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DWT exam 4 > Path: Cancer > Flashcards

Path: Cancer Flashcards

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1
Q

How does a cell proliferate?

A
  • Growth factor signaling pathways
  • GF binds to receptor→activates production or activation of numerous cytoplasmic signal transducing proteins→nucleus
  • Activate transcription factors→DNA
  • Transcription of growth promoters and regulators
    proto oncogenes stimulate growth
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2
Q

proto oncogene

A

genes that stimulate cell growth

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3
Q

Growth factors

A
  • Normal cells require stimulation by GF to proliferate
  • Most soluble GF are made by a cell to act on a neighboring cell (paracrine)
  • Tumor cells can synthesize GF to which they are responsive
  • Examples: PDGF-overexpression in hepatocellular carcinomas
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4
Q

growth factor receptors

A
  • Mutations in growth factor receptors common in cancer
  • Can lead to constitutive signaling that is independent of presence of growth factors
    Examples
  • C-kit
  • Receptor tyrosine kinase
  • Constitutively active
  • Mutations in canine MCTs, GISTs, malignant melanoma
  • Palladia (Toceranib), Gleevec (Imatinib), Kinavet (Masitinib)
  • EGF-receptor family
  • HER2 amplification in human breast cancer
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5
Q

RAS

A

ras is a normal protooncogene that is activated by receptor tyrosine kinase activity
* ras encodes for a protein that binds to GDP/GTP
* inactive ras binds GDP
* surface receptor binding facilitates swapping of bound GDP for GTP (active ras)

Ex:
* BRAF-pancreatic carcinoma
* KRAS-prostatic carcinoma

Signal transducing protein

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6
Q

RAS

A

ras is a normal protooncogene that is activated by receptor tyrosine kinase activity
* ras encodes for a protein that binds to GDP/GTP
* inactive ras binds GDP
* surface receptor binding facilitates swapping of bound GDP for GTP (active ras)

Ex:
* BRAF-pancreatic carcinoma
* KRAS-prostatic carcinoma

Signal transducing protein

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7
Q

PI3

A

PI3 kinases are normal proto-oncogenes in AKT signaling
* Like ras it is activated by growth factor binding and initiating receptor tyrosine kinase activity

Ex: Canine mammary tumors

Signal transducing proteins

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8
Q

PI3

A

PI3 kinases are normal proto-oncogenes in AKT signaling
* Like ras it is activated by growth factor binding and initiating receptor tyrosine kinase activity

Ex: Canine mammary tumors

Signal transducing proteins

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9
Q

Myc

A

Transcription factor
Very broad activities
* Activates the expression of many genes involved in cell growth
* In some contexts, can upregulate expression of telomerase
* Can reprogram somatic cells to pluripotential stem cells
* Canine lymphoma and prostate carcinoma

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10
Q

tumor suppressor genes

A

encode proteins which control cell growth (“the brakes”)
Deletion mutations in these genes = “brake failure”

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11
Q

Rb protein

A

The protein product of Rb inhibits cell proliferation (nuclear transcription brakes)
* active form binds to and inhibits transcription factors → prevents cells from advancing from G1 to S phase
* mutated Rb is inactive → brake failure on cell division
* Ex: Canine hemangiosarcoma and osteosarcoma

tumor suppressor

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12
Q

P53

A

Tumor suppressor that regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
* Guardian of the genome
* Prevents propagation of genetically damaged cells
* normal cells have low levels of p53 (held in check by MDM2)
* Ex: Canine melanoma and many more

IMPORTANT

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13
Q

apoptosis

A

Apoptosis is normal and protective (Normal biochemical pathways that lead to cell death)
**Intrinsic and extrinsic apoptosis **

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14
Q

Intrinsic apoptosis

A

Most commonly affected in cancer
Bcl-2 protein
* Normally inhibit release of cytochrome c which would otherwise initiates intrinsic pathway
* encodes a protein that inhibits apoptosis→pro cell survival
* unregulated expression of this protein product prolongs cell lifespan by preventing apoptosis

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15
Q

extrinsic apoptosis

A

Less commonly affected in cancer
FLIP
* anti-apoptotic→pro cell survival
* blocks the extrinsic pathway by binding procaspase-8 without activating it
* Unregulated expression also prolongs life span
* Decreased expression of Fas can make cells less susceptible to induction by FasL→decreased susceptibility to apoptosis→pro survival

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16
Q

In order to metastisize cells must:

A

They must successfully
* Invade the extracellular matrix, AND
* Disseminate through the vessels unharmed, AND
* Locate a suitable distant site/tissue to live, AND
* Successfully grow/proliferate there

17
Q

Vascular dissemination and homing of tumor cells

A

Tumor cells tend to aggregate with each other and blood cells
* Platelets
* Coagulation factors

Where tumor cells leave capillaries is related to anatomic location and vascular drainage of the primary tumor
* Also tropism of tumors for particular tissues

18
Q

types of tumor antigens

A
  • Products of mutated genes-Oncoproteins
  • Overexpressed or aberrantly expressed cellular proteins (PSA in humans)
  • Tumor antigens produced by oncogenic viruses
  • Oncofetal antigens
  • Altered cell surface glycolipids andglycoproteins
  • Cell type specific differentiation antigens (Cytokeratin, vimentin)
19
Q

