

A

Proto-oncogenes: gain of function mutations=>oncogenes

Tumor suppressor genes: Generally loss-of-function mutations

Genes regulating apoptosis: can be gain- or loss-of function

Genes responsible for DNA repair: Generally loss of function, affected cells acquire mutations at an accelerated rate (aka genomic instability)

31
Q

Once established, tumors evolve genetically based on _____________ of the fittest.

A

survival/selection

-Mutations are acquired at random.
-Resulting in tumor cells being genetically
heterogeneous.

32
Q

Tumor ________ compete for access to nutrients with fittest _________ dominating tumor mass.

As a result, the tumor will become more aggressive over time. (tumor progression)

This also explains changes in tumor behaviors following therapy.
-Tumors that recur after therapy are almost always resistant to initial treatment.

A

subclones; subclones

33
Q

Oncogenes:

A

Promote excessive cell growth, even in the absence of normal growth-promoting signals.
-created by mutations in proto-oncogenes
(unmutated cellular counterparts)
-Encode oncoproteins that participate in
signaling pathways driving cell proliferation.

Can include: growth factors or their receptors, signal transductors, transcription factors, or cell cycle components.

Proto-oncogenes:
-Ras
-PI3 K
-Myc
-Cyclins and cdks

34
Q

-Downstream component of receptor tyrosine kinases signaling pathways.

-Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors.

  -Approx. 15& to 20% of all human tumors 
  contain mutated versions of RAS
      ex) 90% of pancreatic adenocarcinomas 
              and cholangiocarcinomas
       -50% of colon, endometrial, and thyroid 
            cancer
       -30% of lung adenocarcinomas and 
             myeloid leukemia -Important downstream signaler for lots of growth factors: EGF, PDGF, and CSF-1
A

Ras (oncogenes)

35
Q

Very common in certain cancers
ex) 30% of breast carcinomas have PI3K gain-of-function mutations

A

PI3K (oncogenes)

36
Q

-Immediate early response gene
Induced by Ras/MAPK signaling

when activated:
-Increases cell proliferation and growth
-Contributes of other hallmarks of cancer
Warburg effect (can upregulate glycolytic
enzymes)
Increased telomerase activity (contribute
to endless replicative activity)
May also allow more terminal
differentiated cells to gain
characteristics of stem cells.
-Implicated in cancers of breast, colon, lung

A

MYC (transcription factor): onconogene

37
Q

Which of the two cell cycle checkpoints regulated by cdk-cyclin complexes do you suppose is more important in cancer?

A

G1 & G2

cdks & cyclins (onconogenes)

38
Q

Gain-of-function mutations in cyclin D and Cdk4:

How would this affect progression through the G1/S checkpoint?

A

Cells may enter the S phase without appropriate control mechanisms, potentially leading to uncontrolled proliferation and an increased risk of accumulating DNA damage and mutations.

FYI: implicated in melanomas, sarcomas, glioblastomas

39
Q

Products of ____________ apply brakes to cell proliferation.

-Abnormalities lead to failure of growth inhibition

-Many, such as RB and p53 recognize genotoxic stress.

Responds by shutting down proliferation.

Activation of oncogenes aren’t enough for cancer induction usually requires loss of tumor suppressor genes as well.

Types:
-RB
-P53
-CKI’s

A

Tumor suppressor

40
Q

RB: (tumor suppressor)

A

Functions as a key regulator of the G1/S checkpoints

Directly or indirectly inactivated in most human cancers.

Directly- loss of function mutation upregulating CDK4/ cyclin D

Loss of function mutation of CKI’s

41
Q

What form do we normally find RB in a quiescent cell?

A

Rb is primarily found in its hypophosphorylated state, where it acts to maintain cell cycle arrest.

42
Q

What form is RB in to facilitate passing through the G1/S checkpoint?

A

Phosphorylation of Rb is a key regulatory event that enables cell cycle progression when the cell receives appropriate signals for growth and division.

43
Q

“Guardian of the genome”

A

TP53

44
Q

TP53 codes for:

A

P53

45
Q

What is P53?

A

Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis.

