|1||Introduction||Overview and discussion of syllabus
Getting to know each other
What are you expecting to get out of the course?
Literature and database searching
Reading and analyzing a scientific paper
Introduction to some of the techniques and terminology used throughout the course
Discussion of general cancer ideas
|2||Genetic Pathways in Cancer||Multiple genetic pathways function to protect our cells from uncontrolled growth, i.e. cancer. Genes within these pathways are divided into two classes: (1) tumor suppressor genes, which normally function to suppress growth, and (2) oncogenes, which normally function to promote growth. This week we will discuss in broad terms these pathways that regulate tumor initiation and/or progression.||Vogelstein, B., E. R. Fearon, S. R. Hamilton, S. E. Kern, A. C. Preisinger, M. Leppert, Y. Nakamura, R. White, A. M. Smits and J. L. Bos. "Genetic alterations during colorectal-tumor development." N Engl J Med. 319 (1988): 525-532.
The New England Journal of Medicine
Chin, L., J. Pomerantz, D. Polsky, M. Jacobson, C. Cohen, C. Cordon-Cardo, J. W. Horner 2nd, and R. A. DePinho. "Cooperative effects of INK4a and ras in melanoma susceptibility in vivo." Genes Dev. 11 (1997): 2822-2834.
Genes and Developement
|3||Cell Cycle Control||It is essential that the different phases of the cell cycle are precisely coordinated and controlled so that one phase is completed before the next one can begin. Errors in coordination can lead to chromosomal aberrations--chromosomes or their parts can be lost, rearranged, or distributed unequally between the daughter cells. This type of alteration is often seen in cancer cells. Therefore, an understanding of how cells determine when and how to multiply or otherwise develop and of how that process can go awry is fundamental to understanding how cancer cells divide and to developing approaches that predict, prevent, or reverse a tumor's growth properties. This week we will discuss how cell cycle control genes were first identified and the role of tumor suppressors in the cell cycle.||Hartwell, L. H., J. Culotti, and B. Reid. "Genetic control of the cell-division cycle in yeast. I. Detection of mutants." Proc. Natl Acad. Sci USA 66 (1970): 352-359.
Proceedings of National Academy of Sciences
Goodrich, D. W., N. P. Wang, Y. W. Qian, E. Lee, and W. H. Lee. "The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle." Cell 67 (1991): 293-302.
|4||Apoptosis||Genetic studies with the small nematode Caenorhabditis elegans have identified a number of genes that regulate programmed cell death (apoptosis). These studies provided the first evidence that cell death is an active process that is under genetic control. Many of these worm genes have mammalian homologs that also regulate apoptosis. Elucidation of the signal transduction pathways of apoptosis has lead to the identification of specific death signaling molecules. This week we will discuss the process of apoptosis and how defects in this pathway lead to cancer.||Hengartner, M. O., and H. R. Horvitz. "C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2." Cell 76 (1994): 665-676.
Lowe, S. W., E. M. Schmitt, S. W. Smith, B. A. Osborne, and T. Jacks. "p53 is required for radiation-induced apoptosis in mouse thymocytes." Nature 362 (1993): 847-849.
Nature Publishing Group
|5||Genomic Stability||Cancers commonly have a large number of genetic changes in their genomes. In 1991, Loeb hypothesized that the basal mutation rate of human cells cannot account for the number of mutations seen in cancers. He reasoned, therefore, that cancers must acquire a "mutator phenotype." We now know that the stability of the genome can be compromised in many different ways and that defects in the ability of a cell to maintain its genome can lead to cancer. This week we will discuss two types of genomic instability: (1) instability of short, repetitive sequences due to loss of DNA mismatch repair and (2) dysfunction of telomeres, which Barbara McClintock first proposed must exist to protect chromosomes from end-to-end fusions.||Strand, M., T. A. Prolla, R. M. Liskay, and T. D. Petes. "Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair." Nature 365 (1993): 274-276.
"Erratum." Nature 368 (1994): 569.
Artandi, S. E., S. Chang, S. L. Lee, S. Alson, G. J. Gottlieb, L. Chin, and R. A. DePinho. "Telomere dysfunction promotes non-reciprocal translocations and epithelial cancer in mice." Nature 406 (2000): 641-645.
|6||No papers to read|
|7||Tissue Specificity and Cells of Origin||Although the important pathways altered in many types of cancer have been identified, most cancers arise from unidentified cell types. This is largely due to the fact that diagnosis often does not occur until cancer has reached an advanced stage. For example, there are more than seven types of epithelial cells in the lung, and it is unclear which of these is first transformed in the many subtypes of lung cancer. It remains important to determine the cellular origins of cancer in order to find markers for early tumor detection and intervention. In addition, the importance of tumor suppressor or oncogene functions within different cell types (sometimes even in the same organ) has not been defined. For example, why do mutations in one oncogene lead to pancreatic cancers, whereas mutations in a similar oncogene seem to be more important in skin cancer? This week we will discuss how mouse models of cancer have been used to explore these questions.||Meuwissen, R., S. C. Linn, R. I. Linnoila, J. Zevenhoven, W. J. Mooi, and A. Berns. "Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model." Cancer Cell 4 (2003): 181-189.
