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Chapter 21 The Genetic (Cell Biology) Basis of Cancer © John Wiley & Sons, Inc.

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Presentation on theme: "Chapter 21 The Genetic (Cell Biology) Basis of Cancer © John Wiley & Sons, Inc."— Presentation transcript:

1 Chapter 21 The Genetic (Cell Biology) Basis of Cancer © John Wiley & Sons, Inc.

2 Chapter Outline  Cancer: A Genetic Disease  Oncogenes  Tumor Suppressor Genes  Genetic Pathways to Cancer  Tumors in Plants © John Wiley & Sons, Inc.

3 Cancer: A Genetic Disease Mutations in genes that control cell growth and division are responsible for cancer. © John Wiley & Sons, Inc. (cell proliferation and differentiation) Carcinogens  DNA mutations

4 Cancer  Cancers arise when critical genes are mutated, causing unregulated proliferation of cells.  These rapidly dividing cells pile up on top of each other to form a tumor.  When cells detach from the tumor and invade surrounding tissues, the tumor is malignant and may form secondary tumors at other locations in a process called metastasis.  A tumor whose cells do not invade surrounding tissues is benign.

5 Tumor – is a condition where there is abnormal cellular growth thus forming a lesion or in most cases, a lump in some part of your body. Benign tumor – grows in confined area Malignant tumor – capable of invading surrounding tissues Cancer – degenerative disease with a cellular condition where there is uncontrolled growing mass of cells capable of invading neighboring tissues and spreading via body fluids to other parts of the body.

6 Named for site of origin Carcinomas – epithelial cells; cover external & internal body surfaces (90%) Sarcomas – supporting tissue; bone, cartilage, fat, connective tissue, pancreas, Liver. Lymphoma & leukemias – blood & lymphatic tissue (leukemia reserved for cancers that reside in bloodstream not as solid tissue)

7 Comparison of Normal and Tumor Growth in the Epithelium of the Skin

8 Location/distribution

9 Growth properties of normal and cancerous cells

10 Hematoxylin (nucleus) and Eosin (cytoplasm) stain

11 Normal cells vs. Cancer cells Normal cell proliferationCancer cell proliferation Anchorage dependentAnchorage independent Density-dependent inhibitionCan grow on top of one another Limited number of cell divisions Immortal Telomere shorteningTelomere maintenance Proliferation dependent upon extracellular signals Constant signal to divide Checkpoints activated at appropriate times Loss of checkpoint Apoptosis functionalApoptosis inhibited independent

12 Basic Properties of a Cancer Cell –In culture, normal cells can be transformed by chemicals or viruses. –Different types of cancer cells share a number of similarities: Aberrant chromosome numbers (aneuploidy) High metabolic requirements Unregulated growth Synthesis of unusual cell surface proteins

13 Invasion Metastasis Why? How? Basal lamina Matrix Stages in the Process of Invasion and Metastasis

14 Loss of cell surface proteins involve in cell-cell adhesion E-cadherin Increased Motility signaling molecules, chemoattractants, protease activator (plasminogen plasmin) Basal lamina

15 Some cells are more capable than others 99%

16 Some preferential sites blood flow patterns: capillaries (5-10 um of diameter vs 20 x 25 um) “seed and soil” Surrounding environment

17 © John Wiley & Sons, Inc. Cancers

18 Cell Cycle Checkpoints  Transitions between different phases of the cell cycle (G 1, S, G 2, and M) are regulated at checkpoints.  A checkpoint is a mechanism that halts progression through the cycle until a critical process is completed. © John Wiley & Sons, Inc.

19 Cyclins and CDKs  Important checkpoint proteins are the cyclins and the cyclin-dependent kinases (CDKs); complexes formed between cyclins and CDKs cause the cell cycle to advance.  The CDKs phosphorylate target proteins but are inactive unless they are associated with a cyclin protein.  Cell cycling requires the alternate formation and degradation of cyclin/CDK complexes. © John Wiley & Sons, Inc.

