1. Cancer – What is it? 1.What is the difference between a benign tumor and a malignant tumor? 2.What is the difference between a sarcoma and a carcinoma? 3.Cancer forms most commonly in what tissues? 4.What are some common mechanisms thought to “cause’ cancer? 5.Are some types of cancer more “curable” than others? True/False? Most cancers are derived from a single abnormal cell Most cancers develop due to a single mutation in a cell’s DNA Name at least three key properties that make cells capable of cancerous growth.

4. Tumors are generally traced to a single cell that has undergone a heritable change that gives it the ability to outgrow its neighbors. Detectable at about a billion cells or more Due to a genetic change (mutation) or an epigenetic change? Genes from maternal or paternal side, can influence the production or inhibition of other genes.

5. Normal incidence of mutation: 10 -6 mutations per gene per cell division Lifetime accumulation of mutations: 10 10 mutations in each gene So Why Isn’t Cancer More Common?

6. Tumors may progressively accumulate mutations They may grow sporadically, increasing in size when a particular advantageous mutation gives a cell a selective advantage over its neighbors Tumors may also regress if advantageous mutations do not occur and the existing cells cannot survive in the environment they create

7. What characteristics give cancer cells an advantage? Genetic instability Defective control of cell death or cell differentiation Loss of proliferation controls Ability to survive in an alien environment

9. Proto-oncogenes Tumor suppressor genes

11. How would you find the identity of an oncogene? Find a convenient “test” cell line that already has some cancer-like characteristics Extract DNA from tumor cells; fragment it; transfect test cells

12. Examples of Cancer-Critical Genes: Ras (oncogene) Myc (oncogene)

14. Find at least two abnormalities in this human karyotype. Pairs of chromosomes should be the same colors

15. What characteristics give cancer cells an advantage? Genetic instability Defective control of cell death or cell differentiation Loss of proliferation controls Ability to survive in an alien environment

17. Myeloid leukemia

18. What characteristics give cancer cells an advantage? Genetic instability Defective control of cell death or cell differentiation Loss of proliferation controls Ability to survive in an alien environment

19. Replicative cell senescence

20. What characteristics give cancer cells an advantage? Genetic instability Defective control of cell death or cell differentiation Loss of proliferation controls Ability to survive in an alien environment

22. 22 Preferential metastatic sites Primary tumourCommon distant site (s) Breast’ adenocarcinomaBone, brain, adrenal Prostate adenocarcinomaBone Lung small cell carcinomaBone, brain, liver Skin cutaneous melanomaBrain, liver, Bowel Thyroid adenocarcinomaBone Kidney clear cell carcinomaBone, liver, thyroid Testis carcinomaLiver Bladder carcinomaBrain NeuroblastomaLiver, adrenal

23. Colon adenocarcinoma in lung tissue. Glandular structure and cells very similar to colon. Necrosis internally.

24. Reason for organ selectivity Mechanistic theory: determined by the pattern of blood flow. “ Seed and soil ” theory: the provision of a fertile environment in which compatible tumor cells could grow

25. Determining factors Appropriate growth factors or extracellular matrix environment Compatible adhesion sites on the endothelial lumenal surface Selective chemotaxis at which the organ producing some soluble attraction factors to the tumor cells

27. 5 major steps in metastasis 1.Invasion and infiltration of surrounding normal host tissue with penetration of small lymphatic or vascular channels; 2.Release of neoplastic cells, either or single cells or small clumps, into the circulation; 3.Survival in the circulation; 4.Arrest in the capillary beds of distant organs; 5.Penetration of the lymphatic or blood vessel walls followed by growth of the disseminated tumor cells

28. 28 Tumor invasion 1.Translocation of cells across extracellular matrix barriers 2.Lysis of matrix proteins by specific proteinases a)MMP2 and MMP9, which cleave type IV collagen the major constituent of basement membrane, are believed to be of special importance b)Serine protease involved in ECM degradation are plasmin, plasminogen activators and cathepsin G. 3.Cell migration

29. Interaction between tumour cells and the surrounding connective tissue

31. 1.Integrin: cell-matrix adhesion Integrin can affect the transcription of MMP genes 2.E-cadherin/catenin adhesion complex: cell- cell adhesion Reduce expression of E- cadherin and catenin increase the invasiveness of tumor cells

32. p120 catenin

33. Cell migration 1.Small Rho GTPase family 2.Motility promoting factors

34. Small Rho GTPase Stimuli Cdc42 GTP Rac1 GTP Pak1 LIM kinase Cofilin Actin polymerisation MLC Kinase MLC Phosphorylation Contraction Stress fibers Detachment Filopodia Lamellipodia

35. Rho GTPase is required for the transition of invasive phenotype

36. How Can We Mimic and Study Metastasis?

38. Cancers are formed viaTumor Initiators,Tumor Promoters, or Viruses Tumor initiators – damage DNA Aflatoxin Vinyl chloride Benzene Arsenic Asbestos Tumor promoters – not mutagenic themselves; promote growth and differentiation without affecting DNA. They do this via inflammatory response – causes secretion of growth factors and proteases in the local environment. Can regress if the promoter is removed (example: warts). palytoxin thapsigargin

39. Viruses and Cancer

43. Major Treatments for Tumors (benign and metastatic) Surgery Chemotherapy Radiation New Treatments

44. Drugs http://www.chemocare.com/bio/ http://www.chemocare.com/bio/ Retinoic Acid – derivative of vitamin A; used to control cell growth and differentiation; binds to a class of nuclear receptors; used in cancers such as skin cancers, cutaneous T-cell lymphoma, acute promyelocytic leukemia, lung cancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, and head and neck cancers. Adriamycin/Doxorubicin Cancers treated with adriamycin include: bladder, breast, head and neck, leukemia (some types), liver, lung, lymphomas, mesothelioma, multiple myeloma, neuroblastoma, ovary, pancreas, prostate, sarcomas, stomach, testis (germ cell), thyroid, uterus Targets fast dividing cells of all types; antibiotic nature of these drugs destroys cells

45. Radiation (external or internal)

46. Brachytherapy