Brown, K., D. Strathdee, S. Bryson, W. Lambie, and A. Balmain. "The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted." Current Biol. 8 (1998): 516-524.
|8||Stem Cells and Cancer||It has long been hypothesized that stem cells that maintain adult tissues may be the cells in which malignancies first arise, but little evidence for this hypothesis is available. Furthermore, it has been proposed that tumors maintain a subset of cells, called tumor stem cells, that maintain the malignancy and may be responsible for therapeutic resistance. This week we will discuss the most recent advances that have now made it possible to examine these hypotheses and the implications of these findings for clinical practice.||Cozzio, A., E. Passegue, P. M. Ayton, H. Karsunky, M. L. Cleary, and I. L. Weissman. "Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors." Genes Dev. 17 (2003): 3029-3035.
Al-Hajj, M., M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F Clarke. "Prospective identification of tumorigenic breast cancer cells." Proc. Natl Acad. Sci. USA 100 (2003): 3983-3988.
|9||Differentiation and Cancer||Differentiation limits the proliferative capacity of cells; terminally differentiated cells have exited the cell cycle and exist in a quiescent state to perform any of a number of specialized functions. When cells lose the ability to differentiate they retain the ability to proliferate indefinitely. This week we will discuss how the process of differentiation relates to cancer and how certain cancer therapies work by inducing differentiation of tumor cells.||Kleinsmith, L. J., and G. B. Pierce. "Multipotentiality of single embryonal carcinoma cells." Cancer Res. 24 (1964): 1544-1551.
Rego, E. M., L. Z. He, R. P. Warrell Jr, Z. G. Wang, and P. P. Pandolfi. "Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins." Proc. Natl Acad. Sci. USA 97 (2000): 10173-10178.
|10||Metastasis and Cell-Cell Interactions||Metastasis is the process during which cancer cells spread from the organ in which they arose and establish secondary tumors in distant organs. To do so, cancer cells must subvert the mechanisms that exist to maintain appropriate interactions between cells and to define cellular boundaries. This week we will discuss several recent approaches to identify key factors controlling metastasis.||Clark, E. A., T. R. Golub, E. S. Lander, and R. O. Hynes. "Genomic analysis of metastasis reveals an essential role for RhoC." Nature 406 (2000): 532-535.
Erratum in: Nature 411: 974 (2000).
Yang, J., S. A. Mani, J. L. Donaher, S. Ramaswamy, R. A. Itzykson, C. Come, P. Savagner, I. Gitelman, A. Richardson, and R. A. Weinberg. "Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis." Cell 117 (2004): 927-939.
|11||Angiogenesis||Over thirty years ago, Dr. Judah Folkman observed that the growth and spread of cancers seemed to depend on their ability to induce formation of nearby blood vessels. Folkman called this process angiogenesis, from the Greek words angio, for vessel, and genesis, for beginning. This week we will discuss the relationship between blood vessel formation, tumor growth, and metastasis and focus of potential anti-cancer therapies that target the vascularization process.||Folkman, J., E. Merler, C. Abernathy, and G. Williams. "Isolation of a tumor factor responsible or angiogenesis." J Exp Med. 133 (1971): 275-288.
Journal of Experimental Medicine
O'Reilly, M. S., T. Boehm, Y. Shing, N. Fukai, G. Vasios, W. S. Lane, E. Flynn, J. R. Birkhead, B. R. Olsen, and J. Folkman. "Endostatin: an endogenous inhibitor of angiogenesis and tumor growth." Cell 88 (1997): 277-285.
|12||Rational Design of Cancer Therapeutics||The tremendous success of Gleevec, an inhibitor of the Bcr-Abl tyrosine kinase that is constitutively activated in chronic myelogenous leukemia (CML), in treating CML has confirmed that directed therapeutics based on cancer genetics and biology will be effective. This week we will discuss several examples of new chemotherapeutics that have emerged from cancer research.||Druker, B. J., S. Tamura, E. Buchdunger, S. Ohno, G. M. Segal, S. Fanning, J. Zimmerman, and N. B. Lydon. "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells." Nature Med. 2 (1996): 561-566.
Paez, J. G., P. A. Janne, J. C. Lee, S. Tracy, H. Greulich, S. Gabriel, P. Herman, F. J. Kaye, N. Lindeman, T. J. Boggon, K. Naoki, H. Sasaki, Y. Fujii, M. J. Eck, W. R. Sellers, B. E. Johnson, and M. Meyerson. "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy." Science 304 (2004): 1497-1500.
|13||The Future of Cancer Research||What is the future of cancer research? Will the studies we have discussed lead to means of prevention and intervention, rather than just treatment? This week we will discuss current methods of cancer screening, studies to development new tests, and other innovations for the future.
In the second half of this class, we will have a general discussion about the proposal and the articles analyzed over the course.
|Koutsky, L. A., K. A. Ault, C. M. Wheeler, D. R. Brown, E. Barr, F. B. Alvarez, L. M. Chiacchierini, and K. U. Jansen. "A Controlled Trial of a Human Papillomavirus Type 16 Vaccine." N Engl J Med 347 (2002): 1645-1651.|