The Cancer Chronicles

by George Johnson

  3. “For decades now”: Hanahan and Weinberg, “The Hallmarks of Cancer” (italics added).

  4. don’t necessarily have to occur through mutations: The seminal paper on epigenetics is Andrew P. Feinberg and Bert Vogelstein, “Hypomethylation Distinguishes Genes of Some Human Cancers from Their Normal Counterparts,” Nature 301, no. 5895 (January 6, 1983): 89–92. [http://www.nature.com/nature/journal/v301/n5895/abs/301089a0.html] For a historical overview see Andrew P. Feinberg and Benjamin Tycko, “The History of Cancer Epigenetics,” Nature Reviews Cancer 4, no. 2 (February 2004): 143–53. [http://www.ncbi.nlm.nih.gov/pubmed/14732866] Epigenetic changes in germ cells—sperm or eggs—might even be passed from parent to child, though the significance of that is uncertain.

  5. found to be mutated in different cancers: Päivi Peltomäki, “Mutations and Epimutations in the Origin of Cancer,” Experimental Cell Research 318, no. 4 (February 15, 2012): 299–310. [http://www.ncbi.nlm.nih.gov/pubmed/22182599]

  6. proposed that cancer actually begins with epigenetic disruptions: Andrew P. Feinberg, Rolf Ohlsson, and Steven Henikoff, “The Epigenetic Progenitor Origin of Human Cancer,” Nature Reviews Genetics 7, no. 1 (January 2006): 21–33. [http://www.ncbi.nlm.nih.gov/pubmed/14732866]

  7. a contentious idea called the cancer stem cell theory: Piyush B. Gupta, Christine L. Chaffer, and Robert A. Weinberg, “Cancer Stem Cells: Mirage or Reality?” Nature Medicine 15, no. 9 (2009): 1010–12; [http://www.nature.com/nm/journal/v15/n9/full/nm0909-1010.html] Jerry M. Adams and Andreas Strasser, “Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones?” Cancer Research 68, no. 11 (June 1, 2008): 4018–21; [http://cancerres.aacrjournals.org/content/68/11/4018.abstract] and Peter Dirks, “Cancer Stem Cells: Invitation to a Second Round,” Nature 466, no. 7302 (July 1, 2010): 40–41. [http://www.nature.com/nature/journal/v466/n7302/full/466040a.html] The basic idea was suggested as early as 1937 (J. Furth and M. C. Kahn, “The Transmission of Leukaemia of Mice with a Single Cell,” American Journal of Cancer 31 [1937]: 276–82), and cancer stem cells were identified in a blood cancer by Dominique Bonnet and John E. Dick: “Human Acute Myeloid Leukemia Is Organized as a Hierarchy That Originates from a Primitive Hematopoietic Cell,” Nature Medicine 3, no. 7 (July 1, 1997): 730–37. [http://www.nature.com/nm/journal/v3/n7/abs/nm0797-730.html]

  8. the more confusing it seemed: For a taste of the controversy see John E. Dick, “Looking Ahead in Cancer Stem Cell Research,” Nature Biotechnology 27, no. 1 (January 2009): 44–46; [http://www.nature.com/nbt/journal/v27/n1/full/nbt0109-44.html] Elsa Quintana et al., “Efficient Tumour Formation by Single Human Melanoma Cells,” Nature 456, no. 7222 (December 4, 2008): 593–98 [http://www.nature.com/nature/journal/v456/n7222/abs/nature07567.html]; Priscilla N. Kelly et al., “Tumor Growth Need Not Be Driven by Rare Cancer Stem Cells,” Science 317, no. 5836 (July 20, 2007): 337 [http://www.sciencemag.org/content/317/5836/337.abstract]; Richard P. Hill, “Identifying Cancer Stem Cells in Solid Tumors: Case Not Proven,” Cancer Research 66, no. 4 (February 15, 2006): 1891–96 [http://cancerres.aacrjournals.org/content/66/4/1891.abstract]; and Scott E. Kern and Darryl Shibata, “The Fuzzy Math of Solid Tumor Stem Cells: A Perspective,” Cancer Research 67, no. 19 (October 1, 2007): 8985–88. [http://www.ncbi.nlm.nih.gov/pubmed/17908998]

  9. shed their identity and reverted: One hypothesis is that they would make the transformation through the epithelial-mensenchymal transformation, which is discussed in chapter 6 of this book.

