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The Evolution of Cancer

The Evolution of Cancer. Lynn M. Matrisian, Ph.D. Dept. Cancer Biology lynn.matrisian@vanderbilt.edu June, 2011. Definitions. Metastatic. Normal. Benign. Malignant.

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The Evolution of Cancer

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  1. The Evolution of Cancer Lynn M. Matrisian, Ph.D. Dept. Cancer Biology lynn.matrisian@vanderbilt.edu June, 2011

  2. Definitions Metastatic Normal Benign Malignant • Cancer:A malignant tumor characterized by potentially unlimited growth with local expansion by invasion and systemic expansion by metastasis • Tumor: an abnormal mass, a growth • Benign: “of a gentle disposition”, not life-threatening • Malignant: “malevolent or malicious”; capable of invading and metastasizing • Metastatic:transfer to another part of the body (Webster’s)

  3. There are more than 200 different kinds of cancer Classified anatomically Men789,620 Women739,940 Prostate 28% Lung & bronchus 15% Colon & rectum 9% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin 4% lymphoma Kidney 4% Leukemia 3% Oral cavity 3% Pancreas 3% 28% Breast 14% Lung & bronchus 10% Colon & rectum 6% Uterine corpus 5% Thyroid 4% Melanoma of skin 4% Non-Hodgkin lymphoma 3% Ovary 3% Kidney 3% Leukemia 2010 Estimated US new Cancer Cases, ACS

  4. The Problem: Cancer Incidence The Bigger Problem: Cancer Mortality • Cancer is the #2 killer of Americans, and #1 killer of those under the age of 85 • >1500 people die of cancer every day in the U.S. • Cancer accounts for 1 in 4 deaths in the U.S. The Cost of Cancer • ~$263 B/year ($102B medical costs) • 1 in 2 men and 1 in 3 women will get cancer in their lifetime • 1.5M cancers were diagnosed in 2010 not including non-melanoma skin cancers (>2M) • 78% of cancers are diagnosed at age 55 and older • Approx 5% of cancer is strongly hereditary • At least 1/3 of cancers are due to tobacco use and another 1/3 are related to nutritional imbalance/inactivity/obesity ACS Cancer Facts & Figures 2010

  5. Cancer is not a new disease • Egypt, 1500 B.C.: “no cure” • Greece, Hippocrates 300 B.C.: “karkinos” • Rome, Galen 160 A.D.: “oncos”

  6. “Why is there so much more cancer than there used to be?” • Success in curing other diseases Death Rate Per 100,000 1950 2004 HeartDiseases CerebrovascularDiseases Pneumonia/Influenza Cancer * Age-adjusted to 2000 US standard population. Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality Data: US Mortality Public Use Data Tape, 2004, NCHS, Centers for Disease Control and Prevention, 2006 • Population increase • (151 to 310M, 1950-2010) Cancer Incidence Rates All Sites Combined, All Races, 1975-2008 • Life expectancy increase • (68.2 to 78.4, 1950-2008) Rate Per 100,000 Men Both Sexes Women 1975 2008 *Age-adjusted and adjusted for delay in reporting. Kohler et al, JNCI: March 31, 2011 release ACS, CDC, NCI, NAACCR

  7. Evolution of Cancer • Cellular evolution (normal to malignant) • Evolution of cancer treatment

  8. Normal vs cancer: cellular evolution Normal prostate vs prostate cancer

  9. Wheater’s Functional Histology Vanderbilt Cell and Tissue Biology Breast and prostate: cells that line the ducts that lead to the outside of the body Vanderbilt Cell and Tissue Biology Cancer commonly occurs in epithelial cells Lung and skin: cells in contact with air Colon and bladder:cells in contact with food and its breakdown products

  10. Exposure to carcinogens (cancer-causing agents) can initiate tumor evolution Metastatic Normal Benign Malignant Skin: UV irradiation from the sun Lung: Cigarette smoke Prostate and breast: ? Sometimes mistakes just happen! 10-6/gene/cell div

  11. Evolution “Tumor development proceeds via a process formally analogous to Darwinian evolution, in which a succession of genetic changes, each conferring one or another type of growth advantage, leads to the progressive conversion of normal human cells into cancer cells.” Foulds 1954 Nowell 1976

  12. Cancer is progressive and cumulative

  13. T T G A T G Mutations T T C A T G

  14. AGCGTTCGATGACC AGCGTCCGATGACC DNA Mutation RNA Cell behaves different! Protein Nucleotides DNA Genes Chromosomes Cell nucleus

  15. How cancer cells behave differently: the Hallmarks of Cancer No longer needs to be told to grow Ignores signals to not grow Ignores signals to die Feeds itself: Calls in new blood vessels Invades and metastasizes Never grows old Hanahan and Weinberg, Cell, 2000

  16. T T G A T G Invades and metastasizes The evolution of cancer cells Ignores signals to die No longer needs to be told to grow Chromosomes break DNA mutations

  17. Cancer can be local, regional, or systemic – it evolves Local Systemic Regional Lymphatics & lymph nodes Why curing cancer has been tricky!

  18. The evolution of cancer treatment • Black bile: no reason to remove it • Blood letting, leeching, purging • Surgery • 1846 Boston – anesthesia (ether) • 1869 Scotland – antiseptic (carbonic acid) • 1900: Baltimore – William Halsted “mistaken kindness” • Radiation • 1896 Chicago – Emil Grubb X-rays • 1902 Paris - Marie Curie radium The Emperor of All Maladies, Siddhartha Mukherjee

  19. The evolution of cancer treatment • Chemotherapy • Germany, 1878 Paul Ehrlich stains bacteria with dyes and speculates on “magic bullets” • Boston: 1950’s Sidney Farber treats leukemia with a drug that inhibits cell growth • Rapid evolution of cytotoxic therapies for systemic disease The Emperor of All Maladies, Siddhartha Mukherjee

  20. Evolutionary parallels Local Regional Systemic Surgery Radiation Chemotherapy All are designed to eliminate growing cells

  21. T T G A T G What’s next? Design a drug that attacks the behavior associated with that mutation

  22. Targeted cancer therapy Her2/neu EGF Receptor Abl Herceptin Iressa & Tarceva Gleevec Signal to grow

  23. Individualized Cancer Therapy Targeted therapies Treatment A Molecular Diagnostics Treatment B Test for specific mutation Treatment C Treatment D Many magic bullets?

  24. Some good news • The 5-year survival rate for cancer is 67.4% (2001-2007, up from 50% in 1975-1977, varies by race/ethnicity) • There are 11.4M cancer survivors (2006 data) • The number of cancer deaths is DECREASING! Male 21% decrease 1991-2006 Female 12.3% decrease 1991-2006 • 767,000 cancer deaths avoided • decrease in tobacco use in men • improved early detection • improved treatment ACS Cancer Facts & Figures 2010, CA Cancer J Clin 60, 2010

  25. Scientific evolution Local Regional Systemic Surgery Radiation Chemotherapy Individualized cancer therapy

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