MCB 2210 001 4 27 2015 Cancer Cells Cancer causes roughly one fifth of the deaths in the US each year Carcinomas are cancers that arise from epithelial cells and are the most common cancers in humans Sarcomas arise from connective or muscle tissues Leukemias and lymphomas arise from blood cells Several fundamental cellular properties are altered during carcinogenesis the generation of cancer o Cancer cells break the most basic rules of cell behavior that build and maintain organisms Numerous proteins have been identified because abnormalities in their function can lead to uncontrolled cell growth increased cell division decreased cell death enhanced cell migration etc These proteins are involved in DNA repair cell signaling cell cycle control cell growth programmed cell death cytoskeletal rearrangements and tissue architecture Cancer cells are defined by two heritable properties o 1 They reproduce in defiance of the normal restraints on cell growth and division o 2 They invade and colonize territories normally reserved for other cells A normal cell that grows and proliferates out of control will give rise to a tumor new growth neoplasm If the neoplastic cells are not invasive they are considered benign A tumor is considered a cancer if it is malignant if its cells have acquired the ability to invade other tissues o This invasiveness or spread of cancer cells is called metastasis Cancer cells contain somatic mutations These mutations can be triggered by chemical carcinogens or from radiation o Some cancers are also caused by viruses o Cancers can arise from the inheritance of mutant genes that predispose cells for accumulated somatic mutations o Most cancers derive from a single abnormal cell and even when a cancer has metastasized its origins can usually be traced to a primary tumor in a specific organ The primary tumor is derived from division of a single cell that initially experienced some heritable change Subsequently additional changes accumulate in the descendants of this cell allowing them to outgrow out divide and out live their neighbors Caretaker genes encode proteins involved in DNA repair o Caretaker genes with LOF mutations contribute to cancer Proto oncogenes and tumor suppressor genes encode many members of the classes of factors o Whether a signaling protein is a tumor suppressor or proto oncogene really depends on whether its pathway normally inhibits or promotes growth and proliferation o Proto oncogenes with GOF mutations contribute to cancer o Tumor suppressor genes with LOF mutations contribute to cancer DNA repair defects give rise to hereditary cancers Loss of function mutations in tumor suppressor genes promote cancer o Tumor suppressor genes encode proteins that inhibit cell proliferation by several mechanisms o Prominent tumor suppressors include Proteins that regulate or inhibit cell cycle progression e g Rb is a protein that inhibits progression from G1 to S Receptors or signal transducers for hormones or developmental signals e g TGF Checkpoint control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal e g p53 is the guardian of the genome Proteins that promote apoptosis programmed cell death Enzymes that function in DNA repair which are encoded by caretaker genes Rb regulates the G1 S restriction point o Unphosphorylated Rb binds to E2F transcription factors to prevent activation of many genes required for DNA synthesis e g DNA polymerases o CyclinD CDK4 phosphorylates Rb o Phosphorylated Rb releases E2F thereby activating transcription of genes required for S phase o Overproduction of CyclinD loss of p16 or loss of Rb is common in human cancers Gain of function mutations in proto oncogenes promote cancer o Cells that are rounder and less adherent to surrounding cells and the dish that form 3D clusters and that continue to grow while normal cells have become quiescent are said to have undergone oncogenic transformation In this experiment an oncogene called rasD was identified This gene encodes a constitutively active version of Ras a small GTPase that controls many signal transduction pathways which are activated by growth factors A mutant ras gene is found in most human colon bladder and pancreatic cancers but not in normal human cells Any gene such as ras that if mutated is capable of transforming cells in culture or inducing cancer in animals is called a protooncogene Overexpression of RasD is sufficient to transform some cultures of 3T3 cells into tumor cells but it is not sufficient to transform primary fibroblast cultures This is because some 3T3 cells have loss of function mutations in several regulators of the cell cycle o Multi hit model for cancer induction Several events are required for carcinogenesis In this study mice were engineered to overexpress the protooncogene c myc and the oncogene rasD using a mammary tumor virus promoter Similar cooperative effects can be seen in cultured cells Interestingly oncogenes carried by viruses that cause tumors in animals are seen derived from proto oncogenes that were hijacked from the host genome and altered to be oncogenic Some examples of viral variants of cellular proto oncogenes are v ras a mutant active version of the gene encoding the small GTPase Ras which controls signal transduction cascades downstream of growth factor receptors by activating proteins called MAP kinases v myc a mutant version the gene encoding the transcription factor c myc which regulates expression of 15 of human genes v src a mutant active version of the gene encoding the tyrosine kinase c src which participates in many signaling pathways plus actin cytoskeletal rearrangements o Hybridization methods using DNA microarrays can be used to detect duplications or deletions of genes in tumor cells Fluorescently labeled DNA fragments from normal cells and tumor cells are hybridized to a DNA microarray in which each spot corresponds to a defined position in the normal genome A red signal represents an amplification e g duplication of cmyc a green signal signifies a deletion A yellow signal indicates that gene content is unchanged The development and metastasis of human colorectal cancer takes place in multiple steps o Inactivating mutation in APC causes increase in heritable forms of condensed chromatin followed by DNA hypermethylation o Mutations that lead to genetic instability o Activating mutations in K Ras signaling pathway o Activating mutations in PI 3 kinase signaling pathway o Mutations