  10. the wave of the future: Three papers published in August 2012 set off a surge of publicity in favor of the theory along with a skeptical backlash. For a summary, including citations, see Monya Baker, “Cancer Stem Cells Tracked,” Nature 488, no. 7409 (August 2, 2012): 13–14.

  11. the annual meeting: American Association for Cancer Research, 102nd Annual Meeting, “Innovation and Collaboration: The Path to Progress,” April 2–6, 2011, Orange County Convention Center, Orlando, Florida.

  12. more than 16,000 scientists: “AACR Hosts Successful 102nd Annual Meeting in Orlando,” Previous Annual Meetings, AACR website. [http://www.aacr.org/home/scientists/meetings-workshops/aacr-annual-meeting-2013/previous-annual-meetings/annual-meeting-2011.aspx]

  13. an amazing video flythrough: High-definition stills and videos in two and three dimensions are available on the Amgen website.[http://angiogenesis.amgen.com]

  14. Amgen had been working on an angiogenesis inhibitor: Beth Y. Karlan et al., “Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined with Weekly Paclitaxel in Patients with Recurrent Ovarian Cancer,” Journal of Clinical Oncology 30, no. 4 (February 1, 2012): 362–71. [http://jco.ascopubs.org/content/30/4/362]

  15. extended the lives: The technical term used in the study was “overall survival.”

  16. “Judah is going to cure cancer”: Gina Kolata, “A Cautious Awe Greets Drugs That Eradicate Tumors in Mice, New York Times, May 3, 1998.

  17. “the most exciting cancer research of my lifetime”: James Watson, “High Hopes on Cancer,” New York Times, letter to the editor, May 7, 1998.

  18. “remarkable and wonderful”: Kolata, “A Cautious Awe Greets Drugs.”

  19. metastasizing more vigorously: Erika Check Hayden, “Cutting Off Cancer’s Supply Lines,” Nature News 458, no. 7239 (April 8, 2009): 686–87. [http://www.nature.com/news/2009/090408/full/458686b.html]

  20. add a few months to a patient’s life: Avastin product page, Genentech website. [http://www.gene.com/gene/products/information/oncology/avastin]

  21. the Food and Drug Administration … revoked approval: Andrew Pollack, “F.D.A. Revokes Approval of Avastin for Use as Breast Cancer Drug,” New York Times, November 18, 2011. [http://www.nytimes.com/2011/11/19/business/fda-revokes-approval-of-avastin-as-breast-cancer-drug.html]

  22. standard chemotherapy was accompanied by Herceptin: Edward H. Romond et al., “Trastuzumab Plus Adjuvant Chemotherapy for Operable HER2-positive Breast Cancer,” New England Journal of Medicine 353, no. 16 (October 20, 2005): 1673–84. [http://www.ncbi.nlm.nih.gov/pubmed/16236738] Also see Luca Gianni et al., “Treatment with Trastuzumab for 1 Year After Adjuvant Chemotherapy in Patients with HER2-positive Early Breast Cancer: A 4-year Follow-up of a Randomised Controlled Trial,” Lancet Oncology 12, no. 3 (March 2011): 236–244. [http://www.lancet.com/journals/lanonc/article/PIIS1470-2045(11)70033-X/abstract]

  23. Genentech could reduce the time to market: An early end to a clinical trial is not necessarily considered a good thing. See F. Trotta et al., “Stopping a Trial Early in Oncology: For Patients or for Industry?” Annals of Oncology 19, no. 7 (July 1, 2008): 1347–53 [http://annonc.oxfordjournals.org/content/19/7/1347.abstract]; Margaret McCartney, “Leaping to Conclusions,” BMJ: British Medical Journal 336, no. 7655 (May 31, 2008): 1213–14 [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2405859]; and Victor M. Montori et al., “Randomized Trials Stopped Early for Benefit: A Systematic Review,” JAMA: The Journal of the American Medical Association 294, no. 17 (November 2, 2005): 2203–9. [http://www.ncbi.nlm.nih.gov/pubmed/16264162]

