The Cancer Chronicles (35 page)

33.
signals are sent to healthy cells:
These discoveries grew from early research on the role of the tumor microenvironment. See, for example, D. S. Dolberg and M. J. Bissell, “Inability of Rous Sarcoma Virus to Cause Sarcomas in the Avian Embryo,”
Nature
309, no. 5968 (June 7, 1984): 552–56 [
http://www.ncbi.nlm.nih.gov/pubmed/6203040
]; and D. S. Dolberg, M. J. Bissell, et al., “Wounding and Its Role in RSV-mediated Tumor Formation,”
Science
230, no. 4726 (November 8, 1985): 676–78. [
http://www.ncbi.nlm.nih.gov/pubmed/2996144
]

34.
Macrophages and other inflammatory cells:
Lisa M. Coussens and Zena Werb, “Inflammation and Cancer,”
Nature
420, no. 6917 (December 19, 2002): 860–67. [
http://dx.doi.org/10.1038/nature01322
]

35.
compared to bodily organs:
Mina J. Bissell and Derek Radisky, “Putting Tumours in Context,”
Nature Reviews Cancer
1, no. 1 (October 2001): 46–54. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975572
]

1.
an embryo is so much like a tumor:
The complex process of implantation is described in Haibin Wang and Sudhansu K. Dey, “Roadmap to Embryo Implantation: Clues from Mouse Models,”
Nature Reviews Genetics
7, no. 3 (March 1, 2006): 185–99. [
http://www.nature.com/nrg/journal/v7/n3/abs/nrg1808.html
] For some of the parallels with tumorigenesis see Michael J. Murray and Bruce A. Lessey, “Embryo Implantation and Tumor Metastasis: Common Pathways of Invasion and Angiogenesis,”
Seminars in Reproductive Medicine
17, no. 3 (March 15, 2008): 275–90. [
http://www.ncbi.nlm.nih.gov/pubmed/10797946
]

2.
enzymes erode the surface:
L. A. Salamonsen, “Role of Proteases in Implantation,”
Reviews of Reproduction
4, no. 1 (January 1999): 11–22. [
http://www.ncbi.nlm.nih.gov/pubmed/10051098
]

3.
molecules help ensure a tight grip:
Maaike S. M. van Mourik et al., “Embryonic Implantation: Cytokines, Adhesion Molecules, and Immune Cells in Establishing an Implantation Environment,”
Journal of Leukocyte Biology
85, no. 1 (January 2009): 4–19.[
http://www.ncbi.nlm.nih.gov/pubmed/18784344
]

4.
messages are sent to the immune system:
Van Mourik et al., “Embryonic Implantation.”

5.
begins stimulating angiogenesis:
D. M. Sherer and O. Abulafia, “Angiogenesis During Implantation, and Placental and Early Embryonic Development,”
Placenta
22, no. 1 (January 2001): 1–13. [
http://www.ncbi.nlm.nih.gov/pubmed/11162347
]

6.
the more parallels they find:
Melissa Marino, “In the Beginning: What Developmental Biology Can Teach About Cancer,”
Lens
online magazine, Vanderbilt Medical Center website, February 2007. [
http://www.mc.vanderbilt.edu/lens/article/?id=170
]

7.
epithelial-mesenchymal transition:
The seminal article is Jean Paul Thiery, “Epithelial-Mesenchymal Transitions in Tumour Progression,”
Nature Reviews Cancer
2, no. 6 (June 2002): 442–54. [
http://dx.doi.org/10.1038/nrc822
] Good reviews include Yibin Kang and Joan Massagué, “Epithelial-Mesenchymal Transitions: Twist in Development and Metastasis,”
Cell
118, no. 3 (August 6, 2004): 277–79; [
http://www.ncbi.nlm.nih.gov/pubmed/15294153
] Jonathan M. Lee et al., “The Epithelial-Mesenchymal Transition: New Insights in Signaling, Development, and Disease,”
Journal of Cell Biology
172, no. 7 (March 27, 2006): 973–81; [
http://www.ncbi.nlm.nih.gov/pubmed/16567498
] Jing Yang and Robert A. Weinberg, “Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis,”
Developmental Cell
14, no. 6 (June 2008): 818–29; [
http://www.ncbi.nlm.nih.gov/pubmed/18539112
] and Raghu Kalluri and Robert A. Weinberg, “The Basics of Epithelial-Mesenchymal Transition,”
Journal of Clinical Investigation
119, no. 6 (June 1, 2009): 1420–28. [
http://www.jci.org/articles/view/39104
] For an account by some naysayers see David Tarin, Erik W. Thompson, and Donald F. Newgreen, “The Fallacy of Epithelial Mesenchymal Transition in Neoplasia,”
Cancer Research
65, no. 14 (July 15, 2005): 5996–6001. [
http://www.ncbi.nlm.nih.gov/pubmed/16024596
] Both sides of the controversy are described in Heidi Ledford, “Cancer Theory Faces Doubts,”
Nature
472, no. 7343 (April 21, 2011): 273. [
http://www.ncbi.nlm.nih.gov/pubmed/21512545
]

