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Y1 - Pathology > 11_Neoplasia III > Flashcards

11_Neoplasia III Flashcards

1
Q

3 stages of carcinogenesis:

  • initiation*
  • promotion*
  • progression*
A
  • initiation: causes permanent DNA damage, is rapid and irreversible and has “memory”
    • initiator alone is not tumorigenic, unless applied repeatedly
    • high dose of initiator is toxic
  • promotion: stimulate selective proliferation of initiated cells
    • promoter alone is not tumorigenic
    • do not affect DNA directly and are reversible
  • progression: involves invasive and metastatic mechanisms
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2
Q

agents causing DNA mutations?

A
  • Chemicals
  • Radiation
  • Oncogenic Viruses
  • Bacteria
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3
Q

what are the two types of initiating agents?

A
  • Direct acting - do not require metabolic activation, e.g., alkylating agents used in cancer therapy
  • Indirect acting - require metabolic activation in vivo to get ultimate carcinogen; pro-carcinogen
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4
Q

describe the interaction between direct acting initiators and ultimate carcinogen?

A
  • Direct acting and the ultimate carcinogen are highly reactive electrophiles that react with nucleophilic sites (DNA, RNA and proteins) in the cell
    • Results in formation of covalent adducts between the carcinogen and the DNA, RNA or protein
    • This interaction by itself is not lethal and DNA is the primary target
  • Covalent adduct formation leads to generation of mutation in the genes during replication
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5
Q

how are indirect carcinogens metabolized?

A
  • Most indirect carcinogens are metabolized (activated) by cytochrome P-450-dependent mono-oxygenases
    • Genes that encode these enzymes are polymorphic
    • Their activity and inducibility varies among different individuals
  • Thus, susceptibility to carcinogenesis is regulated in part by polymorphism in these genes
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6
Q

metabolism of N-2-acetylaminofluorene

(first and second phase)

A
  • First phase: Oxidation to N-hydroxy-N-2-acetylaminofluorene: present in rats but absent in guinea pigs
  • Second phase: sulfation at hydroxy group; double the rate in male than female rats; this reaction and resultant carcinogenesis
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7
Q

describe the scheme of events in chemical carcinogenesis

A
  1. carcinogen
  2. electrophilic intermediates
  3. binding to DNA adduct fromation
  4. permanent DNA lesion
  5. cell proliferation
  6. preneoplastic clone
  7. malignant neoplasm
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8
Q

list the examples of cancer and sources associated with the chemical carcinogens?

A
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9
Q

aflatoxins:

define, and how does one get poisoned by aflatoxin?

A
  • Potent naturally occurring toxic substances
    • Among 18 different types, the major members are: aflatoxin B1, B2, G1, G2.
    • Mycotoxins produced by fungi Aspergillus flavus and A. parasiticus.
  • Poisoning results from ingestion of aflatoxins in contaminated food (diet is the major way for exposure) or through occupational exposure
    • Poisoning affects domestic and non-domestic animals and humans
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10
Q

aflatoxin toxicity

A
  • Large doses of aflatoxin (> 6,000 mg) can cause acute toxicity
  • Small doses for prolonged periods are carcinogenic
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11
Q

describe the sources and mechanism of radiation carcinogenesis:

A
  • Radiation (UV rays, x-rays, nuclear fission, radionuclides) is strongly oncogenic
  • Mechanism:
    • Radiation causes chromosome breakage, translocations and point mutations
    • Latent period of radiation-associated tumors is extremely long
  • Suggests that progeny of the initially damaged cell accumulate additional mutations, induced by other environmental factors
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12
Q

UV Radiation:

types of cancer, pathology, and physiology

A
  • UV radiation causes skin cancers: basal cell carcinomas, squamous cell carcinomas, melanomas
  • Pathology:
    • UV rays damage DNA - form pyrimidine dimers and other photoproducts
    • In individuals with xeroderma pigmentosum, the nucleotide excision repair mechanism is defective
    • Hence, those individuals have a greater predisposition to getting skin cancers
  • Physiologically: altered DNA is repaired by a series of enzymes of nucleotide excision repair
    *
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13
Q

what are some examples of viral oncogenesis?