Most frequently mutated gene in human cancer

Loss of function mutation found in more than 50% of cancers including:
-Lung
-colon
-breast
(three leading causes of cancer death)

Can include mutations in P53 of Mdm2

46
Q

How can mutated P53 contribute to carcinogenesis?

A

It allows cells to bypass critical control mechanisms, leading to uncontrolled growth, genomic instability, resistance to apoptosis, and other features that promote cancer development and progression. The loss of functional p53 is a significant factor in many types of cancer.

47
Q

P53 functions in the presence of DNA damage:

A

Arrests the cell cycle until DNA can be repaired.

48
Q

P53 stimulates DNA reair:

A

If DNA repair is successful=> cell cycle can resume

If DNA repair fails => P53 will activate pro-apoptotic pathways

49
Q

True or False: P53 mutations are commonly responsible for genomic instability, driving tumor progression.

A

True

50
Q

With loss of ______, DNA damage goes unrepaired & driver mutations accumulate in oncogenes & other cancer genes-> malignant transformations

A

P53

51
Q

_______ are frequently mutated or otherwise silenced in many human malignancies.

A

CDKI’s

52
Q

-Inherited mutations implicated in familial forms of melanoma.

-Acquired mutations detected in many cancers
ex) bladder cancers, head and neck tumors, all, cholangiocarcinoma

-________ can also be silenced by hypermethylation rather than mutation (epigenetic change)
-Occurs in some cervical cancers

A

P16; P16 (CDKI)

53
Q

P16 function:

A

Inhibits Cdk4-Cyclin D complex (G1-cdk complex)

needed for progression through the cell cycle

54
Q

What do you notice about the common oncogenes and tumor suppressor genes we have discussed? Where do they all affect the cell cycle?

A

Loss of normal cell cycle control is a major contributor to malignant transformation.

At least 1 of the 4 key regulators of the cell cycle is dysregulated in the significant majority of all human cancers.

p16, cyclin D, Cdk4, RB

G1/S checkpoint & phases

55
Q

β-Catenin:

A

APC:
-Very commonly mutated in colorectal cancers
-Part of Wnt-B-catenin pathway

E-Cadherin:
-Loss of function mutations can contribute to loss of contact-inhibition in tumors and metastasis

56
Q

Hallmarks of cancer:

A

1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Altered cellular metabolism
4) Evasion of apoptosis
5) Limitless replicative potential
6) Sustained angiogenesis
7) Ability to invade and metastasize
8) Ability to invade the host immune system

57
Q

Cancer cells take up high levels of glucose and demonstrate increased conversion of glucose to lactate.
-Even in the presence of ample oxygen
-Also called aerobic glycolysis

A

Warburg effect

58
Q

Why do you suppose a cancer cell is relying on glycolysis alone for ATP production?

A

Provides rapidly dividing tumor cells with metabolic intermediates needed for synthesis of cellular components.

-Mitochondrial oxidative phosphorylation does not!

59
Q

Normal human cells divide _______ times and then become senescent.

A

60-70

60
Q

Cell permanently exits the cell cycle & never divides again

A

Senescent

61
Q

Cancer cells can evade senescene:

A

-Likely due to loss of functions mutations in p53
and p16

-Allows cell to pass through G1/S checkpoint

62
Q

Cancer cells have also demonstrated the ability to express ___________

A

telomerase

-Very minimally expressed in most somatic cells
-Allows cancer cells to continue replicating indefinetly

63
Q

Radiation is ____________ and _____________

A

Mutagenic; carcinogenic

64
Q

UV Radiation:

A

Associated with squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin

65
Q

Ionizing radiation:

A

-Medical X-Rays
-Occupational exposure
-Nuclear plant accidents

66
Q

Many ___ and ___ viruses have been proven to be oncogenic.

A

RNA & DNA

67
Q

RNA Viruses:

A

Human T-cell leukemia virus type 1 (HTLV-1)

-Associated w/ leukemia

68
Q

DNA viruses:

A

-HPV: Human Papillomavirus
-EBV: Epstein Barr virus
-HBV(&HCV): Hepatitis B virus
-Merkel cell Polyomavirus
-HHV8: Human herpesvirus 8

BMS 100 Test 2 (16 decks)

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