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basic overview of cancer cell cycle, stem-cell, cancer stem-cell Monday, January 30, 2012 • useful refs: • harvey lodish Molecular Cell Biology • robert weinberg Biology of Cancer • useful weblinks: • http://mydsn.org/docs-tools/BIO240/ Chapter-11.ppt • http://www.hugo-international.org/resources/ Isik_Yulug_Molecular_Basis_of_cancer.ppt Monday, January 30, 2012 hallmarks of cancer Monday, January 30, 2012 Fig. 25-1: Six characteristics of metastatic (malignant) tumor cells Benign tumor cells Necessary for continued are not metastatic. proliferation. Blood supply necessary for the tumor to grow and spread. Intravasation and extravasation. Necessary for continued proliferation. Requires protease activity to penetrate basement membranes and the extracellular matrix. Otherwise the tumor cells will die, Otherwise the tumor will not grow. Inhibition of one or more of these characteristics can inhibit cancer progression. Monday, January 30, 2012 CANCER cell cycle dysregulation, proliferative disorder Monday, January 30, 2012 Cell Cycle Monday, January 30, 2012 Progress in Cell Cycle is regulated by Genes ✤ (Keep in mind what would happen in cell cycle in cancer cells) Monday, January 30, 2012 Proliferative driver of cell cycle: Cyclins Expression of cyclins fluctuates at certain phases of the cell cycle Figure 8.9 The Biology Of Cancer (© Garland Science 2007) Monday, January 30, 2012 Cyclin-Cdk complex ✤ Cyclin binds to Cdk (Cyclin dependent kinase) and forms Cyclin-Cdk complex (an active enzyme that prepare cell to enter or next phase of cell-cyle by targeting certain substrate) Monday, January 30, 2012 Restric(on Point (R): Decision making point the late G1 phase of the cell cycle at which a cell commits itself to comple(ng the remaining phases of the cell cycle, remaining in G1, or exi(ng the ac(ve cell cycle and entering into Go Figure 8.10 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 UPREGULATION OF CYCLIN D BY RECEPTORS Table 8.1 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 drug ther apy $($ )$* ! " 2 " 2 ) 4 )/ * 4 4 535 5 ( 4 4 14/ 1/ - -88 8 4 Monday, January 30, 2012 Figure 1. Signal Transduction Pathways Controlled by the Activation of EGFR. Three steps can be schematically defined in the activation of EGFR-dependent intracellular signaling.2-17 First, the bin specific ligand occurs in the extracellular portion of the EGFR or of one of the EGFR-related receptors (HER2, HER3, o Dysregulation of cell cycle causes cancer Monday, January 30, 2012 Oncogenic mutation causes cancer normal cells All found in cancer cells Monday, January 30, 2012 Table 8.3 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 CyclinD1 CDK2 Overexpression causes cancer in mice MMTV-D1K2 mammary and salivary tumors. A, H&Eand trichrome-stained histologic sections of MMTVD1K2 and MMTV-neu mammary tumors. B, morphologic characterization of several representative tumors arising in the 34 (L34-) and 44 (L44-) transgenic lines. C, left, immunoblot analysis of extracts from four different MMTV-D1K2 and four different MMTV-neu mammary tumors demonstrating expression of the FLAG-tagged cyclin D1-Cdk2 transgene product (FLAG (D1K2)) and c-neu. Tumor lysates were also analyzed for the levels of Ecadherin, α-SMA, and actin as a loading control. C, center, immunoblot analysis demonstrating the hyperphosphorylation of Rb on multiple residues in a MMTV-D1K2 tumor extract relative to a MMTV-neu tumor extract. P-Rb and P-p130 represent the phospho-forms of Rb and p130, and Rb and p130 represent the corresponding unphosphorylated forms. Multiple products of E2F-dependent genes are up-regulated in the MMTV-D1K2 tumor relative to the MMTV-neu tumor including BRCA1, p107, and E2F1. Hira serves as a loading control. C, right, lysates from MMTV-neu and MMTV-D1K2 tumors were subjected to immunoprecipitation with antiFLAG–agarose to isolate complexes containing the cyclin D1-Cdk2 fusion protein. Immunoblot analysis indicated that these complexes contain the cyclin D1-Cdk2 fusion protein (FLAG), p21, p27, and PCNA. Corsino P et al. Cancer Res 2007;67:3135-3144 ©2007 by American Association for Cancer Research Monday, January 30, 2012 Summary I ✤ Proliferative driver by Proto-oncogenes ✤ Alteration of proto-oncogene becoming oncogenes drives malignancy (amplification, translocation) by pushing overexpression of cyclins ✤ Proto-oncogene: EGFR/HER1, HER2, MYC ✤ Oncogenes: EGFR Amplification, EGFR mutation, HER2 amplification, C-MYC amplification Monday, January 30, 2012 Oncogenic mutations alone are not sufficient Monday, January 30, 2012 History 1970s • Sir Henry Harris asked: • Is malignancy –Dominant, or –Recessive? • Performed cell fusion Figure 7.1 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 Harris Cell fusion experiment • the phenotype of fused cells showed loss of tumorigenicity • implied the presence of tumor supressor