(DNA or RNA)

A
  • Certain forms of cancer are of viral origin; either DNA or RNA viruses
  • DNA oncogenic viruses
    • Human Papillomaviruses (HPV)
    • Epstein-Barr Virus (EBV)
    • Hepatitis B virus (HBV)
  • RNA oncogenic viruses
    • Human T-Cell Leukemia Virus type 1 (HTLV-I)
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14
Q

HPV is epitheliotropic

(true/false)

A
  • TRUE, all characterized HPV strains only infect epithelial cells; e.g.
    • skin
    • anogenital mucosa
    • oropharyngeal mucosa
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15
Q

which proteins play a major role in immportality and malignant transformation of HPV genome?

A
  • E6 & E7 proteins play major role in immortality & malignant transformation of infected cells
  • E5 has role, but not required to maintain cancer phenotype
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16
Q

there are 100+ HPV strains identified,

how is risk defined, and

what are the 3 risk categories?

A
  • risk is based on transformative potential of strain’s E proteins.
    • LOW/INTERMEDIATE/HIGH
  • Low: episomal; found in low grade lesions
  • Intermediate: found in benign lesions & invasive cancers
  • High: integrated; usually found in carcinomas; occasionally seen in benign lesions
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17
Q

what are the 4 high risk HPV strains?

A

16, 18, 45, 56

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18
Q

p53

(genome guardian)

define, physiology

A
  • def: Transcription factor that regulates cell cycle progression
  • physiology:
    • In response to DNA damage, stops the cell cycle progression and upregulates DNA repair enzymes
    • If repair is not possible, p53 induces apoptosis
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19
Q

Rb:

fxn, mechanism, pathology

A
  • fxn: regulates progression from G1 to S phase
  • mech: When RB is phosphorylated, E2F is released and may activate gene expression that is needed for G1-to-S transition
  • pathology:
    • Viruses like HPV may highjacks RB
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20
Q

how does HPV E7 promote inappropriate entry into the cell cycle?

A
  • E7 can remove Rb from E2F–>
  • So the cell cycle can progress EVEN WITHOUT THE GROWTH SIGNAL
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21
Q

how does the function of p53 differ with the presence of E6?

A
  • with p53 –> stops DNA replication
  • p53 + E6 –> E6 binds to p53, removing it from the dna –> E6 degrades p53 –> allows uncontrolled DNA replication
22
Q

can HPV-infection by itself cause cancer?

what are the implications of this?

A
  • HPV-infection alone (even with high-risk types) is not enough for development of tumors
  • IMPLICATIONS: Suggests that infection acts as an initiating agent and additional somatic mutations are essential for malignant transformation
    • These mutations can be brought about by cigarette smoking, coexisting microbial infections, dietary deficiencies, and hormonal changes
    • PREVENTABLE: vaccination and molecular HPV testing (by PCR)
23
Q

Epstein barr virus:

family, fxn, assoc. w/ which cancers?

A
  • family: herpes
  • fxn in cancer: may provide a proliferative advantage for mutated cells for a two-step carcinogenesis process, but may also cause genetic instability.
  • assoc. in pathogenesis of :
    • Burkitt’s lymphoma, B-cell lymphomas, Hodgkin’s disease, and nasopharyngeal cancer
  • Mechanism:
    • EBV infects epithelial cells of the oropharynx and B lymphocytes via the CD21 receptor
    • Exists as an circular episomal element in the B cell nucleus, but does not replicate
    • Immortalizes the infected B cells - LMP-1, EBNA
24
Q

which translocation is associated w/ Burkitt’s lymphoma?

what is tx for Burkitt’s lymphoma?

A
  • t(8;14)
  • tx w/ cyclophosphamide
25
Q

hepatocellular carcinoma is assoc. w/ which viruses?

mechanisms

A

HBV and HCV

  • HBV ( double-stranded DNA virus) link between chronic infection with HBV and hepatocellular carcinoma (HCC)
    • Integrates into host DNA –>
    • Produces viral proteins, especially HBx exert multiple effects on signaling, transcription, apoptosis, cell-cycle progression, and viral replication, so their role remains unclear.
  • HCV is a single-stranded RNA virus; causes chronic hepatitis.
    • Multiple viral proteins, including structural, exert apparent oncogenic effects.
26
Q

HBx protein

(encoded by, and fxn)

A
  • HBV encodes HBx protein - a transcriptional activator of several growth promoting genes - thus disrupting normal growth control processes
  • HBx binds to p53 and interferes with its growth suppressing properties
27
Q

difference between acutely transforming and slow transforming viruses?