8.
holding its annual meeting:
Society for Developmental Biology Sixty-Ninth Annual Meeting, August 5–9, 2010, Albuquerque, NM. I also attended the Seventieth Annual Meeting, July 21–22, 2011, in Chicago. For a nice overview of developmental biology, see Sean B. Carroll,
Endless Forms Most Beautiful: The New Science of Evo Devo
(New York: Norton, 2006). The website of the Society for Developmental Biology [
http://www.sdbonline.org
] provides a portal to numerous resources like WormAtlas, with detailed and annotated maps of
C. elegans,
and FlyBrain, which covers the
Drosophila
nervous system.

9.
“Organogenesis”:
The proceedings of the Albuquerque conference are in
Developmental Biology
344, no. 1 (2010): 391–542. [
http://www.sciencedirect.com/science/journal/00121606/344/1
]

10.
wingless, frizzled, smoothened, patched, and disheveled:
Though I have tried to be consistent in my own usage, I have not religiously followed the rules for when to render the names and symbols of genes in upper case or lower case or italics or roman. Apologies to the specialists who may find that distracting.

11.
possible treatments for baldness:
Andrzej Dlugosz, “The Hedgehog and the Hair Follicle: A Growing Relationship,”
Journal of Clinical Investigation
104, no. 7 (October 1, 1999): 851–53. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC408568
]

12.
“The quirky sense of humour”:
Ken Maclean, “Humour of Gene Names Lost in Translation to Patients,”
Nature
439, no. 7074 (January 19, 2006): 266. [
http://dx.doi.org/10.1038/439266d
]

13.
It now goes by the less evocative name Zbtb7:
Tom Simonite, “Pokemon Blocks Gene Name,”
Nature
438, no. 7070 (December 14, 2005): 897. [
http://www.nature.com/nature/journal/v438/n7070/full/438897a.html
]

14.
Since it was discovered in 1993:
R. D. Riddle, C. Tabin, et al., “Sonic Hedgehog Mediates the Polarizing Activity of the ZPA,”
Cell
75, no. 7 (December 31, 1993): 1401–16. [
http://www.ncbi.nlm.nih.gov/pubmed/8269518
]

15.
sheep grazing in the mountains:
The story of cyclopamine is told in Philipp Heretsch, Lito Tzagkaroulaki, and Athanassios Giannis, “Cyclopamine and Hedgehog Signaling: Chemistry, Biology, Medical Perspectives,”
Angewandte Chemie
(international ed. in English) 49, no. 20 (May 3, 2010): 3418–27. [
http://www.ncbi.nlm.nih.gov/pubmed/20429080
]

16.
holoprosencephaly:
Max Muenk, “Translational Concepts to Disease: Holoprosencephaly as an Example,” lecture presented July 22, 2011 at the Society for Developmental Biology Seventieth Annual Meeting, Chicago, IL.

