Cancer- abnormal cell growth (cell growth not under "normal" control) Benign tumors are self-limiting- have contact inhibition Malignant tumors can metastasize and induce tumors in other tissues 24-1, 1055

Cancer cells have high DNA:cytoplasm ratios, several nucleoli in nucleus, and may have abnormal numbers of chromosomes Malignant cells less differentiated (cell fate less determined) than benign cells Benign tumors usually pose no threat except what may be posed by their physical presence Benign tumors can become malignant

24-6, 1060 Progression of colon cancer

Cell culture – some cells lose normal control of growth and proliferation in culture- change in morphology, reduced need for growth factors, substrate-loss of contact inhibition (keep moving and growing) transformation or malignant transformation cell strain-lasts about 50 divisions cell line-immortal if continually fed and diluted fibroblasts-"fibrous germinating cells" normal transformed

Cells can be transformed with radiation, oncogenes, chemicals, and viruses In addition to the characteristics just listed, they also… >have increased mobility of integral membrane proteins phospholipid itself not more mobile-but instead connections between protein and cytoskeleton altered >increased glucose transport (GLUT with lower Km for glucose) >reduced or absent fibronectin (protein that forms meshwork over normal cells in culture) >altered gene transcription -but only 3% of total mRNAs unique to transformed state

Oncogenes encode proteins that can transform cells in culture or cause cancer in animals Proto-oncogenes are the "normal" copies of a gene, that if mutated, will become oncogenes src - the gene ("sarc") Src - the protein that src makes

7 classes of proteins that are coded for by oncogenes 24-9, 1064

24-7, 1061 oncogenes work cooperatively to produce cancers

, Activation of oncogenes-often result in signal constantly “on”

A single mutation (V for G) reduces GTPase activity and converts to oncogene

p16-cyclin kinase inhibitor Rb-inhibits E2F-transcription factor required for synthesis of DNA replication machinery-(such as DNA polymerase) 24-19, 1075

p53-arrests cells in G1 who have had significant DNA damage mutations in p53 show up in >50% of human cancers

p53 is a tetramer-if only one allele is mutated, messes up nearly all copies of functional protein

Other factors indirectly activate oncogenes DNA viruses-viral DNA inserted specifically or at random into genome RNA viruses- random or specific integration-once incorporated into genome called provirus-if incorporated into genome can be passed to progeny 0.1-1% of total genome is proviral in mice HIV, hepatitis B, papilloma, Epstein-Barr viruses all can cause cancer in humans

phorbol esters-mimic DAG-constitutively active PKC Aflatoxins- from mold on grains-potent mutagen

Other Cancer Tidbits… epigenetic events may cause some cancers >p16 present and not mutated, but heavily methylated in many cancers -Cancer and EMF link? 6 studies say yes, 9 no EMF cause increase in calcium signaling, RNA synthesis, gene expression, src kinase No effect of DNA mutation, chromosomal aberration, NO production, tumor promotion, DNA synthesis, cell proliferation 11 of 13 studies attempting to repeat a previously published effect failed

Breast Cancer BRCA1, BRCA2 genes were thought to give high probability of breast cancer if mutated Now the correlation is breaking down tamoxifen treatment in healthy women at high risk reduces incidence of breast cancer by 45% side effects of increased endometrial cancer risk and blood clots (but only if you begin taking it after 50)