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Genetic Basis of Neoplasia (Proto-oncogenes (Examples (Aberrations leading…
Genetic Basis of Neoplasia
Hallmarks of Cancer
Insensitivity to anti-growth signals
deactivating mutations in tumor suppressor genes
lose retinoblastoma suppressor
Tissue invasion and metastasis
tumor cells break the basement membrane and invade the ECM, spread to distant sites via the blood stream or lymphatics
inactivate E-cadherin
Self sufficiency in growth signals
activating mutations in oncogenes (autonomous growth)
activate H-Ras oncogene
Limitless replicative potential
aberrant expression of telomerase--prevents telomere shortening that normally would induce cellular senscence/death
Sustained angiogenesis
new blood vessel growth to the site of the tumor, allowing the cells to get oxygen and nutrients
produce VEGF inducer
Evading apoptosis
mutations in apoptotic genes or over-expression of anti-apoptotic genes allow cancer cells to escape apoptosis
produce IGF survival factors
Causes of Cancer
Extrinsic
Infectious agents
viruses
Feline leukemia virus (full of malignant T cells)
retroviruses
can activate oncogenes by insertional mutagenesis
upstream insertion from promotor
can become acutely transforming oncoviruses
recombination
other infectious agents
led to discovery of the
intrinsic causes
Environmental exposures
gamma-irradiation
UV light
second hand smoke
chemicals (asbestos)
Intrinsic
GENES
Cancer is an
acquired
genetic disease: cancer genes are altered (mutated) in somatic cells
Important groups of genes involved
Tumor suppressor genes
Apoptosis genes
DNA repair genes
Proto-oncogenes
They contribute to cancer by boosting cell proliferation, blocking terminal differentiation, and suppressing apoptosis
Proto-oncogenes
oncogenes are
always dominant
only need one mutated copy to get uncontrolled cell growth
can become oncogenes, leading to unregulated cell growth, when mutated or expressed in high levels
growth factor receptors
(EGFR, PDGFR, Ras)
leads to tryosine kinase activity and initiates intracellular signaling cascade through G protein, Ras. Constitutive activity leads to uncontrolled cell growth
normal regulatory genes that promote cell growth
transcription factors
(Myc, NFKB)
complex master transcription factors that regulate hundreds of genes involved in cellular proliferation
cell cycle regulators
(CDK, cyclins)
control cell cycle progression--mutations leading to constitutive activity will promote cell cycle progression and accumulation of mutations since cell cycle will not stop to allow for DNA repair
Examples
Myc translocation in Burkitt lymphoma
Fusion positive cancers, tend not to have many mutations--driven simply by a chromosomal translocation (not a lot of point mutations in other genes). immunologically silent, important target of immunotherapy
Constitutive expression of Myc
Philadelphia chromosome t(9;22) is a hallmark on chronic myelogenous leukemia (CML)
BCR/Abl is a protooncogene, constitutively active tyrosine kinase from fusion
Can be inhibited by Imatinib (revolutionized therapy of CML)--easy to block by preventing ATP binding, but patients usually resistant to treatment after a while because cancer finds another way
Raleigh chromosome occurs in canine CML (BCR-Abl is similar across species
activating mutations of the tyrosine kinase c-Kit in canine mast cell tumor
tyrosine kinase inhibitors in dogs and cats
Kinavet (masitinib)
targets: Kit (PDGFR)
tumor types: MCTs
Gleevec (imatinib)
targets: Kit, Abl, PDGFR
tumor types: MCTs, sarcomas, CML
Palladia (toceranib)
targets: Kit, VEGFR, PDGFR, Fit-3
tumor types: MCT, sarcomas, carcinomas, melanoma, myeloma
Aberrations leading to constitutive NFKB activity promote aggressive lymphomagenesis, carcinogenesis and drug resistance
NFKB is a transcription factor in immune responses
Holds p65 and p50 complex in place waiting for inflammatory signal
signal leads to cascade and assembly upstream of IKK complex, then proteosome is degraded and nucleus sends out factors
Inflammation and Cancer
Tumors: Wounds that never heal
Breach of vessel integrity during inflammation also facilitates intravasation thus
METASTASIS
Tumor Suppressor Genes
Retinoblastoma
Rb
dividing cells that require the
E2F
transcription factor, which can be sequestered by Rb
E2F controls the transition from G1 to S phase
temporary release of E2F is achieved via phosphorylation of Rb by Cdk/CycD complexes
Nonproliferating cell
