cancer and oncogenes bioscience in the 21stinbios21/pdf/fall2014/lowekrentz_09242014.pdf · cancer...
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Incidence of cancer
Muta?ons collected
Ø Original hypothesis – 2 muta?ons, one in signaling and one in the nucleus.
Ø Sta?s?cal analysis says more like 5 or 6 muta?ons are probably important for most cancer in humans.
Ø Typically at least one muta?on is in a cell growth pathway.
More numbers
Ø The 5 year survival rate is now about 66% for all cancer.
Ø Overall death rates from cancer are con?nuing to decline at somewhere between 1% and 2% per year.
Ø The most progress has been made in the most common forms of cancer.
Ø But, overall deaths from cancer will likely not con?nue to drop – why?
Abili?es acquired Ø Grow rapidly Ø Dissociate from neighboring cells Ø Invade adjacent ?ssue Ø Recruit vasculature and invade blood vessels or lympha?c system
Ø Escape immune system Ø Arrest in a new loca?on Ø Get into target ?ssue Ø Proliferate in new loca?on
Carcinoma
Increased cell proliferation
Additional possible changes here include decreased ability to catch mistakes
Malignant
Epithelial to mesenchymal transition.
Cells are able to change characteristics and gain the ability to migrate across barriers or through membranes.
Cancer Evolu?on http://scienceblog.cancerresearchuk.org/2012/08/03/the-queen-in-the-hive-scientists-find-more-evidence-for-cancer-stem-cells/
One example pathway
Normal Epithelium Hyperplastic epithelium APC Less Me of DNA
Early Adenoma KRas Intermediate Adenoma Smad4
Late Adenoma p53 Carcinoma Invasion and Metastasis
But repair enzymes fix most problems
Ø If you cannot fix the all of the DNA damage, mistakes accumulate more rapidly and cancer usually starts earlier.
Ø An example when repair is not complete is individuals with Li-‐Fraumeni syndrome whose cells do not recognize damage (faulty p53).
Ø Another example is Xeroderma Pigmentosum, where pa?ents cannot repair UV damage and get skin cancer more rapidly than most people – with much less exposure
Growth factors and the cell cycle
Together these pathways control a complicated set of events that result in a balance of proteins and other factors leading to cell growth and division.
Mitogens (Accelerators)
SCF is over produced
In many Small Cell Lung Carcinoma patients, lots of SCF (stem cell factor) is produced and the cells also contain the growth factor receptor for this molecule. Therefore, continuous growth signaling occurs.
Types of genes that get mutated Ø Oncogenes – gain of func?on (accelerators)
Ø Hybrid proteins that change func?on Ø Over-‐produc?on of a protein Ø Ac?vity increases Ø CANCER ONLY NEEDS ONE BAD COPY
Ø Suppressor – loss of func?on (brakes) Ø They can’t stop growth Ø USUALLY YOU LOSE BOTH GENES if there is a defect leading to cancer
Drug An?bodies • An?bodies against growth factor receptors or mutated overac?ve forms of the receptors.
R
ü Antibodies might recruit the immune system ü Antibodies might block ligand binding to remaining receptors ü Antibodies might block receptor function
Small molecule drugs
• Small molecule inhibitors.
• Some of these small molecule drugs are ini?ally effec?ve, but cancer cells can some?mes acquire muta?ons that make them less effec?ve over ?me. Some cancer cells make pumps to dump the drugs back out.
Long term goals
• Ul?mately, targe?ng the stem cells that are cancerous rather than only the most rapidly growing cells will be important.
• Development of specific drugs based on specific cancer situa?ons is also con?nuing (personalized medicine).
• hgp://www.cancer.gov/
What we discussed.
Ø It takes mul?ple muta?ons to get cancer. Ø The collec?on of muta?ons is more rapid and complex than in typical evolu?on.
Ø Muta?ons in oncogenes and suppressors both play roles.
Ø Cancer cell development progresses over ?me, and cancer stem cells may remain.
Ø Treatments are becoming more specialized.