2. The Cell Cycle & Cancer What went wrong?!?

3. What is Cancer? Cancer is essentially a failure of cell division control or unrestrained, uncontrolled cell division and growth.

4. Keeping It All In Check 1.Proto-oncogenes normally activates cell division growth factor genes become oncogenes (cancer-causing) when over expressed if switched “ON” can cause cancer examples: Rb, p53, BRACA-1, APC 2.Tumor-suppressor genes normally inhibits cell division if switched “OFF” can cause cancer examples: src, ras, HER-2, myc

5. The Development of Cancer Cancer develops only after a cell experiences multiple key mutations or “hits” to its genome; essentially turning cell division inhibition mechanisms (Tumor Suppressor Genes) OFF and Proto-Oncogenes ON simultaneously. unlimited growth turn ON growth promoter genes ignore checkpoints turn OFF tumor suppressor genes (p53) escape apoptosis turn OFF suicide genes immortality = unlimited divisions turn ON chromosome maintenance genes promotes blood vessel growth turn ON blood vessel growth genes overcome anchor & density dependence turn OFF touch-sensor gene

6. Proto-Oncogenes The proto-oncogene can become an oncogene by a relatively small modification of its original function. There are three basic methods of activation: 1.A mutation within a proto-oncogene, or within a regulatory region (for example the promoter region), can cause a change in the protein structure, causingmutation an increase in protein (enzyme) activity a loss of regulation 2.An increase in the amount of a certain protein, caused by an increase of protein expression (through misregulation) an increase of protein (mRNA) stability, prolonging its existence and thus its activity in the cell gene duplication (one type of chromosomal abnormality), resulting in an increased amount of protein in the cell 3.A chromosomal translocation (another type of chromosomal abnormality)chromosomal translocation There are 2 different types of chromosomal translocations that can occur: 1.translocation events which relocate a proto-oncogene to a new chromosomal site that leads to higher expression 2.translocation events that lead to a fusion between a proto-oncogene and a 2nd gene (this creates a protein with increased cancerous/oncogenic activity) Examples: p53, BRACA-1, Rb, APC

7. Tumor Suppressor Genes Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following: Repression of genes that are essential for the continuing of the cell cycle. If these genes are not expressed, the cell cycle does not continue, effectively inhibiting cell division. Repression of genes Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue. CouplingDNA damage If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses to the whole organismapoptosis Some proteins involved in cell adhesion prevent tumor cells from dispersing, effectively blocking metastasis. These proteins are known as metastasis suppressors.metastasismetastasis suppressors Examples: p53, src, ras, HER-2, myc

8. What causes these mutations? Mutations in cells can be triggered by: UV radiation chemical exposure radiation exposure Excessive exposure to heat cigarette smoke pollution age genetics

9. Tumors Mass of abnormal cells Benign tumor abnormal cells remain at original site as a lump p53 has usually found a way to halt cell divisions most do not cause serious problems & can be removed by surgery Malignant tumor cells leave original site lose attachment to nearby cells carried by Circulatory and/or Lymphatic system to other tissues start more tumors = metastasis impair functions of organs throughout body

10. Traditional treatments for cancers Treatments target rapidly dividing cells radiation kills rapidly dividing cells chemotherapy stop DNA replication stop mitosis & cytokinesis stop blood vessel growth

11. New “miracle drugs” Drugs targeting proteins (enzymes) found only in cancer cells. Example; Gleevec treatment for adult leukemia (CML) & stomach cancer (GIST) 1st successful drug targeting only cancer cells without Gleevec with Gleevec