A

Two diff’t mechanisms of retrovirues transforming cells

  • Acutely transforming viruses contain a trans-forming viral oncogene such as src, abl, or myb
  • Slow transforming viruses do not contain a v-onc
    • the proviral DNA integrates in a host cell genome near a proto-oncogene.
    • Under control of the strong retroviral promoter, the adjacent normal/mutated protooncogene is overexpressed.
    • This mechanism of transformation is called insertional mutagenesis
28
Q

HTLV-1 and RNA oncogenic virus

assoc w/, target of transformation, and mech

A
  • Associated with T-cell leukemia/lymphoma - is a slow transforming virus; does not contain v-onc
  • CD4+ T-cell is the major target for transformation
  • Unknown mech
29
Q

what are the various effects of a tumor on the host?

A
  • Pressure and compression of surrounding tissue
  • Pressure on blood vessel –> ischemia
  • Hormone production: can be proper (i.e., endocrine tumors) or from improper gene expression (paraneoplastic syndrome)
  • Cachexia of malignancy: not well understood
30
Q

oncometabolism:

warburg effect

A
  • Warburg Effect: Preference of rapidly growing cells for aerobic glycolysis over mitochondrial oxidative phosphorylation
  • Mitochondria generate intermediates that can be of use in cellular proliferation
  • Produced by signaling cascades downstream of growth factor receptors
  • Positron-emitting Tomography (PET) Scanning: use of 18fluorodeoxyglucose in tumor visualization and staging
31
Q

oncometabolism:

mutations in the Kreb’s cycle

A
  • Mutations of coding genes of enzymes of the Krebs cycle
    • Isocitrate dehydrogenase: amino acid substitution at active site causes production of 2-hydroxyglutarate (instead of oxalosuccinate and a-ketoglutarate)
    • This interacts with TET2, a regulator of DNA methylation, which in turn affects gene expression
32
Q

how do tumor cells evade the immune system?

A
  • Tumors can be recognized as “non-self” and then destroyed by the immune system
  • Selection of tumor clones best able to avoid the host immune system
    • Outgrowth of antigen-negative variants
    • Reduction of histocompatibility molecules
    • Immunosuppression mediated by presence of factors on tumor cells (i.e., PD-1 ligand inactivation of T-lymphocytes)
33
Q

what is the single best indicator to determine if a tumor is malignant?

what is this assoc. w/ re: prognisis?

A
  • *presence of metastases or invasion
    • (benign neoplasms do NOT metastasize)
  • gliomas of the CNS do not metastasize but are highly invasive and malignant
  • presence of metastasis –> poor prognosis
34
Q

how does metastases spread?

(3 ways)

A
  1. seeding through body cavities & surfaces
    • e.g. ovarian CA
  2. sentinel nodes: spread through the lymphatic system
    • LN metastases can cause secondary metastasis to distant organ sites
  3. hematogenous spread (sarcomas): the blood vessels
    • tumor cells repeatedly spread from the primary tumor to distant sites w/ very few of these cells progressing to an overt metastasis.
35
Q

primary tumor:

difference b/w early and late dissemination models

A

There are two schools of thought when it comes to the development of metastatic cells from primary tumours:

  • early dissemination: metastatic cells from a primary tumor can occur before the primary cancer is detected.
    • evidence: mutational profiles of metastatic lesions often do not have late mutations acquired by primary tumor
  • late dissemination: as the primary tumor progresses subsequent mutations give tumor cells the ability to metastasize.
36
Q

what is the process of metastasis?

A
37
Q

intravasation:

define

A
  • process by which tumour cells enter the lumen of blood vessels or lymphatics by crossing the endothelium and associated pericytes.
    • There are a number of growth factors associated with this process that are not fully understood.
    • The leaky blood vessels formed via tumour-mediated angiogenesis are more permeable to intravasation of tumour cells than normal structurally intact microvasculature found elsewhere in the body.
38
Q

how do cancer cells survive in circulation?

