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The Molecular Biology of Cancer • What is cancer? • What is molecular biology? • What role does molecular biology play in cancer? What is cancer? • A cancer cell is: “…a savage cell that somehow corrupts the forces that normally protect the body, invades the well-ordered society of cells surrounding it, colonizes distant areas, and, in a finale to its cannibalistic orgy of flesh-consumingflesh, commits suicide by destroying its host.” Pat McGrady, The Savage Cell What is cancer? • The number two killer in the U.S. • Right behind heart disease. US Mortality, 2006 Rank Cause of Death No. of deaths % of all deaths • 1. Heart Diseases 631,636 26.0 • 2. Cancer 559,888 23.1 • 3. Cerebrovascular diseases 137,119 5.7 • 4. Chronic lower respiratory diseases 124,583 5.1 • 5. Accidents (unintentional injuries) 121,599 5.0 • 6. Diabetes mellitus 72,449 3.0 • 7. Alzheimer disease 72,432 3.0 • 8. Influenza & pneumonia 56,326 2.3 • 9. Nephritis* 45,344 1.9 • 10. Septicemia 34,234 1.4 2009 Estimated US Cancer Cases* Men 766,130 Women 713,220 Prostate 25% •27% Breast Lung & bronchus 15% •14% Lung & bronchus Colon & rectum 10% •10% Colon & rectum Urinary bladder 7% • 6% Uterine corpus Melanoma of skin 5% Non-Hodgkin lymphoma 5% • 4% Non-Hodgkin lymphoma Kidney & renal pelvis 5% • 4% Melanoma of skin Leukemia 3% • 4% Oral cavity 3% • 3% Kidney & renal pel Pancreas 3% • 3% Ovary All Other Sites 19% Thyroid • 3% Pancreas •22% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2009. What is cancer? • Malfunction of the control systems that regulate cell growth and death grow divide “Mother” Cell “Daughter” Cells Cell Proliferation & death in the Adult • Human body (~150 lbs) consists of about 1 x 1014 cells (100 trillion). • Each day we lose and replace a number of cells that corresponds to ~2.5 lbs. • Certain cells in the mucosal lining of the intestine are replaced 4,400 times during our life. This represents ~25 miles of intestine. • Epidermal cells are replaced about 1,000 times and connective tissues are replaced about 400 times. • Bone marrow weighs on average 3.2 lbs. Its turnover time is two weeks. During our lifetime, we produce 3 tons of bone marrow. What controls cell growth and death? • Proteins! • Oncogenes produce proteins Onc (oncoproteins) that promote growth. • Tumor suppressors = proteins that TS inhibit growth or promote cell death TS die grow divide “Mother” Cell Onc “Daughter” Cells X What is molecular biology? • The study of the production of proteins, using the instructions written in genes. • In other words, genes are blueprints for making proteins. • We say a gene “codes for” a protein, or “encodes” a protein, because the instructions are written in code: the genetic code. Basic Gene Expression genome cell chromosomes genes DNA proteins Proteins act alone or in complexes to perform many cellular functions Genes contain instructions for making proteins Basic Gene Expression gene: ---TTCAAGTGG--- ---AAGTTCACC--Transcription mRNA: ---UUCAAGUGG--Translation protein: ---Phe Lys Trp--- Mutation gene: ---TTCAATTGG--- ---AAGTTAACC--Transcription mRNA: ---UUCAAUUGG--Translation protein: ---Phe Asn Trp--- How do mutations arise? • DNA replication machinery makes mistakes (G-C becomes T-A). • DNA becomes damaged. (DNA in each cell receives >104 lesions every day.) • This damage forces mistakes during DNA replication, which converts the damage to mutations. Fig. 20.28 What damages DNA? • Chemicals – Environmental agents (cigarette tar) – Cellular agents (oxygen is toxic!) • Radiation – UV (Strong sunlight induces about 100,000 lesions per exposed skin cell per hour.) – Ionizing radiation (e.g., x-rays) causes chromosome breaks (very toxic!) Fig. 20.29 Why do mutations matter? • Mutations can activate oncogenes. – For example, a translocation fuses the bcr and abl genes, activating the abl oncogene. Chronic myelogenous leukemia (CML) results. Unique translocation in Chronic Myelogenous Leukemia (CML) gleevec = Druker, B. J. Blood 2008;112:4808-4817 Copyright ©2008 American Society of Hematology. Copyright restrictions may apply. Onc Why is bcr-abl an oncogene? • The abl gene codes for a membrane receptor with protein tyrosine kinase activity (Abl). • A protein tyrosine kinase puts phosphate groups on the amino acid tyrosine in proteins. • The Abl protein is at the beginning of a signal transduction pathway that leads to activation of genes that promote cell division. Fig. 12.36 Why is bcr-abl an oncogene? • The abl gene codes for a membrane receptor with protein tyrosine kinase activity (Abl). • A protein tyrosine kinase puts phosphate groups on the amino acid tyrosine in proteins. • The Abl protein is at the beginning of a signal transduction pathway that leads to activation of genes that promote cell division. • Bcr-Abl constantly sends the