Mechanisms Of Cancer Development And Progression PDF

Mechanisms of Cancer Development and Progression Dr. Van Den Berg How does cancer start? (carcinogenesis) Acquire a gene mutation -Loss of a gene (loss of function) Cancer Causing Mutations DNA Repair Mechanisms and Response Carcinogenesis: DNA Damage 1. Point mutations (K-ras oncogene in lung cance...

Mechanisms of Cancer Development and Progression Dr. Van Den Berg How does cancer start? (carcinogenesis) Acquire a gene mutation -Loss of a gene (loss of function) Cancer Causing Mutations DNA Repair Mechanisms and Response Carcinogenesis: DNA Damage 1. Point mutations (K-ras oncogene in lung cancer) 2. Gene deletion (eg., suppressor/repair gene ~ loss of chromosome 17q, causing p53 gene deletion in colon cancer) 3. Chromosomal translocation (broken ends, joined incorrectly) a. (t9:22) ~ Chronic myeloid leukemia (CML) The new chromosome is called the ‘Philadelphia chromosome’ – The fusion protein produced is called BCR-ABL The tyrosine kinase activity of the ABL in not regulated Imatinib (Gleevec) is an inhibitor of this tyrosine kinase Dasatinib (Sprycel) is now available for imatinib-resistant CML b. (t8:14) ~ Burkitt’s lymphoma (translocates the myc oncogene) DNA Repair Mechanisms Tumor Suppressor Function is Often Lost in Cancer ATM-Ataxia-telangiectasia Loss of function of tumor suppressor proteins leads to unregulated cell proliferation and cell survival Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Oncogenes-cancer causing genes 1. Over 100 have been identified 2. Growth promoting genes in human genome 3. Are a necessary part of normal cell growth (protooncogenes) 4. Are part of cells’ signal transduction pathway (ex. Tyrosine kinase) 5. Incorrect expression results in unregulated cell growth 6. Often exists in two forms - cellular & viral 7. “Oncogene addiction” is a term used when tumor growth is primarily dependent upon a specific oncogene activity Gain of function of Function Effects: Oncogenes Oncogenes are popular targets for molecular targeted drugs https://www.google.com/search? q=oncogenes&espv=2&source=lnms&tbm=isch&sa=X&ved=0ahUKEwi81c- Sustaining Proliferative Signal Receptor Tyrosine Kinase Signaling A Few Important for Cancer PTEN Epidermal Growth Factor Receptor (EGFR) Human Epidermal Receptor 2 (HER2) Insulin-like Growth Factor-I Receptor (IGF-IR) Platelet-Derived Growth Factor Receptor (PDFGR) Vascular Endothelial Growth Factor Receptor (VEGFR) Proliferation in the cancer cell Hyper-responsive growth factor receptor pathways (Oncoproteins) 1. Tumor cell can synthesize more growth factor (ligand) to activate its own receptors (autocrine signaling) 2. Tumor manipulates surrounding tissue to synthesize growth factor to stimulate tumor growth (paracrine signaling) 3. Tumor cell elevates expression of the growth factor receptor: Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer 4. Tumor cell may express a receptor that is structurally altered (mutated) making it continuously active without ligand: Epidermal Growth Factor Receptor (EGFR) in lung cancer 5. Downstream kinases (transducers) may develop receptor independent activity B-Raf in melanoma Sustaining Proliferative Signal Reproductive Hormone Receptors In breast cancer: Estrogen Receptor (ER) and Progesterone Receptor (PR) ER ER In prostate cancer: Androgen Receptor (AR) Proliferation Sustaining Proliferative Signal Cycli nB Growth factor and hormone signaling increase expression of Cyclins (A, B, D and E) and CDKs promote cell cycle progression Cycli n D, E CDK-Cyclin Dependent Kinase Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Evading Growth Suppressors Tumor Suppressors Food for thought.... JM is a patient who works in a coal mine for 20 years and he has a 30 year history of smoking. He develops lung cancer which is surgically removed. Studies of his tumor show it expresses amplified c-myc. Is c-myc an oncogene or tumor suppressor? A. oncogene B. tumor suppressor C. I have no idea, I’m not an oncologist! His tumor also shows a deletion of the PTEN gene. Is PTEN an oncogene or tumor suppressor A. oncogene B. tumor suppressor C. I have no idea, I’m not an oncologist! Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Limitless Replication Mammalian cells carry an intrinsic program that limits replication – This process is independent of other cell signaling stimuli. – Cells have a certain number of doublings and then stop growing ~ this is called senescence Normally, telomeres at the ends of chromosomes shorten over time, then cause senescence – Most cancers maintain their telomere length This permits unlimited growth ~ immortalized Limitless Replication Telomere’s role in cell proliferation and aging Limitless Replication Telomere’s role in cell proliferation and aging Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Evading Apoptosis Apoptosis ~ programmed cell death – Represents a major form of cell attrition Acquired resistance to apoptosis is key for most tumors Caspases (proteases) (particularly caspase 8 & caspase 9) are responsible for activating the cell death program – Bcl-2 up-regulation in follicular lymphoma dampens the apoptotic stimulus – Inactivation of the p53 tumor suppressor protein Evading Apoptosis Caspases cleave cellular proteins and DNA Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Sustained Angiogenesis (neo-) Angiogenesis is the process of growing new blood vessels All tumors that grow beyond normal limits will need a blood supply providing food and O2 – This process is carefully regulated Angiogenic growth factors (over 20 known factors) are synthesized and released by the hypoxic tumor – Vascular endothelial growth factors (VEGF) – Fibroblast growth factor (FGF) – Platelet-derived growth factor (PDGF) – Transforming growth factor (TGF α and β) – Angiopoietin-1 By blocking the receptors for these growth factors you can block angiogenesis and tumor growth Sustained Angiogenesis Sustained Angiogenesis -Sustains growth of primary tumor -Facilitates metastasis Sustained Angiogenesis Hallmarks of Cancer: What Does It Take for a Tumor to Succeed? Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Activating Invasion and Metastasis The hallmark of most malignant cancers are their ability to metastasize ~ spread to distant regions of the body – Metastasis is responsible for 90% of cancer deaths (not the primary tumor - which in some cases can be removed) Cell adhesion molecules (CAM’s) are required to anchor cells to adjacent tissue – Belong to the immunoglobulin & calcium-dependent cadherin (E-cadherin) family – E-cadherin function is lost in many epithelial cancers Activation of extracellular proteases Tumor Heterogeneity Activating Invasion and Metastasis Ensures normal tissue homeostasis Emerging Hallmarks and Drug Treatment Targets Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013) Copyright © 2011 Elsevier Inc. Terms and Conditions Emerging Hallmarks: Deregulating Cellular Energetics Emerging Hallmarks Which tumor-derived growth factor(s) stimulate(s) vascular endothelial cells to create new vessels inside of the tumor? a. Epidermal Growth Factor b. Insulin-like Growth Factor c. Hepatocyte Growth Factor d. Vascular Endothelial Growth Factor Current or Future Targeted Therapies