A
  • Cancer cells in the circulation are subject to immune attack and circulatory shear forces.
  • In order to evade this cancer cells attach to platelets forming heterotypic clumps or attach to clotting factors such as thrombin and fibrinogen –> forming emboli ( homotypic clumps).
    • These clumps may also help cancer cells evade anoikis, a normally occurring process in which apoptosis follows the loss of cell-to-cell adhesion.
    • In addition, certain intestinal epithelial tumours have mutations in their tyrosine kinase receptors that enhance their ability to evade anoikis.
39
Q

arrest:

in metastasis (define)

A

The organ @ which CA cells arrest–> determined by anatomical and molecular factors.

  • Organ microvasculature and its relation to the primary tumour influences metastasis.
    • e.g. liver (large capillary bed) is the site for metastasis for many 1° tumours types, w/ colon cancer metastasis being most common (bs portal vein that carries blood back from the colon empties into the liver)
  • Secondly, chemoattractants predispose arrest of circulating tumour cells. Endothelial cells express E- and P-selectins that bind tumour cells.
40
Q

extravasation:

in CA metastasis (define)

A
  • differs from intravasation bc BVs at distant sites are generally structurally intact.
    • Certain BVs in the liver and bone marrow are normally fenestrated –> provide less of a barrier to extravasation of tumour cells.
    • In other BVs, extravasation occurs through small gaps created by the normal turnover in endothelial cells or through vessel wall damage that attracts platelets and tumour cells that can be associated with them (homotypic clumps).
    • Finally, primary tumours, through production of proteins, such as MMPs and VEGF, can disrupt endothelial barriers in distant organs. Breast cancer has been shown to use these mechanisms for pulmonary metastasis.
41
Q

proliferation:

in CA metastasis, define

A
  • Proliferation in a metastatic site requires uncontrolled cell replication.
    • Many disseminated tumour cells undergo:
      • attrition,
      • remain dormant or
      • form microcolonies termed micrometastases and do not progress to gross metastases.
    • Experimental models of metastatic cells have shown only 3% of extravasated tumour cells form an obvious metastasis. This low percentage is because the target organ microenvironment must be favorable to tumour cell proliferation
42
Q

angiogenesis:

in CA metastasis, define

A
  • Metastatic proliferation requires the creation of new blood vessels (angiogenesis)
    • triggered by hypoxia in the developing tumour.
    • occurs in a disorganized fashion
    • promoted by vascular endothelial growth factors (VEGF), platelet-derived growth factor (PDGF) and transforming growth factor (TGF).
43
Q

steps associated w/ INVASION & METASTASIS

(**Review slides 67-72, 78-79 of lecture 11)

A
  1. detachment of tumor cells from each other
  2. attachment to ECM (extracellular matrix)
  3. degradation of ECM
  4. migration of tumor cells
  5. intravasation
  6. extravasation
  7. proliferation and angiogenesis
44
Q

what is the importance of tumor-mediated angiogenesis?

A
  • Growth of solid tumor limited by its blood supply
    • bc it can only get nutrition from diffusion (which is more limited)
  • Hypoxia induces necrosis (or apoptosis)
  • Neovascularization (leaky blood vessels) allows for metastasis –> can grow and metastasize further
45
Q

circulating tumor cells (CTC)

define, and fxn

A
  • def: tumor cells released from tumors into blood stream
  • have a key role in future metastasis
46
Q

what are the common sites of metastasis for the following organs?

A
47
Q

what may be related to organ tropism?

A
  • Expression of adhesion molecules on tumor cells whose ligands are expressed on endothelial cells of target organs
  • Target organs may liberate chemo-attractants that recruit tumor cells to the site
  • Target organ an unpermissive environment, e.g., inhibitors of proteases prevent establishment of a tumor colony
48
Q

what is the seed and soil hypothesis?

A

The certain organ tissues are predisposed to metastasis because their microenvironment is compatible with tumor cells. Stromal interaction with metastatic cells is vital to the proliferation of metastatic cells.

49
Q

grading vs. staging

A
  • Grading of a cancer is based on the degree of differentiation, growth rate, and intact borders.
  • Staging of a cancer is based on the size of the primary lesion, its spread to regional lymph nodes and presence or absence of blood-borne metastases- done by oncologist and pathologist
50
Q

what are the breast cancer and prostate cancer GRADING SYSTEMS?

A
  • breast CA: Nottingham Grading system
  • prostate CA: Gleason System
51
Q

what is the key cancer staging system?

A

TMN staging

(tumor size, lymph nodes, metastasis)

Y1 - Pathology (14 decks)

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