: active p16 binds Cdk4 so CycD cannot bind; active Rb/E2F complex inhibiting S phase genes
Proliferating cell:
p16 inactive or absent so Cdk4/CycD bind (active protein kinase complex) --> phosphorylate Rb and cause Rb to be inactive, E2F is actively expressed so S phase genes are activated
Rb gets phosphorylated and degraded to allow E2F to move to regulate genes
Make a tumor:
Lose Rb entirely
Make more CycD
Lose p16
p53
: transcription factor that regulates expression of genes that block cell cycle or induce apoptotic death
activated in response to cell damage or adverse environment, preventing cellular proliferation and/or eliminating cells that are irreparably damages
mutations lead to a failure to halt cell cycle; cells proliferate and accumulate mutations promoting oncogenesis
feline and canine neoplasms (squamous cell carcinoma)
induced by DNA damage (UV light)
mutations in TSGs are
recessive
: both alleles need to be inactivated to predispose cancer
NF1:
transcription factor that accelerates GTP hydrolysis to GDP-thus inactivating Ras--mutation of NF1 leads to neurofibromatosis, marked by constitutive Ras activity
normal genes that suppress cancer growth
Viruses (papillomavirus) go to great lengths to inactivate both p53 and Rb
E7 sequesters Rb
E6 targets p53 for degradation
Two Hit Hypothesis
2 hits are needed to make full-fledged neoplasms
p53 mutations--loss of function
Activating Ras mutation
APC = adenomatous polyposis coli gene/TSG loss of function mutation of APC
Pathway
normal colon cells, 2 APC mutations
adenomatous polyp, one Ras mutation
dysplasic polyp, two TP53 mutations
colon carcinoma, other events; chromosomal abberations
metastatic carcinoma
Two types of TSG: Gatekeepers & Caretakers
Caretakers: stabalize the genome
MSH2
Heterozygous loss leads to hereditary non-polypsis colon cancer
BRCA1
Heterozygous loss leads to breast and ovarian adenocarcinomas
mutations lead to genetic instability
Gatekeepers: control cell growth
p53
Rb
mutations lead to uncontrolled proliferation
The Stem Cell Concept
Push them down to differentiation pathway to slow them down and make the susceptible to different treatments (problem is that they are always proliferating when dedifferentiated)
Death
Chaotic (necrosis)
Organized (apoptosis)
Bcl-2 blocks release of cytochrome c from mitochondria and caspase activation
prevents apoptosis by blocking caspase activation--prevents cells from dying (anti-apoptotic gene)
t(14;18) translocation in follicular lymphoma affects Bcl-2--additional mutations with Bcl-2 expression helps cancer
Vasculogenesis (de novo formation) vs Angiogenesis (vessel sprouting)
Angiogenesis
Provides oxygen and nutrient supply
Once cells get further away from blood source, pH drops (acidic environment) and )2 drops down, so need to produce factors to make blood vessels grow
VEGF can be induced by HIF1 in response to hypoxia
Key angiogenic factor is
VEGF
Monoclonal antibody treatment that blocks VEGF to starve the tumors has been effective
Hypoxia will drive the production of VEGF and the cells will start to produce it to encourage blood vessels
Controlled by the net balance of
both positive and negative regulators
Inhibitors:
Thrombospondin, angiostatin, endostatin, canstatin, tumstatin
Activators:
VEGF, FGF, PDGFB, EGF, LPA
Anti-angiogenesis
Anti-tumor therapy
Regression of drug-senstive tumour cells
Overgrowth of drug resistant tumor cell subpopulations after therapy terminated --> No repsonse
resistance
Anti tumor angiogenesis therapy
Regression of tumor blood vessels and tumor mass
induction of dormancy
Therapy terminated: regrowth of dormant tumor, repeat therapy: regression of blood vessels and tumor mass
response
Directed against endothelial cells
Metatstatic Pathways
Transcoelomic spread
Venereal spread
Lymphatic spread mostly found with carcinomas
Prostate cancers tend to metastasize to bone in humans and dogs
Intravasation is an efficient process but ultimately most circulating cells die
Hematogenous spread mostly found with sarcomas
Lungs
Omentum
Blocking the interaction between CXCL12 and CXCR4 results in fewer metastases (
chemokines: new variation on the seed and soil concept
)
Tumor Progression
Dysplasia/
adenoma
Normal
epithelium
Invasive carcinoma
Carcinoma in situ
Intravasation
Extravasation
Treatments for Cancer
Most common
Radiation therapy
Chemotherapy
Surgery
is not always possible
is not effective against metastatic disease
still accounts for the majority of cures
IMMUNOTHERAPY