Path: Cancer Flashcards
How does a cell proliferate?
- Growth factor signaling pathways
- GF binds to receptor→activates production or activation of numerous cytoplasmic signal transducing proteins→nucleus
- Activate transcription factors→DNA
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Transcription of growth promoters and regulators
proto oncogenes stimulate growth
proto oncogene
genes that stimulate cell growth
Growth factors
- 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
growth factor receptors
- 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
RAS
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
RAS
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
PI3
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
PI3
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
Myc
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
tumor suppressor genes
encode proteins which control cell growth (“the brakes”)
Deletion mutations in these genes = “brake failure”
Rb protein
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
P53
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
apoptosis
Apoptosis is normal and protective (Normal biochemical pathways that lead to cell death)
**Intrinsic and extrinsic apoptosis **
Intrinsic apoptosis
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
extrinsic apoptosis
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
In order to metastisize cells must:
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
Vascular dissemination and homing of tumor cells
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
types of tumor antigens
- 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)
Antitumor effector mechanism
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
Cancer cells avoiding the immune system
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)
TGFβ and IL-10
Immunosuppression
* Secreted by tumor cells OR TAMs
* Suppress Th1 response
* Convert effector T cells to Treg
Tumor-promoting inflammation
- 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)
Carcinogen
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
Chemical carcinogens
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
