The Cancer Chronicles (38 page)

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; [
http://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
]

1.
Alexander Fleming discovered penicillin:
A. Fleming, “On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. Influenzae,”
British Journal of Experimental Pathology
10 (1929): 226–35. The article was republished in
Bulletin of the World Health Organization
79, no. 8 (2001): 780–90. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566493
] He described the discovery in his Nobel Prize lecture, December 11, 1945: Alexander Fleming, “Penicillin,” in
Nobel Lectures, Physiology or Medicine 1942
–
1962
(Amsterdam: Elsevier Publishing Company, 1964), which is available on the Nobel Prize website. [
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.html
] Unknown to Fleming, scientists before him had also noticed penicillin’s effects (see Horace Freeland Judson,
The Search for Solutions
[London: Hutchinson, 1980], 73–75), and historians have cast doubt on the details of the canonical account: Douglas Allchin, “Penicillin and Chance,” Sociology, History and Philosophy in Science Teaching Resource Center website, University of Minnesota. [
http://www1.umn.edu/ships/updates/fleming.htm
]

2.
Boys thin from malnutrition:
H. A. Waldron, “A Brief History of Scrotal Cancer,”
British Journal of Industrial Medicine
40, no. 4 (November 1983): 390–401. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1009212
]

3.
“The fate of these people”:
Percivall Pott,
The Chirurgical Works of Percival Pott, F.R.S. and Surgeon to St. Bartholomew’s Hospital
(London: Printed for T. Lowndes, J. Johnson, G. Robinson, T. Cadell, T. Evans, W. Fox, J. Bew, and S. Hayes, 1783). The book was originally published in 1775, and the quote is from page 178 of a later, expanded edition (London: J. Johnson, 1808). [
http://books.google.com/ebooks?id=cvS_o4-jIzwC
]

4.
“I have many times made the experiment”:
Potts,
The Chirurgical Works,
179.

5.
Chimney sweeps on the European continent:
Waldron, “A Brief History.”

6.
unknown in Edinburgh:
Robert M. Green, MD, “Cancer of the Scrotum,”
Boston Medical and Surgical Journal
163, no. 2 (November 17, 1910): 755–59. [
http://books.google.com/books?id=Q9YEAAAAYAAJ
]

7.
“from that of a grain of rice”:
K. Yamagiwa and K. Ichikawa, “Experimental Study of the Pathogenesis of Carcinoma,”
Journal of Cancer Research
3 (1918): 1–29. Republished along with a short biography of Katsusaburo Yamagiwa in
CA: A Cancer Journal for Clinicians
27, no. 3 (May/June 1977): 172–81. [
http://onlinelibrary.wiley.com/doi/10.3322/canjclin.27.3.174/abstract
]

8.
“Every city in Italy”:
Bernardino Ramazzini,
Diseases of Workers,
translated from the Latin text
De morbis artificum
of 1713 by Wilmer Cave Wright, with an introduction by George Rosen (Chicago: University of Chicago Press, 1940), 191. This edition includes the Latin text on facing pages. Ramazzini wrote about the nuns in a section called “Wet-Nurses,” 189–93. Also see J. S. Felton, “The Heritage of Bernardino Ramazzini,”
Occupational Medicine
47, no. 3 (April 1, 1997): 167–79. [
http://occmed.oxfordjournals.org/content/47/3/167.abstract
]

9.
nursing of children:
World Cancer Research Fund/American Institute for
Cancer Research,
Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective
(Washington, DC: AICR, 2007), 239–42. [
http://www.dietandcancerreport.org/expert_report/index.php
]

10.
Domenico Rigoni-Stern, observed:
I. D. Rotkin, “A Comparison Review of Key Epidemiological Studies in Cervical Cancer Related to Current Searches for Transmissible Agents,”
Cancer Research
33, no. 6 (June 1, 1973): 1353–67; [
http://cancerres.aacrjournals.org/content/33/6/1353
] and Joseph Scotto and John C. Bailar, “Rigoni-Stern and Medical Statistics: A Nineteenth-Century Approach to Cancer Research,”
Journal of the History of Medicine and Allied Sciences
24, no. 1 (1969): 65–75. [
http://jhmas.oxfordjournals.org/content/XXIV/1/65.extract
]

11.
“The dogma was that cancer”:
All quotations from Riboli are from an interview with the author in London, May 12, 2011.

