An Introduction to Cancer Biology

An Introduction to Cancer Biology

An Introduction to Cancer Biology Geoff Mitchell April 24, 2007 Learning Objectives The students will be able to: Identify the 3 most prevalent cancers for a person of their gender Define cancer Explain why cancer is a genetic disease even though its heritability is rather low Compare the functions of oncogenes and tumor suppressor genes Explain why tumor suppressors are often the 1 st genes mutated in a developing cancer

List the Six Hallmarks of Cancer Describe the advantages of using modern, targeted cancer therapies US Mortality, 2003 No. of % of all deaths deaths Rank Cause of Death 1. Heart Diseases 685,089 28.0 2. Cancer 556,902 22.7

3. Cerebrovascular diseases 157,689 6.4 4. Chronic lower respiratory diseases 126,382 5. Accidents (Unintentional injuries) 109,277 6. Diabetes mellitus 74,219 3.0 7. Influenza and pneumonia

65,163 2.7 8. Alzheimer disease 63,457 2.6 1. Nephritis 42,453 1.7 10. Septicemia 5.2 34,069 1.4 4.5 2006 Estimated US Cancer Cases* Men 720,280 Women

679,510 Prostate 33% 31% Breast Lung & bronchus 13% 12% Lung & bronchus Colon & rectum 10% 11% Colon & rectum Urinary bladder 6%

6% Uterine corpus Melanoma of skin 5% 4% Non-Hodgkin lymphoma 4% Non-Hodgkin lymphoma 4% Melanoma of skin Kidney 3% 3% Thyroid

Oral cavity 3% 3% Ovary Leukemia 3% 2% Urinary bladder Pancreas 2% 2% Pancreas 18% 22% All Other Sites

All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2006. 2006 Estimated US Cancer Deaths* Lung & bronchus 31% Colon & rectum Men 291,270 Women 273,560 26% Lung & bronchus 10% 15% Breast Prostate

9% 10% Colon & rectum Pancreas 6% 6% Pancreas Leukemia 4% 6% Ovary Liver & intrahepatic bile duct 4% 4%

Leukemia Esophagus 4% 3% Non-Hodgkin lymphoma Non-Hodgkin lymphoma 3% 3% Uterine corpus Urinary bladder 3% 2% Multiple myeloma Kidney

3% 2% Brain/ONS All other sites 23% ONS=Other nervous system. Source: American Cancer Society, 2006. 23% All other sites What is cancer? Abnormal cell growth (neoplasia) Malignant as opposed to benign Benign: slow growth, non-invasive, no metastasis

Malignant: rapid growth, invasive, potential for metastasis Is cancer a heritable disease? There are heritable cancer syndromes The majority of cancers, however, are not familial Cancer is a genetic disease, but the majority of mutations that lead to cancer are somatic What causes the mutations that lead to cancer? Viruses: HPV --> cervical cancer Bacteria: H. pylori --> gastric cancer

Chemicals --> B[a]P --> lung cancer UV and ionizing radiation --> skin cancer What do these agents have in common? Mutagens Viruses: insertional mutagenesis Chemicals: DNA adducts UV and ionizing radiation: single and double strand DNA breaks What types of genes get mutated in cancer? Oncogenes are activated

Normal function: cell growth, gene transcription Tumor suppressor genes are inactivated Normal function: DNA repair, cell cycle control, cell death Phenotype of a cancer cell The Six Hallmarks of Cancer Self-sufficient growth signals Resistance to anti-growth signals Constitutively activated growth factor signalling Inactivated cell cycle checkpoint

Immortality Inactivated cell death pathway Phenotype of a cancer cell (cont'd) The Six Hallmarks of Cancer Resistance to cell death Sustained angiogenesis Activated anti- cell death signalling Activated VEGF signalling Invasion and metastasis

Loss of cell-to-cell interactions, etc. p53a classic tumor suppressor The guardian of the genome Senses genomic damage Halts the cell cycle and initiates DNA repair If the DNA is irreparable, p53 will initiate the cell death process Rba classic tumor suppressor Rb binds to a protein called E2F1 E2F1 initiates the G1/S cell cycle transition

When bound to Rb, E2F1 can't function Thus, Rb is a crucial cell cycle checkpoint Tumor suppressors Guardian(s) of the genome Often involved in maintaining genomic integrity (DNA repair, chromosome segregation) Mutations in tumor suppressor genes lead to the mutator phenotypemutation rates increase Often the 1st mutation in a developing cancer Chromosomal Instability HER2/neuan oncogene

A growth factor receptor 25-30% of breast cancers over-express HER2/neu Which hallmark of cancer does this lead to? Herceptin is used as a treatment What can cancer therapies target? Classic cancer therapies target rapidly dividing cells Target the DNA Ionizing radiation

Chemotherapy Many side effects Hair loss Weakened immune system Problems with GI tract What can cancer therapies target? A person's immune system will not target tumor cells because they appear to be self Some new therapies focus on activating one's immune system against a cancer What can cancer therapies target?

Modern, targeted therapies attack specific proteins that are abnormally expressed in a tumor May block over-expressed growth factor receptors --> Herceptin Generally, there are few side effects since these therapies are specifically targeted to cancer cells

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