Lecture 17: Cancer as a microevolutionary process

Cancer Natural selection is a very potent tool Free living cells (bacteria, yeast) compete to survive There is no natural selection and competition among the cell of the body Selection process within cancer cells population creates cells that can destroy the organism Events that happen within the tumor Mutation Uncontrollable division Connection between cells is lost Natural selection laws rule the cells The cells acquire more and more mutations that help them invade other tissues Two stages of cancer treatment Cell starts to divide uncontrollably giving rise to a tumor - neoplasm Cells acquire the ability to invade surrounding tissues and form secondary tumors - metastases Metastasis: cancer cells break loose p, enter the bloodstream or lymphatic vessels and form secondary tumors Two stages of cancer development Noninvasive tumor - benign Metastasizing tumor - malignant Cancers are called according to the tissue or cell type Carcinoma: epithelial cells Sarcoma: muscle or connective tissue Leukemia: hemopoietic cells Most cancers are derived from single mutated cell Chromosomal translocation analyses X-chromosome inactivation analyses in female tumor cells Cancer originated from a single mutation Evidence 1: In all cancer cells of a patient translocation is exactly the same Evidence 2: Female tissues are the mixtures of cells in which one or the other X-chromosome is inactivated Philadelphia chromosome translocation happens at the exact same positions in all patients • A. True • B. False What factors can contribute to carcinogenesis (generation of cancer)? Mutagens Chemical carcinogens Ionizing radiation (X-rays), UV Viruses Genetic predisposition Increased rate of mutations in some individuals (DNA repair defect) Evolution of tumor involves successive rounds of mutation and natural selection Many mutations are needed: To break control systems To survive with limited amounts of oxygen and nutrients To adjust in other tissues Rate of evolution in cancer depends on: Mutation rate Number of individuals Rate of reproduction Selective advantage of mutants over the normal Instability can result from: Defect in DNA repair Inability to maintain chromosome integrity How to increase a pool of cells available for mutations? Destroy cell division controls Destroy apoptosis pathways Alter the ability of the cells to differentiate: more than 50% of stem cells progeny should stay the stem cells and less differentiate Selective advantage: telomeres do not shorten in cancer cells Normal cells No or low levels of telomerase (except germ line and some stem cells) Telomeres shorten with each division They can only divide limited number of times (replicative senescence) Cancer cells High levels of telomerase Telomeres do not shorten They can divide unlimited number of times Key properties of cancerous cells: Disregard external and internal signals regulating cell proliferation (including those for replicative senescence) Avoid suicide/apoptosis Are genetically unstable (aids tumor evolution) Are invasive (can move out of primary tissue) Are metastatic (survive and proliferate in secondary tissues) Able to recruit adequate blood supply (many tumors show enhanced production of angiogenic factors)