Gen Path L22 23

• regulate cell growth and differentiation
• tissue-specific manner
• members of phosphorylation-dephosphorylation cascades pathway
• can be activated and deactivated
• prone to malfunction - "protooncogenes", can't be modulated anymore
• abnormal expression causes inappropriate cellular growth in an inappropriate place - a neoplasm.

• Normal - requires suitable microenvironment, nutrients, growth factors, etc.
• Neoplastic - less need for external signals

• GAPs apply brakes to RAS activation, and PTEN serves the same function for PI3K.
• RAF activates MAPK -> C-Myc, cell cyclin -> cell growth

• A. Viral invasion - rare in human
• 1. A transduced proto-oncogene mutated and returned to the cell.
• 2. A provirus inserted in the vicinity of a protooncogene.
• B. Somatic mutation - inherited healthy gene mutated
• C. Genetic rearrangements
• 1. Gene amplification.
• 2. Chromosomal translocations

• Non-transforming to start with
• picks up normal proto-oncogene in animal cell
• becomes transforming, carrying the oncogene, mutated
• has a number of strong promoters that enhance transcription
• very strong signal
• humans are immunologically heterogeneous and less susceptible

• over-expression of an oncogene due to acquisition of a transcriptional promoter
• avaian provirus enhance c-myc in chicken and causes avian hematopoietic neoplasia (AHN, avian leukemia)

• normal proto-oncogene is damaged/mutated because of carcinogen and oncogene arises
• mutation of Ras, can't be deactivated

• Amplification of the N-MYC gene in human neuroblastomas.
• Amplified N-MYC is seen as extra chromosomal double minutes (DM), or a chromosomally integrated, homogeneous staining region (HSR).
• Huge amount of N-MYC produced

• 1. ERBB1 (the EGF receptor gene) over expressed
• in squamous cell ca, lung, glioblastoma, head & neck Ts
• 2. ERBB2 (HER-2/NEU) amplified in 25% Br ca, ovary, lung, etc; can also be overexpressed w/o being amplified - leads to increased aggressiveness and poor prognosis
• 3. ERBB4 (HER-4) - mutations in melanomas (the most frequently mutated PTK in melanomas)

Herceptin, antibody to HER-2

Burkitt’s lymphoma - when c-myc is translocated to chromosome coding Ig and chronic inflammation happens -> requires very strong expression of Ig -> also causes strong expression of c-myc -> lymphoma

• Viral promoter insertion - AHN
• Chromosomal translocation - Burkitt’s lymphoma (8-14), plasmacytoma in mice
• Amplification - chronic myelogenous leukemia (CML, no differentiation, no RBC and platelet produced, unusual bleeing, can be recognized by dentists; Breakage-Aberrant recombination mutations between chromosomes 9 and 22 forming BCR-ABL, involving tyrosine kinase activity, can be cured by tyrosine kinase inhibitor)

• The Philadelphia chromosome in CML, first example
• Leukemia and lymphomas - reciprocal translocations, non-random trisomy
• Solid tumors - band deletion, chromosome loss (meningioma
• Sub microscopic deletions

• Activated proto-oncogenes: c-myc (Burkit), Ras, ABL (CML), EGF (ERBB1 (sq ca, lung), ERBB2 (HER-2/NEU, br ca, ov ca), ERBB4 (HER-4, skin))
• Tumor suppressor genes: BCRA-1/2 (br ca, ov ca), Rb (retinoblastoma), p53 (50%, carcinoma), APC (adenomatous polyposis coli), VHL (VHL syndrome, angiomas and angiosarcomas, neuroblastomas)
• Cell death controlling genes:
• (a) Suppression of apoptosis eg bcl-2 - oncogene-like
• (b) Enhancement of apoptosis eg bax - TS gene-like

• Intrinsic - release of cytochrome C
• Extrinsic - external signals

• Extrinsic factors - Physical and chemical factors
• Intrinsic factors
• - Genomes
• - Viruses
• - Hormones

• Soot in chimney - scrotal Ca
• coal tar -> skin Ca in mice
• isolation of 3,4-benzpyrene, 3-methylcholanthrene, dimethylbenzanthracene
• Dimethylnitrosamine
• Aromatic amine - eg. naphthylamine
• BeO
• Aflatoxin - the most powerful carcinogen
• N-methyl-BIS-amine - can be used in chemotherapy too
• Heavy metals

carcinogen -> proximate carcinogen -> ultimate carcinogen, eg. carbonium ion (electrophillic center, attacks intracellular target)

• immunosuppressant and carcinogenic: Mercury, Lead, Cadmium, Aluminum, Arsenic and Uranium.
• causing ten-fold increase in cancer mortality.

