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Normal cell growth

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- Cell proliferation is mitogen dependent - Cell growth is anchorage dependent - Cell growth is contact inhibited - Cells are mortal

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Cancer phenotype

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- Loss of normal cell-cell interactions - Loss of normal cell cycle regulation

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Cancer arises when?

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Somatic mutation creates gene that causes cell to uncontrollably proliferate. Creates a neoplasm

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Monoclonal origin

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Most tumors derived from a single abnormal ancestor

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Benign tumors

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Limit their growth, don't do much harm

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Malignant tumors

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Kill organism

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Cancer cells

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- Abnormally high mitotic rate - Become similar to stem cells - Show disordered growth (anaplasia) - Can colonize distant tissues (metastasis) - Genetically unstable - Grow in absence of mitogens - Immortal

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Proto-oncogenes (c-onc)

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Code for normal cell functions involved in growth and differentiation.

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Tumor cell characteristics

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- Inappropriate regulation of cell growth - Loss of contact inhibition - Unstable number of chromosomes - Release transforming growth factors - Protease secretion - Altered surface proteins - Altered gene transcription

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Malignant

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Capable of spreading. Metastasis

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Slow transforming RVs

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c-onc not damaged, but transcription rate is increased. - Promoter insertion - Enhancer insertion

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Do non-viral tumors contain oncogenic DNA sequences?

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Yes.

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Rous sarcoma virus

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RV containing small RNA genome with *gag, pol, and env* genes. v-src not required for replication.

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v-src

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Viral oncongene. Causes abnormal proliferation of virus infected cells. Expressed at high rate under direction of viral promoter and enhancer in LTRs.

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Normal SRC proto-oncogene

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Closely related to v-src. Both code to NR-TPK loosely bound to membrane.

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Base substitution in oncogenes

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Ras allele point mutations

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Normal Src kinase

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Controlled by GF receptors and focal adhesion proteins. Stimulates mitosis by phosphorylating same proteins as GF receptors

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Ras allele

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Classical point mutations turns normal ras into tumor DNA. 3 AA positions involved

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Ras mutations

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Normal ras: GGT-GCA-CAA (Gly-Ala-Gln) Lung carcinoma ras: TGT Ki MSV ras: AGT-ACA

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Proto-oncogene

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Gene that normally codes for growth promoting protein becomes *abnormally activated*. ---> Oncogene Only requires activation of one copy of gene. (Dominant expression)

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Oncogene

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Mutated proto-oncogene

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Tumor suppressor genes

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Codes for inhibiting protein, prevents cancerous growth. *Expressed as a recessive trait*- both copies must be inactivated to promote abnormal growth.

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Classes of proto-oncogenes

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- Growth inhibiting proto. - Growth inhibiting cancer suppressor genes - Genes that regulate apoptosis - Genes that regulate DNA repair

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Oncogenic protein

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Bind growth factor to its specific receptor, activation turns on signal transduction pathway to activate DNA transcription. Cell enters cell cycle, results in cell division.

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Proto-oncogene activation

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Single activating mutation is sufficient to produce abnormal cell growth. (GOF mutation) -Products are growth-stimulating proteins

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Tumor suppressor gene activation

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Two inactivating mutations necessary for abnormal cell growth. (LOF mutation) -Normal products are growth inhibiting proteins, so inactivation means loss of inhibition.

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Proto-oncogene conversion

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- Mutations - Translocations - Over expression - Inappropriate expresion during cell cycle Mechanisms that can covert them to tumorigenic genes

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Proto-oncogene conversion mechanisms

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- Structural changes to gene, resulting in oncoprotein - Regulatory changes in gene expression, resulting in enhanced production of growth promoting protein

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Proto-oncogene normal functions

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- GFR - Adhesion molecules - ras (signal transducer) - cyclin D (cell cycle regulator) - myc (TF) - p53 - BRCA-1/2 (DNA repair) - Rb (cell cycle inhibitor)

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Growth factors

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Uncommon as oncogene products. - simian sarcoma (sis) gene, only one known to code for GF - Some spontaneous cancers stimulate autocrine loop

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Growth factor mechanism

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- Activation of oncogene coding for GF - Abnormal amount of GF - Receptors bind GF and signal transducer - Stimulation of cell growth

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Growth factor receptors

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RTKs over-expressed or structurally altered in malignant tumors.

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GF receptor mechanism

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- Amplification of oncogene coding for GFR - Abnormal amount of GFR produced - Receptors bind signal transducer - Cell growth stimulation

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erb-B oncogene

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Codes for EGF receptor that has lost EC ligand binding domain. *Phosphorylates products at all times, even in absence of EGF*

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neu oncogene

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Single substitution point mutation keeps receptor active at all times

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Signal transducing proteins

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- Mutant signal transducer protein produced - Mutant transducer remains active after release of GF - Mitogen independence and anchorage independence

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P13K

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P13K ---> + Akt ---> Inhibits GSK3 ---> Inhibits cyclins

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ras proteins lost?

