Cancer Types of Cancers Benign or metastatic four groups determined by the type of the original cell bone marrow - leukemias lymph node and spleen - lymphomas mesoderm (muscle, bone, cartilage) - sarcomas epithelial (glands, breast, skin, lungs,etc.) - carcinomas (85% of total) Characteristics of Cancer Cells Uncontrolled growth immortal they don't need growth factors no contact inhibition they can spread to new sites in the body (metastasis) they progressively lose the characteristics of the normal cell from which they are derived they acquire new characteristics (transform) they can grow in soft agar they produce new cell surface markers The Causes of Cancer Multiple somatic mutations are needed to create a cancerous cell. these mutations can be caused by: Carcinogens Mutagenic chemicals Radiation Growth promoting agents Viruses Retroviruses Rous sarcoma virus carries a cellular oncogene (v-src) Avian leukosis virus activates a cellular oncogene (c-myc) DNA tumor viruses (insertional mutagensis) Adenovirus, SV40, Hepatitis B virus (HBV) A tendency to get cancer can be inherited Individuals inherit one "bad" allele but still need a somatic mutation in the other "good" allele retinoblastoma (40%), Wilms tumor (all), breast cancer (5%) Functions of cancer genes Multiple mutations are needed to create the typical cancer cell These mutations are in the genes that regulate cell growth, genes that protect the individual by killing damaged or unneeded cells, genes that repair the DNA, genes that determine cellular characteristics, and genes to promote angiogensis Oncogenes - induce or maintain uncontrolled growth growth factors such as sis growth factor receptors, erb-B proteins in the signaling pathway from a growth factor receptor such as protein kinases like src and G-proteins such as ras transcription factors that activate genes in response to growth factors (fos and jun) Tumor suppressor genes - block cell growth or remove damaged cells Two forms of retinoblastoma (tumors of the retina) familial and sporadic Familial (40%) - an inherited form of cancer, occurs early in life, is inherited as a dominant trait Sporadic (60%) &endash; not heritable, occurs late in life, only in one eye Explanation: mutations are recessive, both copies must be mutated to get cancer - in heritable form one allele is already mutated pRb, the protein made from the retinoblastoma gene, is a nuclear protein pRb binds to a transcription factor, E2F, inactivating it pRB is phosphorylated when the cell enters the S phase of the cell cycle (by CDK) The phosphorylated form of pRb releases E2F allowing it to turn on genes needed for cell division Mutated forms of the protein fail to bind E2F, allowing it to remain active and promote cell division Other tumor supressor genes Wilms Tumor &endash; a zinc-finger transcription factor Appears to shut down division of a small subset of kidney cells during development BRCA1 - heritable breast cancer (5%) a secreted protein that inhibits division of neighboring cells p53 - a transcription factor that blocks entry into S phase if there is DNA damage If there is too much damage to repair, causes apoptosis - programmed cell death DNA instability DNA repair genes damage to these leads to mutations in the oncogenes and tumor suppressor genes MLH1 (mismatch repair), ATM (arrest cell division in response to radiation damage), p53, FCC, etc. Other cancer genes Telomerase activation of telomerase is necessary for immortality Angiogensis genes Tumors need to promote the growth of new blood vessels to support their growth Metastasis genes Proteinases to cut through the extracellular matrix, etc. How are cellular genes converted into oncogenes? point mutations G to T in Ha-ras causes gly(12) to become val(12) in p21 translocation chronic myelocytic leukemia (CML) - t(9;22) Philadelphia chromosome - moves c-abl on ch. 8 into a gene, bcr, on ch. 22 Burkitt's lymphoma - t(8;14) moving myc gene on ch. 8 into antibody H-chain gene on ch. 14 recombination with a virus v-src, v-Ha-ras, v-myc, v-myb, etc. activation myc amplification Ki-ras in double minute chromosomes loss of proper regulation myc If oncogenes are dominant, why is malignancy recessive? heterokaryons of tumor cells and normal cells are normal time course of most tumors suggest multiple mutations are required Vulnerability to cancer as a genetic trait recessive - caused by mutations that increase the mutation rate xeroderma pigmentosum - UV repair; leads to skin cancer ataxia-telengiectasia - X-ray repair; leukemia and lymphomas msh2 - microsatellite instability, leads to colon cancer (1/200 people carry the allele) dominant - caused by loss of tumour suppressor genes retinoblastoma, p53, DCC A model: Colon Cancer Like most cancers colon cancer follows a progression as mutations are accumulated First, a mutation in one allele of the APC gene Causes a proliferation in the epithelium Second, a mutation in the K-ras oncogene Intermediate adenoma Third, loss of the DCC tumor supressor Fourth, loss of the p53 tumor suppressor Cancerous adenoma Fifth, mutations in unknown genes lead to metastasis metastatic cancer [ Biol 207 ] [ Bell ] [ CSU Chico ] [ Library ] This document is maintained by: Jeff Bell Last Update: Wednesday, December 9, 1998