17.
one of every 250 early embryos:
Erich Roessler, Maximilian Muenke, et al., “Mutations in the Human Sonic Hedgehog Gene Cause Holoprosencephaly,”
Nature Genetics
14, no. 3 (November 1996): 357–60. [
http://dx.doi.org/10.1038/ng1196-357
]

18.
can drive the formation of malignancies:
For an overview of sonic hedgehog and cancer see Lee L. Rubin and Frederic J. de Sauvage, “Targeting the Hedgehog Pathway in Cancer,”
Nature Reviews Drug Discovery
5, no. 12 (December 2006): 1026–33 [
http://dx.doi.org/10.1038/nrd2086
]; and Jennifer M. Bailey, Pankaj K. Singh, and Michael A. Hollingsworth, “Cancer Metastasis Facilitated by Developmental
Pathways: Sonic Hedgehog, Notch, and Bone Morphogenic Proteins,”
Journal of Cellular Biochemistry
102, no. 4 (November 1, 2007): 829–39. [
http://onlinelibrary.wiley.com/doi/10.1002/jcb.21509/abstract
]

19.
Gorlin syndrome:
Ervin H. Epstein, “Basal Cell Carcinomas: Attack of the Hedgehog,”
Nature Reviews Cancer
8, no. 10 (October 2008): 743–54. [
http://dx.doi.org/10.1038/nrc2503
]

20.
a cream containing cyclopamine:
Sinan Tabs and Oktay Avci, “Induction of the Differentiation and Apoptosis of Tumor Cells in Vivo with Efficiency and Selectivity,”
European Journal of Dermatology
14, no. 2 (April 2004): 96–102. [
http://www.ncbi.nlm.nih.gov/pubmed/15196999
]

21.
another hedgehog inhibitor:
“FDA Approval for Vismodegib,” National Cancer Institute. [
http://www.cancer.gov/cancertopics/druginfo/fda-vismodegib
]

22.
might help control the genetic switches:
More specifically, Dmrt5 is a transcription factor, a molecule that binds to the genome and regulates the output of a gene.

23.
“zinc fingers,” “Dmrt5,” and “Emma Farley”:
Emma K. Farley et al., “Novel Transcription Factor Involved in Neurogenesis,”
Developmental Biology
344, no. 1 (2010): 493. [
http://www.researchgate.net/publication/47383131_Novel_transcription_factor_involved_in_neurogenesis
]

24.
so many new scraps of information:
Venugopala Reddy Bommireddy Venkata, Cordelia Rauskolb, and Kenneth D. Irvine, “Fat-Hippo Signaling Regulates the Proliferation and Differentiation of Drosophila Optic Neuroepithelia,”
Developmental Biology
344, no. 1 (2010): 506 [
http://www.researchgate.net/publication/47383178_Fat-Hippo_signaling_regulates_the_proliferation_and_differentiation_of_Drosophila_optic_neuroepithelia
]; and Thomas L. Gallagher and Joshua Arribere, “Fox1 and Fox4 Regulate Muscle-specific Splicing in Zebrafish and Are Required for Cardiac and Skeletal Muscle Functions,”
Developmental Biology
344, no. 1 (2010): 491–92. [
http://www.researchgate.net/publication/47383123_Fox1_and_Fox4_regulate_muscle-specific_splicing_in_zebrafish_and_are_required_for_cardiac_and_skeletal_muscle_functions
]

25.
a whimsical turn:
Cristina L. Walcher and Jennifer L. Nemhauser, “1 + 1 = 3: When Two Hormones Are Better Than One,”
Developmental Biology
344, no. 1 (2010): 487; [
http://www.researchgate.net/publication/47383110_113_When_two_hormones_are_better_than_one
] and Nowlan Freese and Susan C. Chapman, “Where’d My Tail Go?”
Developmental Biology
344, no. 1 (2010): 441. [
http://www.researchgate.net/publication/47382941_Where’d_my_tail_go
]

26.
six little words:
The full title was “How Heart Cells Embrace Their Fate in the Chordate
Ciona Intestinalis
” by Stacia Ilchena and James Cooley,
Developmental Biology
344, no. 1 (2010): 502–3. [
http://www.researchgate.net/publication/47383162_How_heart_cells_embrace_their_fate_in_the_chordate_Ciona_intestinalis
]

1.
excavating a canal:
Love Canal’s history is described in Allan Mazur,
A Hazardous Inquiry: The Rashomon Effect at Love Canal
(Cambridge, MA: Harvard University Press, 1998), 8–15.

