Hallmarks of Cancer III (Jahn).pdf

The Hallmarks of Cancer Stephan C. Jahn, Ph.D.  The Hallmarks of Cancer Hanahan, D. and Weinberg, R. The Hallmarks of Cancer, Cell (2000) 100, p. 57-70 Hanahan, D. and Weinberg, R. Hallmarks of Cancer: The Next Generation, Cell (2011) 144, p. 646-674 Hallmark #7: Angiogenesis Growth of n...

The Hallmarks of Cancer Stephan C. Jahn, Ph.D.  The Hallmarks of Cancer Hanahan, D. and Weinberg, R. The Hallmarks of Cancer, Cell (2000) 100, p. 57-70 Hanahan, D. and Weinberg, R. Hallmarks of Cancer: The Next Generation, Cell (2011) 144, p. 646-674 Hallmark #7: Angiogenesis Growth of new blood vessels from pre-existing ones Normal process  Angiogenesis occurs when there is an imbalance: the angiogenic switch Bergers and Benjamin Nat Rev Cancer 3. 2003 Hallmark #8: Inflammation Lawrence 2002 Nat. Rev. Immun. Inflammation Normal wound healing Immune cells appear transiently Innate immune system  Detects foreign agents  Involved in wound healing and clearing of dead cells and cellular debris Adaptive immune response  Immune system specifically detects and targets infectious agents  Supports innate immune system Cancer A wound that never heals  Hallmark #9: Evasion of the Immune System Cancer cells frequently arise in the body These cells are effectively eliminated by the immune system Tumor antigens Tumors can display 2 types of antigens/peptides: A. Tumor specific antigens B. Tumor associated antigens A) TUMOR SPECIFIC ANTIGENS Unique to tumor cells and do not occur on normal cells Usually result from: i) Mutation in tumor cells that generate altered cellular proteins ii) Expression of viral proteins Tumor antigens B) TUMOR ASSOCIATED ANTIGENS  Not unique to tumor cells  Normal antigens - “Self”- expressed at a wrong time and in a wrong way  Most tumor antigens are not specific to tumor cells but are also present on normal cells  i) Expression of oncofetal proteins  ii) Over-expression of proteins Tumor antigens B) TUMOR ASSOCIATED ANTIGENS (cont)  i) ONCOFETAL TUMOR ANTIGENS Found on normal fetal cells Appear early in embryonic development , before the immune system becomes mature If on cancer cells, they are recognized as “Non-Self” and induce an immune response Example: - Alpha fetoprotein (AFP) – liver cancer - Carcinoembryonic antigen (CEA) – 90% of patients with advanced colorectal cancer have increased serum CEA levels Tumor antigens B) TUMOR ASSOCIATED ANTIGENS (cont)  ii) PROTEIN / ONCOGENE OVER-EXPRESSION Several growth factors are over-expressed in tumor cells. These serve as tumor associated antigens. EGFR – ~100X over-expression Transferrin Receptor – Normal cells express < 8000 molecules Melanoma cells express 50,000-500,000 molecules of transferrin per cell Hallmark #10: Immortality What does this mean?  Can divide infinitely How does it relate to cancer? What kind of normal cells have this potential?  Germ cells  Stem cells > regeneration of tissue Normal cells have a “biological clock”  Normal cells have a finite number of replications before they become senescent or die  Telomere length at the end of chromosomes dictates the number of replications a cell will be able to undergo  Biological Clock Cancer cells must overcome this limitation to be able to grow infinitely  Immortalization Azmistowski17 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons Telomerase: overcoming the clock Telomerase is an enzyme that maintains telomere length Telomerase is present in 85% of cancer cells and almost all somatic cells are telomerase negative!