20 The START Checkpoint © John Wiley & Sons, Inc.

21 Mitotic M-cyclins Mitotic M-cdks S cyclins /A Cdc2 (Cell Division Cycle ) = CDK (Cyclin-dependent kinase)

22 Checkpoints in Tumor Cells  In tumor cells, cell cycle checkpoints are often deregulated due to genetic defects in the machinery that alternately raises and lowers the abundance of the cyclin/CDK complexes.  These mutations may be:  in the genes encoding the cyclins or CDKs,  in genes encoding the proteins that respond to specific cyclin/CDK complexes  in genes encoding proteins that regulate the abundance of these complexes. © John Wiley & Sons, Inc.


24 Cancer and Programmed Cell Death  Apoptosis is part of the normal developmental program in animals and is important in the prevention of cancer.  The caspases, a family of proteolytic enzymes, are involved in apoptosis and cleave many target proteins.  If apoptosis is impaired, a cell that should be killed can survive and proliferate, potentially forming a clone that could become cancerous. © John Wiley & Sons, Inc.

25 Major Steps in Apoptosis Necrosis= injury Apoptosis= program for cell death ‘bubble”

26 Induction of Apoptosis by Cell Death Signals or by Withdrawal of Survival Factors IGFR=insulin-like growth factor receptor INSR= insulin receptor Autoproteolysis ATP proteolysis Killer lymphocytes

27 Evidence of a Genetic Basis for Cancer  The cancerous state is clonally inherited.  Some types of viruses can induce the formation of tumors in experimental animals.  Cancer can be induced by mutagens.  Certain types of white blood cell cancers are associated with particular chromosomal abnormalities. © John Wiley & Sons, Inc.

28 Cancer and Genes  Oncogenes are genes that, when mutated, actively promote cell proliferation.  Tumor suppressor genes are genes that, when mutated, fail to repress cell division. © John Wiley & Sons, Inc.

29 Oncogenes … the overexpression of certain genes …the abnormal activity of certain genes …their mutant protein products. © John Wiley & Sons, Inc.

30 Tumor-Inducing Retroviruses and Viral Oncogenes  Retroviruses have an RNA genome.  The Rous sarcoma virus, the first tumor- inducing virus, contains four genes –gag encodes the capsid protein of the virus –pol encodes the reverse transcriptase –env encodes a viral envelope protein –v-src encodes a protein kinase that inserts into the plasma membranes of infected cells. The v- src gene is an oncogene that is responsible for the virus’s ability to induce abnormal cell growth. © John Wiley & Sons, Inc.

31 Proteins Encoded by Viral Oncogenes  Growth factors similar to those encoded by cellular genes  Proteins similar to growth-factor and hormone receptors  Tyrosine kinases that do not span the plasma membrane  Transcription factors homologous to cellular proteins  Any protein © John Wiley & Sons, Inc.

32 Human?

33 Proto-Oncogenes  The proteins encoded by viral oncogenes are similar to cellular proteins with important regulatory functions.  These cellular homologues are called proto- oncogenes or normal cellular genes.  The normal c-oncogenes have introns; the viral v-oncogenes often lack introns.  From c-onco to v-onco….. Replication- defective virusesReplication- defective viruses © John Wiley & Sons, Inc.

34 Replication-defective virus Normal gene Cell-oncogene (c-onc)

35 The Transfection Test to Identify Mutant Cellular Oncogenes © John Wiley & Sons, Inc.

36 Viral Oncogenes and Cancer  Some viral oncogenes produce more protein than their cellular counterpart.  Other viral oncogenes express their proteins at inappropriate times.  Other viral oncogenes express mutant forms of the cellular proteins. © John Wiley & Sons, Inc.

37 The c-ras Gene  The c-H-ras oncogene was identified by the transfection test (homologue to the Harvey strain of the rat sarcoma virus)  The mutant c-H-ras protein has a mutation that impairs its ability to hydrolyze GTP. This keeps the mutant protein in an active signaling mode and causes it to stimulate cell division.  Mutant versions of c-ras have been found in many types of tumors. © John Wiley & Sons, Inc.