  24. a serious risk of congestive heart failure: A study of twelve thousand women who took Herceptin found that mortality from breast cancer was reduced by one-third but that there was a fivefold increase in the risk of cardiac toxicity. See Lorenzo Moja et al., “Trastuzumab Containing Regimens for Early Breast Cancer,” Cochrane Database of Systematic Reviews 2012, issue 4, article no. CD006243, published online April 18, 2012. [http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006243.pub2/abstract]

  25. the “crowning achievement”: Scott A. Stuart, Yosuke Minami, and Jean Y. J. Wang, “The CML Stem Cell: Evolution of the Progenitor,” Cell Cycle 8, no. 9 (May 1, 2009): 1338–43. [http://www.ncbi.nlm.nih.gov/pubmed/19342894] For the story of Gleevec, see Terence Monmaney, “A Triumph in the War Against Cancer,” Smithsonian, May 2011. [http://www.smithsonianmag.com/science-nature/A-Victory-in-the-War-Against-Cancer.html]

  26. by strengthening the body’s immunological def
enses: For an overview see Ira Mellman, George Coukos, and Glenn Dranoff, “Cancer Immunotherapy Comes of Age,” Nature 480, no. 7378 (December 21, 2011): 480–89; [http://www.nature.com/nature/journal/v480/n7378/abs/nature10673.html] Drew M. Pardoll, “The Blockade of Immune Checkpoints in Cancer Immunotherapy,” Nature Reviews Cancer 12, no. 4 (April 2012): 252–64; [http://www.ncbi.nlm.nih.gov/pubmed/22437870] and David L. Porter et al., “Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia,” New England Journal of Medicine 365, no. 8 (August 10, 2011): 725–33.

  27. the patient’s own immune cells are removed: In another approach, killed cancer cells are used to vaccinate patients against their own tumors in much the way that inactivated viruses are used to make influenza vaccines.

  28. as precipitously as they have for heart disease?: Arialdi M. Miniño et al., “Deaths: Final Data for 2008,” National Vital Statistics Reports 59, no. 10 (December 7, 2011). See figure 6, page 9. [http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf]

  29. losing the War on Cancer?: For a measured argument see Sharon Begley, “We Fought Cancer … And Cancer Won,” Newsweek, September 5, 2008. [http://www.thedailybeast.com/newsweek/2008/09/05/we-fought-cancer-and-cancer-won.html]

  30. founder and chairman of the advisory board: Telome Health Inc. website. [http://www.telomehealth.com]

  31. said that she had lost her slide: The speaker was Lynda Chin and the company is Aveo Oncology. Her husband is Ronald DePinho, who went on to become president of MD Anderson Cancer Center. In 2012 the couple was involved in a dispute over an $18 million grant. The details are reported in Meredith Wadman, “Texas Cancer Institute to Re-review Controversial Grant,” Nature News, May 31, 2012. [http://blogs.nature.com/news/2012/05/texas-cancer-institute-to-re-review-controversial-grant.html] Also see Meredith Wadman, “Texas Cancer-centre Head Apologizes for Promoting Stock on Television,” Nature News, June 1, 2012. [http://blogs.nature.com/news/2012/06/texas-cancer-centre-head-apologizes-for-promoting-stock-on-television.html]

  32. “I really want this stuff to work”: Ervin J. Epstein, plenary talk, American Association for Cancer Research 102nd Annual Meeting, April 3, 2011. He also noted he had been a consultant for Genentech and Novartis and owned some stock in a company called Curis.