• Phase I: Oxidation/reduction, hydration, hydrolysis, isomerization, etc; Produces reactive species
• Phase II: conjugated -> more water soluble [eg GST, QR]
• Phase III: Excretion

• Initiation: carcinogen goes through detoxification directly or goes through metabolic activation and becomes electrophilic intermediates (EI) before going in detoxification. Product of detox goes to excretion; EI can also bind to DNA (adduct formation); DNA repair happens and cell becomes normal OR no repair and cell death OR permanent DNA lesion happens and cell becomes initiated
• Promotion: initiated cell -> cell proliferation -> altered differentiation -> preneoplastic clone ->
• proliferation & additional mutations -> malignant neoplasm

• carcinogenic aglycones
• nitrosamines
• steroid metabolites
• amino acid metabolites

• smoking -> bronchogenic Ca
• atmospheric pollution -> bronchogenic Ca
• Food contaminants, aflatoxin ergot
• Smoked food -> gastric Ca
• Food additive, cyclamate
• Insecticides, DDT

• Cancers - Lip and oral cavity is a major site for cancer, squamous cell carcinoma; also the esophagus, lung, pancreas, bladder, kidney
• Cardiovascular disease -> stroke and infarction

• US pathologist
• smoking causes cancer
• active in spreading this information

• Coal tar, shale oil workers -> squamous carcinoma of skin
• aromatic amines in rubber and dyestuff industries -> cancer of bladder
• luminescent dial painters -> Osteogenic sarcoma of bone
• Uranium miners -> carcinoma of bronchus
• Arsenic -> squamous carcinoma of skin
• Asbestos factories -> carcinoma of bronchus and mesotheliomas (cancer around the body)
• vinyl chloride monomer -> hemagioendotheliosarcoma of liver

• High fat -> increase risk of breast and prostate Ca
• Low roughage -> Ca large bowel
• Additives
• Cooking and preservation
• >2/3 of cancer can be prevented by lifestyle
• ~1/3 of cancer can be attributed to diet alone
• Fruit and vegetable - reduces risk of many cancers
• Due to compounds
• - Antioxidants
• - Induce apoptosis in preneoplastic cells
• - Induce cytoprotective enzymes which detoxify carcinogens

• Blocking agents
• - Prevent carcinogen activation
• - Enhance detoxification
• - Trap carcinogens
• Suppressing agents
• - prevent carcinogenesis after attack by carcinogens

• Thorotrast - sarcoma, other tumors
• IM injections of iron for anemia - sarcoma
• DES ( Diethylstilbestrol, synthetic estrogen) during pregnancy for reducing miscarriage risk -> Ca vagina in daughters
• Oral contraceptives - No increase, some benign hepatic tumors

• Breast - estrogens
• Prostate - androgens
• Endometrium - estrogens
• Thyroid - TSH

• Radiation
• - gamma and x-ray -> leukemia in x-ray operators
• - UV -> skin cancer in sailors
• Mechanical
• - burns -> occasional cancer by excessive scarring
• - chronic irriation: clay pipes -> lip carcinoma; dentures -> oral cavity Ca

• radiation -> DNA damage -> incomplete or faulty repair, perpetuated, promote pre-existing conditions
• Chronic hyperplasia has a promotor-like effect
• Increase the chance that a change in DNA is perpetuated

• foreign bodies eg. Bilharzia ova, in urinary bladder
• gallstones

• schistosomiasis
• Ulcerative colitis
• Liver cirrhosis

• Bacteria - H. pylori - associated w/ B-cell lympohoma of stomach (MALTomas) and gastric carcinoma
• RNA oncogenic viruses (retroviruses) - human T-cell leukemia virus type 1 -> target CD4 positive cells, Tax gene and GM-CSF, proliferating T-cells at increased risk for mutations
• DNA viruses
• - HPV 16 & 18 -> target p53 and Rb protein
• - EBV -> Burkitt's?, B-cell lymphoma for HIV+
• - HBV -> liver Ca
• - HHV-8 -> vascular tumor