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Block 2 Cancer > Cancer Principles > Flashcards

Cancer Principles Flashcards

1
Q

Cancer characterized by

A

general breakdown in lines of communication btwn cancer cell and its environment -> mutations -> alter expression and fx of genes that normally regulate cell proliferation, differentiation, and survival

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2
Q

cancer gene mutations can be

A

inherited, arise spontaneously in normal cells, and acquired during the evolution of the tumor

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3
Q

most cancer mutations occur in

A

somatic cells

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4
Q

age related incidence of cancer

A

cancer arises bc multistep process bc accumulate mutations in several genes including proto-oncogenes and tumor suppressor genes long latency period generally exists btwn first mutation and acquiring all others -> most cancers having late onset

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5
Q

tumor progression

A

accumulation of phenotypic trait characteristic of malignant neoplasia
hyperplasia -> dysplasia -> tumor -> metastasis

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6
Q

importnat colon cancer genes/ pathways

A

APC, PI3K, p53, TGF-beta pathway, ras; for diff types of cancers can ID genes that mutate at various stages of the cancer

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7
Q

APC

A

required for cell differentiation (acts as tumor suppressor)

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8
Q

ras

A

GTP protein involved in proliferative signaling acts as oncogene

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9
Q

PI3K

A

lipid kinase, acts as oncogene

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10
Q

p53

A

tumor supressor

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11
Q

TGF-B pathway

A

acts as tumor suppressor

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12
Q

epigenetic changes

A

ex DNA methylation pattern; alter normal gene expression and promote tumorigenesis

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13
Q

driver genes

A

responsible for development and progression fo individual tumor types

  • oncogenes
  • tumor supressor genes
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14
Q

What fosters tumor evolution and development of drug restiances

A
  1. Intra-tumor heterogeneity

2. Interactions between the tumor and tumor microenvionrment

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15
Q

intra-tumor heterogeneity

A

tumors are genetically and phenotypically heterogenous consisting of multiple subpopulations of cells with distinct properties; tumors are subject to harsh environments and only subpopulations of cells harboring mutations and epigenetic modifications with selective advantage will survive and proliferate and expand and populate tumor so tumor microenviorment major determinant of intra-tumor heterogeneity as it changes tumor adapts

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16
Q

what causes intra-tumor heterogenity

A

individual cells of tumor accumulate modifications
Gradually:
- as result of mutagen exposure and DNA replication erros
- Rapidly as consequence of genomic instability
- epigenetic changes may contribute
- splicing variants

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17
Q

tumor microenvironment plays critical role in

A
  • development, evolution, and survival of primary tumor

- ability of tumor cells to invade surrounding tissue and metastasize to distant sites

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18
Q

tumor microenvionrment consists of

A

multiple cell types, ECM components, nutrients, and waste products

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19
Q

Tumor and TME connnection

A

dependent upon signals originating from the other; tumor cells recruit inflammatory cells, activate resident fibroblasts, and secrete factors that block immune fx promoting antiongenesis; they alter microenvionrmne to factor tumor cell

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20
Q

CAFs

A

cancer associated fibroblasts; these with recruited inflamatory cells secrete growth factors, cytokines, and other factors that promote angiogenesis along with secreting proteases (degrade ECM - activating ECM-associated growth factors) and promote tumor cell migration

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21
Q

Cancer stem cells niche

A

CAFs secrete appropriate conditions (niche) for generation and maintenance cancer stem cells

22
Q

different microenvioments

A

tumor cells adapt to primary tumor, surrounding tissue, circulation, metazoic site

23
Q

cancer stem cells

A

aka tumor initiation cells similar ro normal stem cells

  • can undergo asymmetric cell division -> new CSC and proliferating transit amplifying cell that can differentiate
  • > contributes to intra-tumor heterogeneity
    • Most cells in tumor are not highly tumorigenic the cancer stem cells are the small subset that are**
  • these are more resistant to traditional therapies
24
Q

CSC identification criteria

A
  • expression of stem cell specific markers and signaling patheays
  • ability small # of these cells to form new tumors when translpanted into recipient mice
  • following CSCs as they divide via lineage tracing experiments
25
Q

CSC specific properties

A
  • long term self renewal
  • increased proliferative potential
  • capacity to differentiate
  • telomerase expression
  • multi drug resistance
  • enhanced DNA replari
  • ability to remain quiescent

these enable tumors to proliferate indefiencly, regrow following chemo and radiation treatments, and establish metastases as secondary sites

26
Q

Warburg effect

A

tumor-associateed increase in rate of aerobic glycolysis

27
Q

Cancer cell metabolism

A
  • utilize enhanced rate of glycolysis to generate ATP and provide glycolytic intermediates used to synthesize nucleotides and amino acids and TCA cycle to produce precursors for fatty acid synthesis
  • increase glucose uptake for glycolysis
  • increase glutamine uptake for TCA cycle
28
Q

