Chapter 16 Cancer is a genetic disease at the somatic level characterized by gene products derived from mutated or abnormally expressed genes Some are inherited but most are created within somatic cells that divide and form WIDE RANGE OF CAUSES including Single nucleotide substitutions to large scale chromosome rearrangements amplifications and deletions Figure 16 1 Mostly affects somatic cells 1 percent are germ line mutations Rarely arises from a single mutation but from accumulation of mutations in many tumors genes Affects multiple cellular functions repair of damaged DNA cell division apoptosis cellular differentiation migratory behavior and cell cell contact Cancer is a large complex of diseases up to a hundred that behave differently depending on their cellular type origin All cancers share two fundamental properties Abnormal cell growth and division proliferation results in tumors Defects in normal restraints that prevent cells from spreading metastasis Genes controlling this are mutated or not expressed Benign tumors result from unregulated cell growth forming a multicellular mass that can be removed by surgery causing no serious harm primary tumors Malignant tumors result from cells that break loose and form secondary tumors metastases secondary tumors threatening Malignant tumors are cancerous difficult to treat and may become life May contain billions of cells May invade and grow in numerous body parts All cancer cells in primary and secondary tumors are clonal meaning that they originated from a common ancestral cell that accumulated numerous specific mutations Reciprocal chromosomal translocations are characteristic of many cancers Leukemias and lymphomas involve white blood cells Burkitt s lymphoma shows reciprocal translocations between chromosome 8 and chromosomes 2 14 or 22 All cancer cells arise from a single cell that is passed to progeny all translocations in a single Burkitt s lymphoma patient involve the same 2 chromosomes X chromosome inactivation occurs early in development and occurs at random All cancer cells within a tumor both primary and metastatic within one female individual contain the same inactivated X chromosome All cancer cells arose from a common ancestral cell Cancer stem cell hypothesis Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self renewal Evidence is accumulating that cancer stem cells do exist and have been identified in Leukemia brain cancer breast cancer colon cancer ovarian cancer pancreatic cancer prostate cancer Cancer cells show higher than normal rates of mutation chromosomal abnormalities genomic instability The fundamental defect in cancer cells is a derangement of the cell s ability to repair DNA damage The high level of genomic instability in cancer cells is known as the mutator phenotype The genomic instability in cancer cells manifests itself in gross defects such as Translocations aneuploidy chromosome loss DNA amplification chromosomal Often cancers show specific chromosomal defects that are used to diagnose the type and deletions stage of the cancer Chronic myelogenous leukemia CML The C ABL gene on chromosome 9 is translocated into the BCR gene on chromosome 22 This structure is known as the Philadelphia chromosome Figure 16 3 The BCR ABL protein is an abnormal signal transduction molecule in CML cells that stimulate cell proliferation even in the absence of external growth signals Epigenetics is the study of factors that affect gene expression but do not alter the nucleotide sequence of the DNA DNA methylation Histone modifications next The cell cycle is tightly regulated and each step must be completed before entering the Three distinct checkpoints in the cell cycle monitor external signals and internal equilibrium before proceeding to the next stage Cell Cycle Checkpoints G1 S G2 M M G1 S checkpoints monitor cell size and determine whether DNA damage has occured G2 M is where physiological conditions are checked once G1 S are passed prior to mitosis M The formation of the spindle fiber system and the attachment of spindle fibers to the kinetochores associated with the centromeres are monitored In addition to the checkpoints regulation of cell cycle progress is mediated by cyclins and cyclin dependent kinases CDKs that regulate synthesis and destruction of cyclin proteins Figure 16 5 Mutation of misexpression of any of the genes controlling the cell cycle can contribute to the development of cancer Mutated genes controlling G1 S or G2 M checkpoints or those controlling cyclins may allow cells to continue to grow and divide without repairing DNA damage Regulation of cell cycle progress is mediated by cyclins and cyclin dependent kinases CDKs that regulate synthesis and destruction of cyclin proteins Cells halt progress through the cell cycle if DNA replication repair or chromosome assembly is aberrant If DNA damage is so severe that repair is impossible the cell may initiate genetically controlled apoptosis or programmed cell death Prevents cancer Also eliminates cells not contributing the final adult organism of apoptosis cycle cell division An oncogene a cancer causing gene is a mutated or aberrantly expressed proto oncogene a gain of function alteration Proto oncogenes are genes whose products promote cell growth and division Tumor suppressor genes regulate cell cycle checkpoints or initiate the process Tumor suppressor genes produce proteins that halt progress through the cell ras genes are mutated in more than 30 percent of human tumors and encode signal transduction molecules that are associated with the cell membrane and regulate cell growth and division Ras proteins transmit signals from the cell membrane to the nucleus stimulating Alternate between active and inactive state Mutations that convert the ras proto oncogene to an oncogene freeze the ras protein into its active on conformation constantly stimulating the cell to divide The p53 tumor suppressor gene mutated in more than 50 percent of all cancers encodes a nuclear protein that acts as a transcription factor repressing or stimulating transcription of more than 50 different genes p53 protein is continuously synthesized but rapidly degraded and thus is present at low levels The p53 protein becomes more stable and transcriptionally active in response to Chemical damage to DNA Double stranded breaks in DNA by ionizing radiation DNA repair intermediates generated by UV light exposure increases The p53 protein
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