38 Normal Ras Protein Signaling © John Wiley & Sons, Inc.

39 Mutant Ras Protein (V12 or G12V) is Unregulated © John Wiley & Sons, Inc.

40 Mutations in c-ras are Dominant  A single mutant c-ras allele is dominant in its ability to bring out the cancerous state.  Mutations in c-ras and other oncogenes are dominant activators or uncontrolled cell growth.  Most dominant activating mutations in cellular oncogenes occur spontaneously in somatic cells, not in the germline. © John Wiley & Sons, Inc.

41 Cancer is the Result of Several Mutations  A single mutation usually does not result in cancer.  Usually several genes that regulate cell growth are mutated before a cancerous state results. © John Wiley & Sons, Inc.

42 Chromosome Rearrangements: The Philadelphia Chromosome  The Philadelphia chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 with breakpoints in the c-abl gene on chromosome 9 and the c-bcr gene on chromosome 22.  The fusion gene created by this rearrangement encodes a tyrosine kinase that promotes cancer in white blood cells. © John Wiley & Sons, Inc.

43 The Philadelphia Chromosome © John Wiley & Sons, Inc.

44 Chromosomal Rearrangements: Burkitt’s Lymphoma  Burkitt’s lymphoma is associated with reciprocal translocations involving chromosome 8 and a chromosome carrying an immunoglobulin gene (2, 14, or 22).  The translocations juxtapose c-myc to the genes for the immunoglobulin genes, causing overexpression of c-myc in B cells.  The c-myc gene encodes a transcription factor that activates genes for cell division. © John Wiley & Sons, Inc.

45 A Reciprocal Translocation Involved in Burkitt’s Lymphoma © John Wiley & Sons, Inc. 8p21.1

46 Tumor Suppressor Genes Many cancers involve the inactivation of genes whose products play important roles in regulating the cell cycle. © John Wiley & Sons, Inc. C-ras and c-myc……genes required for regulation cell cycle. -increase activity and/or concentration-----oncogene----may form tumors. -decrease activity and/or concentration----anti-oncogene----not tumor formation

47 Knudson’s Two-Hit Hypothesis  When tumor suppressor genes are mutated, a predisposition to develop cancer often follows a dominant pattern of inheritance.  The mutation is usually a loss-of-function mutation in the tumor suppressor gene.  Cancer develops only if a second mutation in somatic cells knocks out the function of the wild-type allele. © John Wiley & Sons, Inc.


49 Verification of the Two-Hit Hypothesis for Retinoblastoma  Several cases of retinoblastoma are associated with a small deletion in chromosome 13q. Mapping refined the RB locus to 13q14.2.  Positional cloning was used to isolate a candidate RB gene that encodes a protein that interact with transcription factors that regulate the cell cycle.  In retinoblastoma cells, both copies of this gene were inactivated.  In cell culture, expression of a wild-type RB allele could revert the phenotype of cancer cells. © John Wiley & Sons, Inc.


51 Cellular Roles of Tumor Suppressor Proteins  The proteins encoded by tumor suppressor genes are involved in  cell division,  cell differentiation,  programmed cell death,  DNA repair. © John Wiley & Sons, Inc.

52 pRB Regulates the Cell Cycle © John Wiley & Sons, Inc. --Retinoblastoma, small-cell lung carcinomas, osteosarcomas, bladder, cervical and prostate carcinomas. --Essential for life. --105 KDa. --Nuclear Protein. --Alter cell cycle.



55 p53 Regulates Cell Cycle and Apoptosis  The p53 tumor suppressor protein is encoded by the TP53 gene (53 KDa).  Inherited mutations in TP53 are associated with Li-Fraumeni syndrome.  Somatic mutations that inactivate both copies of TP53 are associated with the majority of cancers. © John Wiley & Sons, Inc.

56 p53 is a Transcription Factor  Most mutations in that inactivate p53 are in the DNA- binding domain (DBD) and impair its ability to bind enhancer sequences in its target genes. Mutations in this domain are “lost-of-function.”  OD: homo-oligomerazation domain. Mutations in this domain are “dominant negative.”  TAD: transcriptional activation domain © John Wiley & Sons, Inc.