Cancer cells and stress

A
  • normal cells have defense mechanism for damaged or aberrant cells triggered by cell stress -> cells temporarily (quiescence) or permanenty (senescence) growth arrest or apoptose
  • abnormally proliferating cells experience various types cellular stressed so they must acquire mutations in additional driver genes to bypass these defeneses
29
Q

norma cellular stresses

A
  • metabolic
  • proteotoxic
  • mitotic
  • oxidative
  • DNA damage stress
30
Q

Abnormally proliferating cells stressful sitations

A
  • hypoxia
  • oncogene expression
  • genomic instability
  • telomere erosion
31
Q

likelihood of developing cancer

A

based on environmental and heritable factors can be mutagenic or non-mutagenic agents

32
Q

mutagenic environmental risk factors for cancer

A

-directly mutagenize DNA or are metabolized into mutagens
- Chemicals (cigaret smoke, formaledehyde, benzene ect.)
- radiation (sunlight, radon Ect.)
viruses (FeLV ect.)
- antioxidants= chemicals that inhibit mutagenesis and decrease cancer risk

33
Q

conversion of normal cell to pre-neoplastic cell

A

2 step process initiation and promotion

34
Q

initiation

A

exposure to a mutagen (initiation) -> permanent change in DNA; usually activating mutation in gene that = pt of proliferation signaling pathway; direct carcinogens act as initiatiors
- irreversible

35
Q

promotion

A

initiated cells are stimulated to proliferate (hyperplasia) (eg by growth factors); classified as indirect or co-carcinogens
- dependent on presence of promoting agent so reversible

36
Q

how do initiation and promotion -> carcinogenesis

A

promotor -> initiated cells proliferating -> clonal expression of mutated cell ; proliferating cells at higher risk of aquiring mutations

37
Q

driver gene mutations

A

can collaborate with original initiator mutation to produce a pre-neoplastic phenotype (dysplasia)

38
Q

why are proliferating cells more likely to acquire mutations

A
  • DNA réplication erros
  • in proliferating cells mutations often copied during S phase before they can be repaired correctly -> mutations being fixed in genome and passed on to daughter cells
39
Q

any factor that promotes proliferation (especially chronic proliferation_

A

increases risk of acquiring cancer promoting mutations and developing cancer

ex. chronic exposure to toxic chemicals -> damaged cells -> stimulate stem cell proliferation to replace lost cells
2. chronic inflamation

40
Q

chronic inflammation

A

mutagenizes cells and stimulates proliferation increasing cancer risk; during inflammation response neutrophils and macrophages secrete growth factors and cytokines and produce ROS and reactive nitrogen species which can mutagenize DNA

41
Q

hepatosarcoma

A

cirrhosis of the liver and hepatitis C virus both increase risk factors for this cancer; proliferating hepatocytes faced with chromic inflammation accumulate mutations over time that promote tumor development and progression

42
Q

Heritable factors

A

inhertiting inactivating mutation in tumor spuressor gene or germline variant in specific genes such as carcinogen activating enzymes or carcinogen detoxifying enzymes or DNA repair protein variants can affect cancer risk

43
Q

inactivating mutation in tumor supressor

A

increases individuals risk of developing cancer and developing it at earlier age than general pop
ex. BCRA 1 and 2 (breast cancer) and APC (colon cancer)

44
Q

carcinogen activating enzymes

A

ex cytochrome p450 enzymes

decrease in these decreases cancer risk increase increases it

45
Q

carcinogen detoxifying enzymes

A

ex superoxide dismutase, glutathione S-transferase

more = better less= higher risk cancer

46
Q

DNA repair proteins

A

if decreased activity can -> increased cancer risk

47
Q

Hallmarks of cancer

A

essential alterations in cell physiology shared by many cancer in vivo plus properties acquired via conversion fo porto-oncogenes to oncogenes and the inactivation of tumor suppressor genes

48
Q

Original 6 hallmarks of cancer (essential alterations in cell physiology)

A
  1. sustaining proliferative signlaing
  2. evading growth suppressors
  3. resisting cell death
  4. inducing angiogenesis
  5. Activating invasion and metastasis
  6. Enabling replicative immortality
49
Q

4 additional hallmarks of cancer (conversion protocol-oncogenes
-> oncogenes and inactivation tumor spuressor genes -> these)

A
  1. Deregulating cellular energetics
  2. Avoiding immune destruction
  3. Genome instability and mutation
  4. Tumor-promoting inflammation
50
Q

is expression of single oncogene sufficient to transform primary cells

A

no; cells with single oncogene introduced to them will permanently growth arrest or undergo apoptosis have to have additional mutations to evade defenses to get oncogene

51
Q

dysplasia

A

preneoplasic

Block 2 Cancer (10 decks)

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