growth signal. • Thus, the pathway loses control; cells divide without control; cancer gets started. Why do mutations matter? • Mutations can activate oncogenes. – E.g., a translocation fuses the bcr and abl genes, activating the abl oncogene. Chronic myelogenous leukemia (CML) results. • Mutations can inactivate tumor suppressor genes. – E.g., inactivation of the p53 gene leads to many cancers, including breast cancer – Congenital p53 mutation = Li-Fraumeni syndrome. Most mutations that cause cancer are not inherited. • Cancer incidence changes over time. • Migration and altered environment or lifestyle can alter cancer incidence. • Identical twins typically do not develop the same cancers. • World Health Organization and American Cancer Society estimate 60-90% of all cancer cases are due to environmental factors [chemicals, diet, exercise, sun exposure, tobacco use]. Biological attributes (“hallmarks”) shared by most cancers • Generate their own mitogenic signals. • Resist exogenous growth-inhibitory signals. • Evade apoptosis (programmed cell death). Apoptosis A cell fate that plays a key role in embryonic development (e.g. cells between digits, loss of tadpole tail), but also in the maintenance of adult tissues… “From 50 to 70 billion cells die each day due to apoptosis in the average human adult. In a year, this amounts to the proliferation and subsequent destruction of a mass of cells equal to an individual's body weight” (see "Cell Proliferation, Differentiation, and Apoptosis" by Michael Andreeff ''et al.'' in ''Cancer Medicine'', 5th Edition) Biological attributes “hallmarks” shared by most cancers • Generate their own mitogenic signals. • Resist exogenous growth-inhibitory signals. • Evade apoptosis (programmed cell death). • Acquire genomic instability. • Mutation rate increases. • Cells become aneuploid (non-standard number of chromosomes). Protect the Chromosomes • The corrupted genomes of most human epithelial cancers are, like the Yucatan crater formed by the meteor that wiped out the dinosaurs, unambiguous relics of some catastrophic calamity within the tumor cell, a salient reminder of the genomic abyss that opens when the mechanisms that maintain chromosomal integrity fail or are overridden. – Laura Soucek and Gerard Evan (2002) Biological attributes “hallmarks” shared by most cancers • Generate their own mitogenic signals. • Resist exogenous growth-inhibitory signals. • Evade apoptosis. • Acquire genomic instability. • Proliferate without limits (i.e. undergo immortalization). • Acquire vasculature (i.e. undergo angiogenesis). Dr. Judah Folkman “Father of angiogenesis research” 1933 - 2008 Biological attributes “hallmarks” shared by most cancers • • • • • • • Generate their own mitogenic signals. Resist exogenous inhibitory signals. Evade apoptosis. Acquire genomic instability. Proliferate without limits. Acquire vasculature. Invade and metastasize (in more advanced cancers). • Evade elimination by immune system. Control Issues: Cancer At least 5 mutations Normal Cell Cancer Cell Obeys strict rules Divides only when told to Dies rather than misbehaving Stays close to home Disobeys rules Divides at will Bad behavior doesn’t kill Wanders through body Careful with chromosomes Careless with chromosomes Cancer: Is there any good news? Cancer Death Rates* Among Men, US,1930-2005 100 Rate Per 100,000 Lung & bronchus 80 60 Stomach Prostate 40 Colon & rectum 20 Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008. 2005 2000 1995 1990 1985 1980 1975 1970 1965 1960 Liver 1955 1950 1945 1940 1935 0 1930 Leukemia Cancer Death Rates* Among Women, US,1930-2005 100 Rate Per 100,000 80 60 Lung & bronchus 40 Uterus Breast Colon & rectum Stomach 20 Ovary *Age-adjusted to the 2000 US standard population. Source: US Mortality Data 1960-2005, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2008. 2005 2000 1995 1990 1985 1980 1975 1970 1965 1960 1955 1950 1945 1940 1935 Pancreas 1930 0 Cancer death rate dropped nearly 20 percent in 15 yr. • American Cancer Society estimates 650,000 lives spared from cancer 1990 to 2005 • Cancer death rate for men dropped 19.2% – Decreased lung, prostate and colon cancer deaths • Cancer death rate for women dropped 11.4% – Decreased breast and colorectal cancer deaths • The 5-year survival rate for breast cancer is approaching 90% Gleevec • • • • Trade name for Imatinib mesylate. Developed by Novartis. Approved by FDA in 2001. Targets the active site of the Bcr-Abl protein kinase and inhibits the enzyme. Success of Gleevec CML New Cases Deaths 1997 2008 4300 4830 2400 450 •The annual mortality rate has been reduced from 15-20% to 2% •Estimated median survival rate is expected to exceed 20 years based on current data Acknowledgment • I am grateful to Dr. Kristi Neufeld, who prepared some of these slides for her presentation at last year’s Mini College.