Common Definitions of Cancer Biology Terms (PDF)
How To Read Scientific Papers Online Resource
Student Weekly Questions
A collection of student questions on the weekly readings is compiled in the following table.
|WEEK #||TOPICS||READINGS||STUDENT QUESTIONS|
|2||Genetic Pathways in Cancer||
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.
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.
Vogelstein, et al.
(1) These people seemed to look at many tumors but the author still says that “it will require studies of a much larger number of tumors…etc etc” to get more specific results. So how do people decide what is an appropriate number of things to study? I know about the Chi squared test (or something like that) from my genetics class, but don’t know much else.
(2) I have questions concerning the allelic-deletion methods section. The main question being is it known if the specific chromosomes were already mapped so that the proper restriction enzymes were known? If not, how is this process done? Also, I was hoping to have the complete process explained from the DNA extract from the tumor/colonic mucosa to the analysis of the autoradiograph. Could FISH be used to detect the deletions from the extracted DNA and not metaphase spreads?
(3) Could there by any consequences or changes to the results if they allelic deletion compared “both-alleles” allelic deletions versus just the loss of one allele?
_Chin, et al.
(2) I was wondering what exactly a ras mutation is, and I am hoping we can discuss it in class.
(3) These people seemed to say that the mouse model would be accurate for humans because the p53 gene and INK4a gene acts the same in both cases. Is this really enough to justify the accuracy of the model? Is this a standard bio thing? Did I miss any additional arguments made in the paper?
(4) The paper states that there is a high level of p19ARF in p53 deficient cells and that there is the possibility of a regulatory feedback loop. Could we discuss this and what it means in detail and how this could lead to further research?
(5) What do they mean by the sentence “Although mice null for the ink4a homolog develop a cancer-prone condition, etc.”? It seems that this statement counters the hypothesis and results they show about the ink4-melanoma relationship.
(6) On the “Cooperative Effects. . .” paper, they talk about the fact that several potential hot spots have been uncovered on the chromosome supporting the view that predisposition to melanoma appears to have a strong genetic component. I was wondering how these hot spots were determined.
|3||Cell Cycle Control||
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.
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.
_Hartwell, et al.
(1) I am wondering how this research has been developed and expanded upon in relation to cancer biology.
(2) I am curious to know if the cell cycle is the same in all organisms, or if there is a substantial difference between human and yeast cell cycles.
Goodrich, et al.
(1) At some point in the results section, the authors state that T antigen or T antigen peptide neutralizes RB activity. Does this mean that the body’s immune system would suppress RB activity? If so, would this lead to tumors, or increase the risk of developing tumors?
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.
(1) My first question is: how does apoptosis fit into cancer biology? I’m sure the answer is very obvious, but I’m not very clear on the connection between the two.
_Hengartner, et al.
_(1) In the ced-9 paper, in the Results section, the authors state that they “determined the number of surviving cells in the anterior pharynx”, then went on to talk about the heat-shock constructs that they used. Could we go over these methods in class (i.e. how to determine the cell count and how heat-shock is used)?
(2) How does frameshift mutation help determine which of two identified ORFs corresponds to the ced-9 gene?
(3) How does one read tables of lots of DNA sequences in a useful manner?
_Lowe, et al.
_(1) As for the Lowe paper, I did not understand what we were supposed to see in Fig. 3c. It is an agarose gel of the total thymus DNA, but the picture is not very clear.
(2) Have there been more studies on what the functions of p53 are?
(3) Have there been even more categories of cell death discovered?
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.
_Strand, et al.
_(1) What is the difference between and out-of-frame vs. in-frame insertion?
(2) What types of experiments could be performed to determine whether the instability of repeats is the result of increased DNA polymerase slippage or a decrease in the efficiency of mismatch repair?
(3) What is the Fisher exact test?
(4) I did not understand the difference between DNA mismatch repair and DNA polymerase proofreading. If DNA mismatches aren’t fixed by polymerase proofreading, what are they repaired by?
(5) What is fragile X syndrome?
(6) Why did they use both out-of-frame (29 bp) and in-frame (33 bp) insertions of the poly(GT)?
_Artandi, et al.
_(1) What is the difference between clonal NRTs and non clonal NRTs and what is the significance? Would clonal NRTs be present in all metaphase spreads?
(2) What is Kaplan-Meier analysis?
(3) What does telomere PNA stand for?
(4) How does spectral karyotyping work?
(5) I could not understand why cancerous cells would reactivate telomeres, but the authors later stated that it may be needed for tumor progression. If telomere dysfunction leads to cancer, how does the cancer cell get functional telomeres for tumor progression?
(6) How many cell cycles (DNA replications) does it normally take (in humans.. and mice I guess) to completely delete the telomeres?