genes • in 1989 the first tumor supressor gene ie Retinoblastoma (RB) is cloned Monday, January 30, 2012 Retinoblastoma Gene Mutation in both Alleles causes cancer in mice and men retinoblastoma in early childhood Monday, January 30, 2012 medullary tumor of thyroid cancer in Rb ko mice Loss of Heterozygosity (LOH) is a genetic mechanism to inactivate tumor supressor gene (TSG) Monday, January 30, 2012 where does tumor supressor gene belong in cell cycle? Restriction Point (R): Decision making point the late G1 phase of the cell cycle at which a cell commits itself to comple(ng the remaining phases of the cell cycle, remaining in G1, or exi(ng the ac(ve cell cycle and entering into Go Monday, January 30, 2012 RB Phosphorylation Figure 8.19 The Biology of Cancer (© Garland Science 2007) Figure 8.19 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 RB is a key gatekeeper of G1/S transition at R point Loss of RB in precancerous cells relaxes G1/S and promotes cellular proliferation Figure 8.22 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 Figure 8.23a The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 Experimental evidence of C-MYC override TSG function of RB: Artificial C-MYC activation causes S-phase entry in quiescent cells Figure 8.29 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 E2F is controlled by RB Loss of RB function (by losing both alleles due to somatic mutation and Loss of Heterozygosity) causes unregulated entry to cell cycle Date Monday, January 30, 2012 Summary • RB gene is an important tumor suppressor gene that regulates entry into cell cycle • Passing or overriding Restriction Point to start cell cycle is achieved by phosphorylating RB Monday, January 30, 2012 Quality Control in Cell Cycle? live with (genomic) integrity or die (apoptosis) Monday, January 30, 2012 Cell Cycle Checkpoints Purpose: To maintain DNA integrity Mechanisms: Cell cycle arrest (buying time for DNA Repair) Activation of Apoptotic cell death (catastrophic DNA damage) Experimental evidence: Using yeast model, cell cycle is prolonged when yeasts are challenged with damaging agents. DNA analyses showed arrest at specific phase of cell cycle Figure 8.4 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 Monday, January 30, 2012 Monday, January 30, 2012 Monday, January 30, 2012 Figure 9.8 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 Hair loss due to cyclophosphamide Anything to do with genes? which gene is responsible? Date Monday, January 30, 2012 Note: p53 gene is knocked out in the germline using embryonic stem cell homologous recombination technique Monday, January 30, 2012 Summary II: Cell Cycle and TSGs RB p53 • RB and p53 have unique genetic and biochemical roles on controlling cell cycle • Activation of proliferation (by removing RB) also activates apoptotic machinery. Therefore, cancer cells also inactivate wild type p53 to survive Monday, January 30, 2012 CANCER genetic disorder Monday, January 30, 2012 gen sana in corpore sano • majority of cancer patients harbor somatic genetic mutations • minority of cancer patients have inherited germline genetic mutations • enviromental risks will invariably lead to somatic genetic changes • eat healthy keep mutations away (assuming your dna repair genes are intact) Monday, January 30, 2012 CANCER stem cell Monday, January 30, 2012 Monday, January 30, 2012 stem cell dna repair juice Monday, January 30, 2012 Monday, January 30, 2012 Monday, January 30, 2012 http://stemcells.nih.gov/info/2006report/2006chapter9.htm How Do Cancer Stem Cells Arise? The molecular pathways that maintain "stem-ness" in stem cells are also active in numerous cancers. This similarity has led scientists to propose that cancers may arise when some event produces a mutation in a stem cell, robbing it of the ability to regulate cell division. This figure illustrates 3 hypotheses of how a cancer stem cell may arise: (1) A stem cell undergoes a mutation, (2) A progenitor cell undergoes two or more mutations, or (3) A fully differentiated cell undergoes several mutations that drive it back to a stem-like state. In all 3 scenarios, the resultant cancer stem cell has lost the ability to regulate its own cell division. Monday, January 30, 2012 How Does Tumor Develop? Monday, January 30, 2012 CSC HIERARCHY: Are all cancer cells created equal? Dirks, P Monday, January 30, 2012 Monday, January 30, 2012 Figure 11.15 The Biology of Cancer (© Garland Science 2007) Monday, January 30, 2012 properties of cancer stem cells Monday, January 30, 2012 cancer recurrence Monday, January 30, 2012 WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor cells (blue) but may spare stem cells (yellow) that can give rise to a new tumor. In theory, killing cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance. Monday, January 30, 2012 intervention opportunity: targeting cancer stem cell Monday, January 30, 2012 Monday, January 30, 2012