Antitumor effector mechanism

A

Cell mediated immunity is dominant mechanism
Cytotoxic T lymphocytes
* Very important
* Can respond to new antigens
* Many tumors produce proteins to decrease T cell response
* Presence can be marker for better prognosis

Natural Killer (NK) cells
* Very important
* Recognize absence of MHC I or stress-induced proteins expressed on cell surface

Macrophages
* M1 are pro-inflammatory-important anti-tumor effector mechanism

20
Q

Cancer cells avoiding the immune system

A

Cancer cell selection/Immunoediting
* Antigen negative variants
* Loss or reduction of MHC expression

“Sneaking through”
* Weakly immunogenic until tumor burden too large to control

Immunosuppresssion
* TGFβ and IL-10
* Secreted by tumor cells OR TAMs
* Suppress Th1 response
* Convert effector T cells to Treg
* Upregulation of T cell suppression
* CTLA-4
* PD-1
* Myeloid derived suppressor cells (MDSCs)

21
Q

TGFβ and IL-10

A

Immunosuppression
* Secreted by tumor cells OR TAMs
* Suppress Th1 response
* Convert effector T cells to Treg

22
Q

Tumor-promoting inflammation

A
  • Release of factors that promote proliferation
  • Reactive oxygen species production (Genetic damage)
  • Removal of growth suppressors
  • Enhanced resistance to cell death
  • Inducing angiogenesis
  • Activating invasion and metastasis
  • Evading immune destruction (TAMs, MDSCs)
23
Q

Carcinogen

A

an agent that is able to damage DNA, resulting in a heritable, nonlethal mutation that gives rise to neoplasia
* Note, severely damaged DNA will not replicate
* Thus, toxic agents may have the potential to induce tumors, but at high concentrations damage and kill cells before this effect is expressed

Three types:
* Chemical
* Radiation
* Microbes

24
Q

Chemical carcinogens

A

Initiation
* Permanent DNA damage
* Irreversible

Promotion
* Promote proliferation of initiated cells
* No effect on DNA
* Reversible

In some instances, initiator and promotor can be same chemical

Most carcinogens are metabolized by cytochrome p450 enzymes

25
Q

Direct vs indirect acting chemical carcinogen

A

Direct acting
* Require no metabolic conversion to be carcinogenic

Indirect
* Require metabolic conversion to be carcinogenic
* Majority

26
Q

Afalotoxin A1

A

Chemical carcinogen
* Naturally occurring agent produced by some Aspergillus species growing on improperly stored feed
* Strong correlation in humans with incidence of hepatocellular carcinoma and ingestion of this food contaminant
* Tend to have a particular mutation in TP53
* Not found in hepatocellular carcinomas from populations without high levels of this food contaminant

27
Q

UV Radiation

A

Normal host defenses against UV irradiation:
* cutaneous pigments (melanin) absorb irradiation
* aromatic portions of amino and nucleic acids also absorb irradiation
* free radical scavengers minimize damage

The primary target in DNA is pyrimidine molecules
* Photon of light is absorbed by DNA→ **formation of pyrimidine dimers → mutations **
* Pyrimidine dimers result from covalent crosslinking of base pairs

tends to affect non pigmented (white) areas

28
Q

Ionizing radiation

A

alpha, beta, gamma, x-ray
Free radical-mediated DNA damage
Translocations, direct single/double strand breaks→mutation

29
Q

Microbial carcinogenesis

A

Primarily Oncogenic viruses
Retroviruses
* Feline leukemia virus, bovine leukemia virus, avian leukosis virus
* Insert viral genome into cellular DNA of host cell
* Promotors and enhancers control viral gene expression AND nearby cellular host genes
* Most important when insert near a proto-oncogene

DNA viruses
* Viral genes encode oncoproteins capable of transforming infected cells
* Often interfere with the proteins encoded by tumor suppressor genes
* Bovine papillomavirus

Contribution of bacteria is questionable

30
Q

Bovine leukemia virus

A

Randomly inserts into genome
Cattle infected through transfer of blood and blood products containing infected lymphocytes
Three main outcomes
* Persistent infection with no clinical signs
* Persistent lymphocytosis
* Lymphoma (Most common in adults)

31
Q

feline leukemia virus

A

Randomly inserts into genome
Oronasal contact with infectious saliva or urine common mode of transmission
* Infection in utero and through nursing also common

Multiple manifestations
* anemia, neoplasia, immunosuppression, immune- mediated diseases, reproductive problems, enteritis, neurologic dysfunction, and stomatitis
* Lymphoma, leukemia

32
Q

avian leukosis virus

A

Inserts near c-myc
Feco-oral transmission and horizontal transmission

B cell lymphoma
Other neoplasms infected with subgroup J-myelocytomas, hemangiomas, renal tumors

33
Q

Gallid herpesvirus-2

A

Mareks Disease virus (backyard chicken flocks)
Integrates its viral genome into the telomeres of host chromosomes
Encodes a telomerase
Highly contagious through dander in environment
T cell proliferations
* Inflammation, Lymphoma, Neurotropic

34
Q

Papillomaviruses

A

Cutaneous papillomas in horses, dogs, cattle, and others
Young animals preferentially affected
May spontaneously regress
Persistence may suggest immune dysregulation
Characterized by marked epidermal thickening
* Viral proteins prevent suprabasal cells from becoming postmitotic (continued replication)
* Viral protein binds E2F preventing inhibition from Rb

DWT exam 4 (10 decks)

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