57 The Cellular Function of p53  Expression of p53 is very low in normal cells.  Expression of p53 increases in response to DNA damage due to a decrease in degradation.  p53 can inhibit cell division or induce apoptosis. © John Wiley & Sons, Inc.

58 [ increase ] p-p53

59 pAPC controls proliferation and differentiation of cells.  pAPC mutations are associated with adenomatous polyposis coli, which often leads to colorectal cancer.  pAPC regulates the renewal of cells in the epithelium of the large intestine. Loss of pAPC function results in the formation of polyps.  pAPC binds to  catenin, which binds to transcription factors. Cells with mutations in pAPC lose their ability to control  catenin levels.  Familial adenomatous polyposis (FAP):rare autosomal dominant dissease.

60 pAPC © John Wiley & Sons, Inc.


62 phMSH2 regulate genome- wide instability  The phMSH2 protein is a homologue of the bacterial and yeast MutS protein, which is involved in DNA repair.  Mutations in the hMSH2 gene are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a dominant autosomal condition.  Cells in HNPCC tumors exhibit genetic instability. © John Wiley & Sons, Inc.

63 pBRCA1 and pBRCA2 regulate DNA repair.  Mutations in the tumor suppressor genes BRCA1 (Ch17) and BRCA2 (Ch13) have been implicated in hereditary breast and ovarian cancer.  Both genes encode proteins that are localized in the nucleus and have putative transcriptional activation domains.  pBRCA1 and pBRCA2 may be involved in DNA repair in human cells. © John Wiley & Sons, Inc.

64 Genetic Pathways to Cancer Cancers develop through an accumulation of somatic (not a single) mutations in proto- oncogenes and tumor suppressor genes. © John Wiley & Sons, Inc.

65 Multiple Mutations in Cancer  Most malignant tumors cannot be attributed to mutation of a single gene.  Tumor formation, growth, and metastasis depend on the accumulation of mutations in several different genes.  The genetic pathways to cancer are diverse and complex. © John Wiley & Sons, Inc.

66 Pathway to Metastatic Colorectal Cancer © John Wiley & Sons, Inc. Carcinoma-epithelial cells. Adenoma-glandular cells.

67 Pathway to Androgen- Independent Prostate Cancer © John Wiley & Sons, Inc.

68 Hallmarks of Pathways to Malignant Cancer 1.Cancer cells acquire self-sufficiency in the signaling processes that stimulate division and growth. 2.Cancer cells are abnormally insensitive to signals that inhibit growth. 3.Cancer cells can evade programmed cell death (apoptosis). © John Wiley & Sons, Inc.

69 4.Cancer cells acquire limitless replicate potential. 5.Cancer cells develop ways to grow themselves. 6.Cancer cells acquire the ability to invade other tissues and colonize them. © John Wiley & Sons, Inc.

70 Somatic Mutation and Cancer  Somatic mutation is the basis for the development and progression of all types of cancer.  As mutations accumulate and cells become unregulated, genetic instability increases the likelihood that the cells will develop the hallmarks of cancer. © John Wiley & Sons, Inc.

71 Interaction of Ti plasmid DNA with the plant genome Bacteria genetically engineer plants to control their differentiation (tumorigenic) and production of opines that can only be catabolized by the infecting Agrobacterium strain. HOOC-C-NH-C-COOH R1 R2 HH

72 T-DNA transfer, single strand invasion

73 Transfer of T-DNA resembles bacterial conjugation T-DNA is generated when a nick at the right boundary creates a primer for synthesis of a new DNA strand. The preexisting single-strand that is displaced by the new synthesis is transferred to the plant cell nucleus. Transfer is terminated when DNA synthesis reaches a nick at the left boundary. The T-DNA is transferred as a complex of single-stranded DNA with the VirE2 single-strand binding protein. The single stranded T-DNA is converted into double-stranded DNA and integrated into the plant genome. The mechanism of integration is not known. T-DNA can be used to transfer genes into a plant nucleus (transformation).

74 T-DNA transfer to host

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