Cancer Cancer originates in dividing cells –Intestinal lining (colon) –Lung tissue –Breast tissue (glands/ducts) –Prostate (gland) –White blood cells (leukemia) –Stem cells Skin (melanoma) Liver Hematopoietic (myeloma) Does not occur in quiescent cells

Cells and Their Half-Lives Intestinal cells Less than a week Erythrocytes100 days White blood cellsBrief life spans LiverInfrequently replaced MuscleIrregular activation NeuronsLittle or no replacement Skin cellsRegularly replaced Endothelial cellsFrequently replaced

Cancer Loss of cell-cycle control –Cloned cells divide unchecked Results from multiple genetic mutations –Cell cycle genes –DNA repair genes –Apoptosis genes –Growth regulation genes Classified as carcinomas, sarcomas or leukemias (200 types recognized)

Benign Tumors Generally localized and small Fairly common (warts, colon polyps, etc.) Do not break out of originating organ Function very much like cells of origin Generally are easily removed by surgery

Malignant Tumors Remain localized for a time but then invade surrounding tissue Spread by forming metastases –Cells travel through circulation –Can invade any other body tissues Produce few markers of original tissue Very difficult to treat

Cancer Metastasis Basal lamina normally provides barrier Malignant tumor cells can: 1)Break free of attachments to adjoining cells 2)Attach to basal lamina 3)Secrete enzymes that digest extracellular proteins 4)Migrate into circulatory system 5)Penetrate back out of circulatory system to colonize another tissue Rare cells succeed (1 in 10 6 )

Tumor Angiogenesis 10 6 cells is a mass of ~2mm Can not grow more without blood supply Malignant cells overcome this limitation –Secrete growth factors that stimulate angiogenesis (FGF, VEGF,etc.) Requirement for vascular supply suggests possible treatment approach

Cancer is Caused by DNA Mutations DNA from transformed cells can transform normal cells More than 1 mutation is required –E.g., 3T3 cells that already lack p16 (cyclin dependent kinase inhibitor) and then develop mutation to overproduce growth- promoting signal (ras) becomes cancerous Mammals have evolved to prevent accumulated mutations

Genes Associated with Cancer Oncogenes –Mutated forms of proto-oncogenes –Overproduction or over activity is associated with cancer Gain-of-function agents E.g., Myc – Transcription factor that leads to progression through cell cycle –Mutation in one allele is adequate to cause cancer risk

Genes Associated with Cancer Tumor suppressor genes –Encoded proteins that inhibit cell cycle progression or promote apoptosis E.g., APC or Rb –Loss of function agents –Mutations in both alleles are required

Inherited Mutations Some mutations pass through germ line Causes hereditary predisposition –Insufficient alone to cause cancer –~10% of all cancers have hereditary component E.g., Inherited dysfunctional APC gene leads to colon polyps early in life E.g., Inherited dysfunctional Rb gene leads to hereditary retinoblastoma early in life

Cell Cycle Problems Over expression of Cyclin D Loss of p16 function Loss of Rb function

Loss of DNA Repair Problems p53 is an essential checkpoint protein –Prevents proliferation with damaged DNA –Loss of function associated with ½ of all cancers –Cells with p53 arrest in G1 after irradiation –Activated only after cell stress or damage –Induces p21 to inhibit Cdk-cyclin complexes –Falls off to low level if DNA repair is successful –Active as tetramer of 4 units Mutation in one allele creates loss of function

P53 Mutation Frequency in Various Cancers

Chemical Carcinogens Direct acting vs. indirect –Indirect results from non-reactive chemicals being metabolized in liver to carcinogen Oxidative reactions by p450 enzyme complexes rid body of fat soluble toxins –Active carcinogen binds to DNA and causes mutations (e.g., benzopyrene in cigarette smoke causes G to T transversions in DNA – causes mutations of p53 at codons 175, 248 and 273)

Initiators vs. Promoters Initiators –Carcinogens that interact with and cause mutations in DNA Promoters –Interact with cells to promote growth, block differentiation –Leads to additional permanent changes after initiator damage –Does not cause cancer by itself –No reliable test yet found to identify promoters

Radiation Mutations Ultraviolet radiation Ionizing radiation –Gamma- and X-rays –Particle radiation (alpha, beta) Electromagnetic radiation –Power lines, cell phones, etc. –May act as promoter

Cancer Treatments Surgery Chemotherapy Radiation therapy Photodynamic therapy “Magic bullets” Angiogenesis inhibitors Transplantation of hematopoietic stem cells –Whole body radiation to treat metastases Gene therapy –Reintroduce p53 or other tumor suppressor genes –Must get into each and every cancer cell