2.
some 22,000 tons of toxic waste:
“Love Canal: A Special Report to the Governor & Legislature,” April 1981, New York Department of Health website. [
http://www.health.state.ny.us/environmental/investigations/love_canal/lcreport.htm
]

3.
“The odors penetrate your clothing”:
“Chemical Waste at Love Canal, October 18, 1977,” Ecumenical Task Force of the Niagara Frontier Records,
1946–1995 (MS 65), University at Buffalo Libraries, Love Canal Collections website. [
http://library.buffalo.edu/specialcollections/lovecanal/collections/etf.php
]

4.
incorporated the saga into a novel:
Joyce Carol Oates,
The Falls: A Novel
(New York: Ecco, 2004).

5.
the EPA estimated:
“U.S. Finds Risk of Cancer High for Residents Near Love Canal; Three Families Inside Fence,”
New York Times,
November 11, 1979.

6.
admitted to a mathematical error:
Irvin Molotsky, “Rep. LaFalce Says Draft Report Inflated Love Canal Cancer Risk; Mathematical Errors Conceded,”
New York Times,
November 20, 1979.

7.
Another EPA report found:
Irvin Molotsky, “Damage to Chromosomes Found in Love Canal Tests,”
New York Times,
May 17, 1980. The findings were in D. Picciano, “Pilot Cytogenetic Study of the Residents Living Near Love Canal, a Hazardous Waste Site,
Mammalian Chromosome Newsletter
21 (1980): 86–93.

8.
dismissed by a panel:
Richard J. Meislin, “Carey Panel Discounts 2 Studies on Love Canal Health Problems,”
New York Times,
October 11, 1980.

9.
A later study for the Centers for Disease Control:
Clark W. Heath Jr. et al., “Cytogenetic Findings in Persons Living Near the Love Canal,”
JAMA: The Journal of the American Medical Association
251, no. 11 (March 16, 1984): 1437–40. [
http://jama.ama-assn.org/content/251/11/1437
]

10.
a thirty-year retrospective:
“Love Canal Follow-up Health Study,” New York Department of Health website, October 2008. [
http://www.health.ny.gov/environmental/investigations/love_canal/docs/report_public_comment_final.pdf
] For a critique of the report see appendix T, “Public Comments and Responses, Love Canal Follow-up Health Study,” especially the comments by epidemiologist Richard Clapp, 145–47.

11.
Almost half of the 6,026 residents:
Demographic details are described in table 20, page 97 of the “Love Canal Follow-up.”

12.
the birth defect rate:
“Love Canal Follow-up,” 42–43. Altogether there were thirty-seven congenital malformations reported among 1,767 singleton births (those not including twins and triplets) between 1960 and 1996. For comparing incidence rates, the study counted only “consistently and reliably reported” cases as defined by the New York State Congenital Malformation Registry, which had complete records only beginning in 1983. Earlier information came from local hospitals and was not considered solid enough to use in the comparisons. (See pages 29–30 of the report for details. Also see table 19, page 96, and appendix A on page 103.)

13.
higher than for the rest of the state:
That excluded New York City.

14.
slightly more girls had been born:
“Love Canal Follow-up,” 41–43.

15.
no convincing evidence:
“Love Canal Follow-up,” 2.

16.
overall cancer rate was actually a little lower:
That was compared with both the county and the state. See “Love Canal Follow-up,” 39–41.

17.
Rachel Carson’s elegant warning:
Silent Spring
(Boston: Houghton Mifflin Company, 1962).

18.
scathing polemics:
Samuel S. Epstein,
The Politics of Cancer
(San Francisco: Sierra Club Books, 1978) and
The Politics of Cancer Revisited
(Fremont Center, NY: East Ridge Press, 1998).

19.
a modern epidemic of cancer:
The historian Robert N. Proctor captures the zeitgeist in
Cancer Wars: How Politics Shapes What We Know and Don’t Know About Cancer
(New York: Basic Books, 1995). See particularly 54–74.

20.
“the plague of the twentieth century”:
Epstein,
Politics of Cancer Revisited,
14.

21.
“a grim game of chemical roulette”:
Russell Train in a speech to the National Press Club, February 26, 1976. The story was picked up by the Associated Press and appeared the next day in newspapers, including
The Morning Record
(Meriden, CT) and the
Sarasota Herald-Tribune
. [
http://news.google.com/newspapers?nid=2512&dat=19760227&id=_KNHAAAAIBAJ&sjid=d_8MAAAAIBAJ&pg=1388,3515703
]

22.
“the Great Cancer Wars”:
Proctor,
Cancer Wars,
74.