  33. pioneering work on viruses and oncogenes: D. Stehelin, H. E. Varmus, J. M. Bishop, and P. K. Vogt, “DNA Related to the Transforming Gene(s) of Avian Sarcoma Viruses Is Present in Normal Avian DNA,” Nature 260, no. 5547 (March 11, 1976): 170–73. [http://dx.doi.org/10.1038/260170a0]

  34. some of the most perplexing questions: Varmus was talking about the Provocative Questions project, which is described on the National Cancer Institute website. [http://provocativequestions.nci.nih.gov] Also see Harold Varmus and Ed Harlow, “Science Funding: Provocative Questions in Cancer Research,” Nature 481, no. 7382 (January 25, 2012): 436–37. [http://www.nature.com/nature/journal/v481/n7382/full/481436a.html]

  35. cancer of the heart: Timothy J. Moynihan, “Heart Cancer: Is There Such a Thing?” Disease and Conditions, Mayo Clinic Health Information website, April 12, 2012. [http://www.mayoclinic.com/health/heart-cancer/AN01288]

  36. the results have been surprising: Michael R. Stratton, Peter J. Campbell, and P. Andrew Futreal, “The Cancer Genome,” Nature 458, no. 7239 (April 9, 2009): 719–24; [http://dx.doi.org/10.1038/nature07943] and P. Andrew Futreal, Michael R. Stratton, et al., “A Census of Human Cancer Genes,” Nature Reviews Cancer 4, no. 3 (March 2004): 177–83. [http://dx.doi.org/10.1038/nrc1299]

  37. hundreds of mutations may potentially be involved: For a particularly striking example, see H. Nikki March et al., “Insertional Mutagenesis Identifies Multiple Networks of Cooperating Genes Driving Intestinal Tumorigenesis,” Nature Genetics 43, no. 12 (2011): 1202–9. [http://www.ncbi.nlm.nih.gov/pubmed/22057237] Part of the challenge is distinguishing between “driver” and “passenger” mutations. See chapter 12 of this book for details.

  38. the phenomenon of polarization: For the relationship to cancer see, for example, Minhui Lee and Valeri Vasioukhin, “Cell Polarity and Cancer—Cell and Tissue Polarity as a Non-canonical Tumor Suppressor,” Journal of Cell Science 121, no. 8 (April 15, 2008): 1141–50. [http://www.abstractsonline.com/Plan/ViewSession.aspx?sKey=8ca64139-76aa-4f7d-8389-af2402ba7613&mKey=%7b507D311A-B6EC-436A-BD67-6D14ED39622C%7d]

  39. the many different kinds of cell death: Melanie M. Hippert, Patrick S. O’Toole, and Andrew Thorburn, “Autophagy in Cancer: Good, Bad, or Both?” Cancer Research 66, no. 19 (October 1, 2006): 9349–51; [http://cancerres.aacrjournals.org/content/66/19/9349.abs] Michael Overholtzer, Joan S. Brugge, et al., “A Nonapoptotic Cell Death Process, Entosis, That Occurs by Cell-in-Cell Invasion,” Cell 131, no. 5 (November 30, 2007): 966–79; [http://www.cell.com/abstract/S0092-8674(07)01394-3] and Peter Vandenabeele et al., “Molecular Mechanisms of Necroptosis: An Ordered Cellular Explosion,” Nature Reviews Molecular Cell Biology 11, no. 10 (October 1, 2010): 700–14. [http://www.nature.com/nrm/journal/v11/n10/abs/nrm2970.html]

  40. the Warburg effect: The metabolic change, involving glycolysis, was described by Otto Warburg in “On the Origin of Cancer Cells,” Science 123, no. 3191 (February 24, 1956): 309–14. [http://www.sciencemag.org/content/123/3191/309] When carried out in the presence of oxygen, the process is called aerobic glycolysis. The result is increased consumption of glucose, which is why cancer cells light up in PET scans.

  41. take in more of the raw material: Matthew G. Vander Heiden, Lewis C. Cantley, and Craig B. Thompson, “Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation,” Science 324, no. 5930 (May 22, 2009): 1029–33. [http://www.sciencemag.org/content/324/5930/1029]

  42. The slow burn of chronic inflammation: For a good overview see Gary Stix, “Is Chronic Inflammation the Key to Unlocking the Mysteries of Cancer?” Scientific American, July 2007, updated online November 9, 2008. [http://www.scientificamerican.com/article.cfm?id=chronic-inflammation-cancer] More references are in my notes for chapter 10.