12.
came from laboratory experiments:
Some pioneering research was done in the 1940s by Albert Tannenbaum. See “The Initiation and Growth of Tumors. Introduction. I. Effects of Underfeeding,”
American Journal of Cancer
38 (1940): 335–50. [
http://cancerres.aacrjournals.org/content/amjcancer/38/3/335.short
] For some later work see D. Kritchevsky et al., “Calories, Fat and Cancer,”
Lipids
21, no. 4 (April 1986): 272–74 [
http://www.ncbi.nlm.nih.gov/pubmed/3086652
]; D. Kritchevsky, M. M. Weber, and D. M. Klurfeld, “Dietary Fat Versus Caloric Content in Initiation and Promotion of Mammary Tumorigenesis in Rats,”
Cancer Research
44, no. 8 (August 1984): 3174–77 [
http://www.ncbi.nlm.nih.gov/pubmed/6430545
]; G. A. Boissonneault, C. E. Elson, and M. W. Pariza, “Net Energy Effects of Dietary Fat on Chemically Induced Mammary Carcinogenesis in F344 Rats,”
Journal of the National Cancer Institute
76, no. 2 (February 1986): 335–38 [
http://www.ncbi.nlm.nih.gov/pubmed/3080637
]; and M. W. Pariza, “Fat, Calories, and Mammary Carcinogenesis: Net Energy Effects,”
American Journal of Clinical Nutrition
45, no. 1 (January 1, 1987): 261–63. [
http://www.ajcn.org/content/45/1/261.short
]

13.
feeding them different amounts and varieties:
G. J. Hopkins and K. K. Carroll, “Relationship Between Amount and Type of Dietary Fat in Promotion of Mammary Carcinogenesis,”
Journal of the National Cancer Institute
62, no. 4 (April 1979): 1009–12. [
http://www.ncbi.nlm.nih.gov/pubmed/107358
]

14.
Diets too rich in salt:
For an overview see Xiao-Qin Wang, Paul D. Terry, and Hong Yan, “Review of Salt Consumption and Stomach Cancer Risk: Epidemiological and Biological Evidence,”
World Journal of Gastroenterology
15, no. 18 (May 14, 2009): 2204–13. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682234/
]

15.
nitrosamines, N-nitroso compounds, and other substances:
See, for example, P. Issenberg, “Nitrite, Nitrosamines, and Cancer,”
Federation Proceedings
35, no. 6 (May 1, 1976): 1322–26; [
http://www.ncbi.nlm.nih.gov/pubmed/4342
] and William Lijinsky, “N-Nitroso Compounds in the Diet,”
Mutation Research/Genetic Toxicology and Environmental Mutagenesis
443, nos. 1–2 (July 15, 1999): 129–38. [
http://www.sciencedirect.com/science/article/pii/S1383574299000150
]

16.
review some four thousand studies:
World Cancer Research Fund/American
Institute for Cancer Research,
Food, Nutrition, Physical Activity, and the Prevention of Cancer,
585.

17.
“Diets containing substantial amounts”:
World Cancer Research Fund/American Institute for Cancer Research,
Food, Nutrition, Physical Activity, and the Prevention of Cancer,
538.

18.
“predominantly plant-based diets”:
World Cancer Research Fund/American Institute for Cancer Research,
Food, Nutrition, Physical Activity, and the Prevention of Cancer,
522.

19.
“especially rich in cancer-protective chemicals”:
Jane Brody, “Eat Your Vegetables! But Choose Wisely,” Personal Health,
New York Times,
January 2, 2001. [
http://www.nytimes.com/2001/01/02/health/personal-health-eat-your-vegetables-but-choose-wisely.html
]

20.
the disappointing follow-up:
World Cancer Research Fund/American Institute for Cancer Research,
Food, Nutrition, Physical Activity, and the Prevention of Cancer.
Updates are posted on the organization’s Diet and Cancer Report website. [
http://www.dietandcancerreport.org/cup/current_progress
]

21.
“in no case now is the evidence … judged to be convincing”:
World Cancer Research Fund/American Institute for Cancer Research,
Food, Nutrition, Physical Activity and the Prevention of Cancer,
75, 114.

22.
the European Prospective Investigation into Cancer and Nutrition:
Details can be found on the EPIC website. [
http://epic.iarc.fr
]

23.
only the slightest evidence:
Paolo Boffetta et al., “Fruit and Vegetable Intake and Overall Cancer Risk,”
Journal of the National Cancer Institute
102, no. 8 (April 21, 2010): 529–37. [
http://jnci.oxfordjournals.org/content/early/2010/04/06/jnci.djq072.abstract.
]

24.
or even of specific cancers:
For citations see the response to the Boffetta paper by Christine Bouchardy, Simone Benhamou, and Elisabetta Rapiti, “Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation into Cancer and Nutrition,”
Journal of the National Cancer Institute
(December 16, 2010); [
http://jnci.oxfordjournals.org/content/early/2010/12/15/jnci.djq501.short
] and T. J. Key, “Fruit and Vegetables and Cancer Risk,”
British Journal of Cancer
104, no. 1 (January 4, 2011): 6–11. [
http://dx.doi.org/10.1038/sj.bjc.6606032
]