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Lost their OFF switch. Remain active at all times.

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ras mechanism

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Normally inactive. Activation requires GDP phosphorylation. Signal transduction through MAP kinase pathway. GAP binds to ras, cleaves GTP back to GDP.

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ras cancers

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- Lung - Colon - Pancreatic (90%)

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Oncogenic ras

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Make ras unresponsive to GAP. Lost "off" switch, remain in active state.

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Neurofibromin

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Stimulates GTPase activity of Ras. Wants to turn it off.

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Neurofibromatosis Type 1

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Mutation inactivates NF, which normally turns off ras. Tumor cells have elevated ras signaling. - Cafe au lait spots - Benign but disfiguring nerve sheath tumors along peripheral nerves.

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RAF-1

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Similar regulation to ras. Oncogenic form loses negative phosphorylation sites, or whole regulatory domain.

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Cell cycle promoters

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- Oncogenes ---> Activation produces cell growth

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Cell cycle inhibitors

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- Tumor suppressors ---> Inactivation induces cell growth

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pRb

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Inhibits cell cycle. Cyclin D phosphorylates pRb, entering cell into S phase

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Burkitt's lymphoma

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Chromosome 8 and 14 translocation. Results in increased myc protein

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Retinoblastoma

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Homozygous inactivation of RB1 gene in cancer cells, leading to defective G1 checkpoint. (2 hits)

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Sporadic form

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Single tumor, no family history. Require 2 somatic mutations to eliminate both copies of RB1 to develop cancer.

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Familial form

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Autosomal dominant trait, presents in multiple tumors. Born with heterozygous for an inactivating RB1 mutation, require 1 somatic mutation to develop cancer.

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Retinoblastoma gene

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Deletion of 13q14.1. Normally codes for p105-RB, which is expressed in normal retinal tissue and regulates the cell cycle by binding transcription factors.

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Cancer susceptibility syndrome

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Individuals born with heterozygous mutation in a tumor repressor gene. Susceptible to somatic mutation that causes the cell to lose both copies of TSG.

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p53 function

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Detects DNA damage. Attempts to repair damage. If not repaired, cell triggered for apoptosis.

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Mutated/loss of p53

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No cell cycle arrest, therefore no DNA repair. Mutant cells become malignant

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DNA oncogenic viruses

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- HPV - EBV

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HPV Types

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Types 6 and 11 have low risk malignant potential, form genital warts.

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HPV mechanism

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Viral E6/E7 genes integrated in host DNA. E7 binds to pRb, displacing E2F TFs. E6 binds to p53 and degrades it. Changes in transcription lead to increased cell proliferation and increased rate of somatic mutations.

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EBV

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Infects epithelial cells of oropharynx and B-cells. EBC forms an episome in B-cell genome, makes cell immortal. Activates LMP-1 which prevents apoptosis by up-regulating bcl-2 expression.

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Cell surface receptors

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Binding of TGF-B to receptors up regulates transcription of growth inhibitory genes.

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Loss of cadherins

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Favors malignancy by allowing easy disaggregation of cells

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DNA repair regulator genes

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Those born with a mutation in DNA repair proteins have an increased risk of developing cancer. - HNPCC syndrome

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Xeroderma Pigmentosum

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Individuals have increased chance of developing melanomas and squamous cell carcinomas as a result of exposure to UV. Unable to fix DNA regions with chemically modified bases.

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BRCA-1 and BRCA-2

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Associated with breast and ovarian cancer. Proteins involved in homologous recombination repair process.

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Adenomatous polyposis coli (APC)

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Colonic mucosa becomes studded with thousands of polyps. Heterozygotes have a loss of APC in all cells, and inactivation of the remaining APC gene can create a polyp.

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Colorectal Cancers

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Develop from benign tumors. Homozygous inactivation of APC TSG can form a benign polyp.

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B-catenin

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Inactivation of APC gene prevents destruction of b-catenin. Accumulating B-catenin stimulates gene expression permanently.

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Colorectal cancer mechanism

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1. Loss of APC TSG 2. Activation of K-ras oncogene 3. Loss of DCC TSG 4. Loss of p53 TSG 5. Cancer metastasizes

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Apoptosis

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Regulated by bcl-2. Effector is caspase.

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myc lymphoma

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Excess cells produced.

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bcl2 lymphoma

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Excess cells do NOT die.

Cancer, Proto-oncogenes, Tumor Suppressor genes – Flashcards

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