  43. molecules called sirtuins: For a review see Finkel Toren, Chu-Xia Deng, and Raul Mostoslavsky, “Recent Progress in the Biology and Physiology of Sirtuins,” Nature 460, no. 7255 (July 30, 2009): 587–91. [http://www.ncbi.nlm.nih.gov/pubmed/19641587]

  44. the genes residing in the microbes: Steven R. Gill et al., “Metagenomic Analysis of the Human Distal Gut Microbiome,” Science 312, no. 5778 (June 2, 2006): 1355–59. [http://www.sciencemag.org/content/312/5778/1355.short]

  45. a Human Microbiome Project: Peter J. Turnbaugh et al., “The Human Microbiome Project,” Nature 449, no. 7164 (October 18, 2007): 804–10. [http://www.nature.com/nature/journal/v449/n7164/abs/nature06244.html]

  46. “ ’omics”: Joshua Lederberg christened the microbiome, and in a short essay, “Ome Sweet ’Omics,” he commented on the naming phenomenon: The Scientist 15, no. 7 (April 2, 2001): 8. [http://lhncbc.nlm.nih.gov/lhc/docs/published/2001/pub2001047.pdf]

  47. separate the ridiculome from the relevantome: I thought I had invented these words, but an Internet search turns them up in a PowerPoint presentation: Andrea Califano, Brian Athey, and Russ Altman, “Creating a DBP Community to Enhance the NCBC Biomedical Impact, A National Center for Biomedical Computing Work Group Report,” July 18, 2006, National Alliance for Medical Image Computing website. [http://www.na-mic.org/Wiki/images/5/52/Systems_WG7.ppt]

  48. Horace Freeland Judson’s magnificent book: The Eighth Day of Creation: Makers of the Revolution in Biology, expanded ed. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 1996).

  49. microRNAs: Rosalind C. Lee, Rhonda L. Feinbaum, and Victor Ambros, “The C. elegans Heterochronic Gene lin-4 Encodes Small RNAs with Antisense Complementarity to lin-14,” Cell 75 (December 1993): 843–54. [http://www.ncbi.nlm.nih.gov/pubmed/8252621]

  50. the importance … has been overblown: Harm van Bakel et al., “Most ‘Dark Matter’ Transcripts Are Associated with Known Genes,” PLOS Biology 8, no. 5 (May 18, 2010): e1000371; [h
ttp://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000371] and Richard Robinson, “Dark Matter Transcripts: Sound and Fury, Signifying Nothing?” PLOS Biology 8 (May 18, 2010): e1000370. [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1000370]

  51. a sweeping new theory: Leonardo Salmena, Pier Paolo Pandolfi, et al., “A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language?” Cell 146, no. 3 (August 5, 2011): 353–58. The speaker was the lead author, Pier Paolo Pandolfi. [http://www.cell.com/abstract/S0092-8674(11)00812-9]

  52. Junk that is not junk: Even more of the noncoding DNA appears to have found a purpose with the ENCODE project, whose results were announced with an extravagant multimedia website by the journal Nature. For an old-fashioned overview of the results see Consortium, The ENCODE Project, “An Integrated Encyclopedia of DNA Elements in the Human Genome,” Nature 489, no. 7414 (September 6, 2012): 57–74. Upon publication, a backlash ensued from scientists who thought the results, though important, were hyped. See John Timmer, “Most of What You Read Was Wrong: How Press Releases Rewrote Scientific History,” in the online publication Ars Technica, September 10, 2012.

  53. had published a follow-up: Douglas Hanahan and Robert A Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (March 4, 2011): 646–74. [http://www.ncbi.nlm.nih.gov/pubmed/21376230] The ten-year anniversary of the original “Hallmarks” paper was taken as occasion for a critique: Yuri Lazebnik, “What Are the Hallmarks of Cancer?” Nature Reviews Cancer 10, no. 4 (April 1, 2010): 232–33. [http://www.nature.com/nrc/journal/v10/n4/full/nrc2827.html]