25.
a small protective effect:
Anthony B. Miller et al., “Fruits and Vegetables and Lung Cancer,”
International Journal of Cancer
108, no. 2 (January 10, 2004): 269–76 [
http://www.ncbi.nlm.nih.gov/pubmed/14639614
]; Heiner Boeing et al., “Intake of Fruits and Vegetables and Risk of Cancer of the Upper Aero-digestive Tract,”
Cancer Causes & Control
17, no. 7 (September 2006): 957–69 [
http://www.ncbi.nlm.nih.gov/pubmed/16841263
]; and F. L. Büchner et al., “Fruits and Vegetables Consumption and the Risk of Histological Subtypes of Lung Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC),”
Cancer Causes & Control
21, no. 3 (March 2010): 357–71. [
http://www.ncbi.nlm.nih.gov/pubmed/19924549
]

26.
too early to make more than tentative conjectures:
Key, “Fruit and Vegetables and Cancer Risk.”

27.
people who smoke and drink excessively:
M. K. Serdula et al., “The Association Between Fruit and Vegetable Intake and Chronic Disease Risk Factors,”
Epidemiology
7, no. 2 (March 1996): 161–65. [
http://www.ncbi.nlm.nih.gov/pubmed/8834556
]

28.
possibly played a small part:
F. J. van Duijnhoven et al., “Fruit, Vegetables,
and Colorectal Cancer Risk,”
American Journal of Clinical Nutrition
89, no. 5 (May 2009): 1441–52. [
http://www.ncbi.nlm.nih.gov/pubmed/19339391
]

29.
that too remains in dispute:
Key, “Fruit and Vegetables and Cancer Risk.”

30.
“overly optimistic”:
Walter C. Willett, “Fruits, Vegetables, and Cancer Prevention: Turmoil in the Produce Section,”
Journal of the National Cancer Institute
102, no. 8 (April 21, 2010): 510–11. [
http://jnci.oxfordjournals.org/content/102/8/510.short
] He is commenting on Boffetta et al., “Fruit and Vegetable Intake.”

31.
the ten-year risk of getting colorectal cancer:
See Teresa Norat et al., “Meat, Fish, and Colorectal Cancer Risk,”
Journal of the National Cancer Institute
97, no. 12 (June 15, 2005): 906–16. [
http://www.ncbi.nlm.nih.gov/pubmed/15956652
] The study found protective effects of roughly the same magnitude for eating fish. Similar evidence for fiber was reported in Sheila A. Bingham et al., “Dietary Fibre in Food and Protection Against Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition,”
Lancet
361, no. 9368 (May 3, 2003): 1496–501. [
http://www.ncbi.nlm.nih.gov/pubmed/12737858
]

32.
have come to conflicting conclusions:
See, for example, D. D. Alexander and C. A. Cushing, “Red Meat and Colorectal Cancer: A Critical Summary of Prospective Epidemiologic Studies,”
Obesity Reviews
12, no. 5 (May 2011): e472–493; [
http://www.ncbi.nlm.nih.gov/pubmed/20663065
] and Doris S. M. Chan et al., “Red and Processed Meat and Colorectal Cancer Incidence: Meta-Analysis of Prospective Studies,”
PLOS ONE
6, no. 6 (June 6, 2011). [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108955
] For earlier work see Scott Gottlieb, “Fibre Does Not Protect Against Colon Cancer,”
BMJ: British Medical Journal
318, no. 7179 (January 30, 1999): 281; [
http://www.bmj.com//content/318/7179/281.1
] and C. S. Fuchs, W. C. Willett, et al., “Dietary Fiber and the Risk of Colorectal Cancer and Adenoma in Women,”
New En- gland Journal of Medicine
340, no. 3 (January 21, 1999): 169–76. [
http://www.ncbi.nlm.nih.gov/pubmed/9895396
] The World Cancer Research Fund concludes on its Diet and Cancer Report website that the case for fiber is getting stronger. [
http://www.dietandcancerreport.org/cup/current_progress
]

33.
older women who had gained 15 to 20 kilograms:
Lahmann et al., “Long-term Weight Change and Breast Cancer.”

34.
fatness itself … appeared to be the driving force:
See, for example, P. H. Lahmann et al., “Long-term Weight Change and Breast Cancer Risk,”
British Journal of Cancer
93, no. 5 (September 5, 2005): 582–89; [
http://www.ncbi.nlm.nih.gov/pubmed/16136032
] and Tobias Pischon et al., “Body Size and Risk of Renal Cell Carcinoma in the European Prospective Investigation into Cancer and Nutrition,”
International Journal of Cancer
118, no. 3 (February 1, 2006): 728–38. [
http://www.ncbi.nlm.nih.gov/pubmed/16094628
]