23.
Ninety percent of cancer is environmental:
For an account of the origin of the misconception, see Proctor,
Cancer Wars,
55–57; and (keeping in mind its libertarian bias) Edith Efron,
Apocalyptics: Cancer and the Big Lie: How Environmental Politics Controls What We Know About Cancer
(New York: Simon & Schuster, 1984), 429–32.

24.
known and suspected agents:
See National Toxicology Program,
Report on Carcinogens,
12th ed. (Research Triangle Park, NC: U.S. Department of Health and Human Services, 2011). [
http://ntp-server.niehs.nih.gov/?objectid=03C9AF75-E1BF-FF40-DBA9EC0928DF8B15
]

25.
To get a sense of how strongly cancer was influenced:
The migrant studies are summarized in R. Doll and R. Peto, “The Causes of Cancer: Quantitative Estimates of Avoidable Risks of Cancer in the United States Today,”
Journal of the National Cancer Institute
66, no. 6 (June 1981): 1191–1308, reference on 1200–01; Proctor,
Cancer Wars,
24–26; and Efron,
Apocalyptics,
430–32.

26.
seemed to be escalating abruptly:
The numbers were published in Earl S. Pollack and John W. Horm, “Trends in Cancer Incidence and Mortality in the United States, 1969–76,”
Journal of the National Cancer Institute
64, no. 5 (May 1, 1980): 1091–103 [
http://jnci.oxfordjournals.org/content/64/5/1091
]; and in
Toxic Chemicals and Public Protection: A Report to the President by the Toxic Substances Strategy Committee
(Washington, DC: Council on Environmental Quality, May 1980), which is available online through the Hathi Trust Digital Library. [
http://catalog.hathitrust.org/Record/007413257
]

27.
appeared to be the vindication:
For a description of the controversy see Doll and Peto, “Causes of Cancer,” 1279–81; and Efron,
Apocalyptics,
434–36.

28.
warned that the comparisons were invalid:
Doll and Peto, “Causes of Cancer,” 1280–81; and Efron,
Apocalyptics,
435.

29.
commissioned a study:
Doll and Peto, “Causes of Cancer.”

30.
accomplished scientists in their field:
Doll’s later work was called into question when it was revealed after his death that he had accepted consulting fees from chemical companies. In defending his colleague, Peto said that Doll was open about the connections and gave the money to Green College, Oxford, which he helped found. See Sarah Boseley, “Renowned Cancer Scientist Was Paid by Chemical Firm for 20 Years,”
The Guardian,
December 7, 2006. [
http://www.guardian.co.uk/science/2006/dec/08/smoking.frontpagenews
] In the letters section of the next day’s edition other prominent scientists defended Doll’s impartiality (see “Richard Doll Still Deserves Our Respect”). [
http://www.guardian.co.uk/science/2006/dec/09/guardianletters?intcmp=239
] They included the chief executive of the Medical Research Council, the director of Wellcome Trust, and Martin Rees, the president of the Royal Society.

31.
which numbers to trust:
Doll and Peto, “Causes of Cancer,” appendix C, 1270–81.

32.
The situation improved:
Doll and Peto, “Causes of Cancer,” 1281.

33.
In 30 percent of cancer deaths, tobacco was a cause:
Doll and Peto, “Causes of Cancer,” table 20, 1256.

34.
“most of the types of cancer that are common today”:
Doll and Peto, “Causes of Cancer,” 1212.

35.
Any specific case of cancer will have multiple causes:
For the dilemmas involved in sorting out the environmental and genetic factors of a disease, see Kenneth J. Rothman and Sander Greenland, “Causation and Causal Inference in Epidemiology,”
American Journal of Public Health
95 suppl. 1 (2005): S144–50. [
http://www.ncbi.nlm.nih.gov/pubmed/16030331
]

36.
They were a component:
For a recent assessment see Paolo Boffetta and Fredrik Nyberg, “Contribution of Environmental Factors to Cancer Risk,”
BMJ: British Medical Journal
68, no. 1 (December 1, 2003): 71–94 [
http://bmb.oxfordjournals.org/content/68/1/71.abstract
]; and Richard W. Clapp and Molly M. Jacobs, “Environmental and Occupational Causes of Cancer: New Evidence, 2005–2007,” October 2007, Lowell Center for Sustainable Production website. [
http://www.sustainableproduction.org/downloads/EnvandOccCausesofCancer-2007Update-DownloadVersion.pdf
]

37.
“there is too much ignorance”:
Doll and Peto, “Causes of Cancer,” 1251.