(7) Why did they mix in mTERC WT and hets for G1-G2 for the p53 hets (Figure 1b)?
|6||No papers to read|
|7||Tissue Specificity and Cells of Origin||
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.
_Meuwissen, et al.
_(1) What (if any) is the difference between p53 and Trp53?
(2) What is a Kaplan-Meier curve?
(3) What are Clara cells?
_Brown, et al.
_(1) Can we briefly talk about the differences between the different types of tumours (i.e. papillomas, keratoacanthomas, spindle carcinoma, etc)
(2) How exactly did they know/determine that the K5 promoter would target the transgene expression to the hair follicles?
(3) What is pan-Ras antibody, and how does it differ from anti-H-Ras antibody?
|8||Stem Cells and Cancer||
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.
_Cozzio, et al.
_(1) On p. 3033, the authors state “a cancer stem cell does not necessarily overlap with the multipotent stem cell of the tissue in which the tumor arose.” What do they mean by that statement? Do they mean there are two different types of stem cells (tissue and tumor)?
(2) In Fig. 4, they propose a model for MLL-ENL initiated leukemogenesis. Has work been done since this was published refining that model (figuring out what the question marks might be, etc)?
(3) How are titration studies done to determine transformation efficiency?
_Al-Hajj, et al.
_(1) They mentioned in the methods section that they implanted human tumors into the mice. Is this a common method of inducing tumorigenesis? Why wasn’t this method used in the other papers to produce models of human tumors?
(2) I’m not too sure on how to read Figure 4. Are they saying that the shapes are similar so the two sets produce similar cell diversities?
(3) What are xenograft models?
(4) Are NOD/SCID nude mice immunocompromised?
(5) What is the difference between micrometastatic disease and metastases?
(6) What does ESA stain for specifically?
|9||Differentiation and Cancer||
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.
_Kleinsmith, and Pierce
(1) What is the purpose of trying horse, calf, human, and mouse serum for the culture media?
Rego, et al.
(1) Is there any way to better predict interactions between treatments (what is likely to work well together, what is not)?
(2) Are there examples of other diseases that have more tailored treatments?
(3) Nude mice have been mentioned in discussion before, but what exactly are they? And what is the benefit of using them over a different strain?
|10||Metastasis and Cell-Cell Interactions||
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.
_Clark, et al.
_(1) In Table 1, what does SM, F1, F2, and F3 stand for?
(2) Why did this paper focus on RhoC as opposed to any of the other genes listed in Table 1?
(3) Could we go over Table One and explain how to interpret the micro arrays.
(4) What does it mean when the enhanced expression of the three genes in the pulmonary metastases was confirmed by RNAse protection?
(5) Specifically, what is the purpose of going from RNA to cDNA to cRNA? Why can’t the original RNA be hybridized to the micro-array?
_Yang, et al.
_(1) Why do they go through a intravasation then a extravasation stage?
(2) Any idea where the name “Twist” came from?
(3) siRNA let’s discuss & incomplete suppression
(4) What is GAPDH and why is it used as a internal control in RT-PCR?
Folkman, J., E. Merler, C. Abernathy, and G. Williams. “Isolation of a tumor factor responsible or angiogenesis.” J Exp Med. 133 (1971): 275-288.
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.
_Folkman, et al.
_(1) Why does thymus produce neovascularization?
(2) What does it mean when they say that “capillary engorgement blanched upon inhalation of ether”?
(3) What is a Millipore tube, and how was it used to introduce the TAF?
_O’Reilly, et al.
_(1) Are the units correct for the vertical axis in Figure 1? A fraction of a cell per each well?
(2) The authors mentioned that they used nonrefolded protein product in vivo because the folded decreased in volume significantly. Isn’t unfolded protein equivalent to denatured protein? How can it still have the same function?
(3) They mentioned that mice that were treated showed no evidence of drug resistance and no toxicity. Why would drug resistance be an issue at all when they’re just adding the inhibitor?
|12||Rational Design of Cancer Therapeutics||
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.
_Druker, et al.
_(1) What does it mean for a cell to be “benzidine-positive” in Figure 3?
(2) What is the purpose of the colony formation assay.
(3) If only 95% of CML patients have the bcr-abl oncogene, how can we be certain it is the cause of CML? What about the other 5% of patients?
Paez, et al.
(1) In the abstract, it says that they use “unselected tumors.” What does that mean?
(2) In Figure 3a, why do they test three cell lines with wild type EGFR? How are they different? Also, it seems that one of the wild type ones (H1666) is also sensitive to gefitinib.
(3) On the second page, third column, the authors mentioned a B-Raf protein. Is there any connection between this and Ras mutations?
|13||The Future of Cancer Research||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.|