38.
cancer mortality among people under sixty-five:
Doll and Peto, “Causes of Cancer,” 1256. For details see 1281–85 and tables D1 and D3.

39.
largely true for older Americans:
Doll and Peto, “Causes of Cancer,” 1256. See table D2 for the overall rate and D4 for specific cancers. There appeared to be an increase in brain cancer deaths and smaller increases in other nonrespiratory cancers, but the authors attributed these mostly to better record keeping.

40.
not because we were getting much better:
Doll and Peto, “Causes of Cancer,” 1256.

41.
Two smaller studies:
J. Higginson and C. S. Muir, “Environmental Carcinogenesis:
Misconceptions and Limitations to Cancer Control,”
Journal of the National Cancer Institute
63, no. 6 (December 1979): 1291–98; [
http://www.ncbi.nlm.nih.gov/pubmed/390201
] and E. L. Wynder and G. B. Gori, “Contribution of the Environment to Cancer Incidence: An Epidemiologic Exercise,”
Journal of the National Cancer Institute
58, no. 4 (April 1977): 825–32. [
http://www.ncbi.nlm.nih.gov/pubmed/321795
]

42.
began challenging the report:
Samuel S. Epstein and Joel B. Swartz, “Fallacies of Lifestyle Cancer Theories,”
Nature
289, no. 5794 (January 15, 1981): 127–30. [
http://www.nature.com/nature/journal/v289/n5794/abs/289127a0.html
]

43.
When lung cancer rates began rising:
David G. Hoel, Devra L. Davis, et al., “Trends in Cancer Mortality in 15 Industrialized Countries, 1969–1986,”
Journal of the National Cancer Institute
84, no. 5 (March 4, 1992): 313–20. [
http://jnci.oxfordjournals.org/content/84/5/313.abstract
]

44.
While epidemiologists kept watch:
Bruce Ames’s story is told in Proctor,
Cancer Wars,
136–52.

45.
the Ames test:
Bruce N. Ames et al., “Carcinogens Are Mutagens: A Simple Test System Combining Liver Homogenates for Activation and Bacteria for Detection,”
Proceedings of the National Academy of Sciences
70, no. 8 (August 1973): 2281–85. [
http://www.pnas.org/content/70/8/2281.abstract
]

46.
By killing esophagus cells:
Alcohol may also increase cancer risk by breaking down into carcinogenic acetaldehyde and through other mechanisms. For a summary see “Alcohol Use and Cancer,” American Cancer Society website, last revised January 27, 2012. [
http://www.cancer.org/Cancer/CancerCauses/DietandPhysicalActivity/alcohol-use-and-cancer
]

47.
a paper in
Science
:
B. N. Ames, “Dietary Carcinogens and Anticarcinogens,”
Science
221, no. 4617 (September 23, 1983): 1256–64. [
http://www.ncbi.nlm.nih.gov/pubmed/6351251
]

48.
In 1997, he reported:
B. N. Ames and L. S. Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer: Misconceptions,”
FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
11, no. 13 (November 1997): 1041–52. [
http://www.ncbi.nlm.nih.gov/pubmed/9367339
]

49.
In fact he doubted:
Ames and Gold, “Environmental Pollution, Pesticides, and the Prevention of Cancer.”

50.
Half of everything tested:
B. N. Ames and L. S. Gold, “Chemical Carcinogenesis: Too Many Rodent Carcinogens,”
Proceedings of the National Academy of Sciences
87, no. 19 (October 1990): 7772–76. [
http://www.pnas.org/content/87/19/7772.abstract
]

51.
an experiment costing tens of millions of dollars:
Cancer and the Environment
(Washington, DC: U.S. Department of Health and Human Services, March 2003), 25.