Thinking Out of the Target May Offer Clues to the Origin of Cancer

During the past year, many corporations, academic institutions, and government health organizations announced new funding or collaborative efforts totaling billions of dollars to identify genetic targets for novel cancer therapies.

The Tissue-Field Organization Theory

During the past year, many corporations, academic institutions, and government health organizations announced new funding or collaborative efforts totaling billions of dollars to identify genetic targets for novel cancer therapies. The impetus behind these efforts is the predominant theory that cancer is caused by abnormal gene function.1This theory posits that most cancers are attributable to somatic (acquired) mutations, which originate in a single cell, and 5% to 10% are attributable to germline (inherited) mutations.1A small but vocal group of researchers are not convinced that genetic mutations are the primary cause of cancer. They have expressed concern that the increasingly narrow focus on cancer genomics comes at the expense of investigating plausible theories for a unifying origin of cancer. In their view, deciphering the singular origin of cancer may lead to treatments capable of eradicating or preventing most cancers.Although well-respected cancer biologist Mina Bissell from the Life Sciences Division of the Lawrence Berkeley National Laboratory in Berkeley, California, does not deny the role of genetic mutations in cancer, she believes the microenvironment determines whether an aberrant cell becomes cancerous.2Her evidence includes findings from experiments in which identical carcinoma cells caused cancer in adult animals but not their embryonic counterparts. She has also noted that although women with aBRCA1mutation carry the mutation in all 10 trillion cells,BRCA1-linked cancer only occurs in limited tissues; some women with aBRCA1mutation never develop cancer.3

In a 2011 article, Bissell and William Hines highlighted the fact that most investigational genetic-based cancer therapies never show any efficacy.3“Even those drugs that seem to work more effectively [only] increase the life expectancy of patients by 2 to 3 years. This is a marked improvement, but judged against the spectrum of available therapies and the funding spent on development and the incorporation of new agents into clinical practice over the past decade, one would have hoped for more,” they wrote.3

Baker and colleagues made similar arguments in support of the tissue-field organization theory and proposed the “paradigm instability hypothesis” as a reason why “the vast majority of funding for research into early carcinogenesis supports studies involving the somatic mutation theory.”4As they have explained it, most experts subscribe to the somatic mutation theory, making it the dominant paradigm. The more time that passes without a breakthrough in the dominant paradigm, the more convinced the experts become that a breakthrough is imminent—and perhaps also that an alternative paradigm (ie, tissue organization field theory) is correct.4

Other Hypothesis for the Origin of Cancer

The authors said cataloging all the DNA mutations in somatic or inherited cancer will still fail to explain away the paradoxes observed with the somatic mutation theory. They added that the tissue organization field theory satisfactorily explains all those paradoxes.4Scientific researchers Bjorn Brücher and Ijaz Jamall, with the Theodor Billroth Academy, Munich, Germany, believe investigating genetic mutations in cancer is extremely important for understanding biological process.5However, they note that the complexity of these biological processes and the vast number of genetic alterations in human cancer may impede efforts to “find the needle—the origin of cancers—in this huge haystack.” Expanding on early theories of chronic inflammation as a cause of cancer,5,6Brücher and Jamall have proposed a multistep process based on data from plant, animal, and human studies that they believe “can describe the origin of the majority of cancers”:

Our paradigm postulates that cancer originates following a sequence of events that include (1) a pathogenic stimulus (biological or chemical) followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. From these changes a (4) pre-cancerous niche develops, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs.5

The authors said if their hypothesis proves correct, it would suggest most of the genetic polymorphisms observed in cancer occur later or “are epiphenomena that occur after the appearance of the precancerous niche.” It might also prompt development of new interventions that, if used prior to cell transition, could prevent or delay cancer progression.

Michael Karin, UC-San Diego School of Medicine, California, has also suggested inflammation as an important cause of cancer. He and several other researchers across the country are examining the complex relationship between bacteria, inflammation, and cancer.6

Some researchers, including Peter Duesberg at the University of California, Berkeley; Henry Heng, Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan; and Mark David Vincent, London Regional Cancer Program, Ontario; have offered similar models of oncogenesis in which malignant tumors are viewed almost as a parasite.7(Note: Duesberg has largely been shunned by the scientific community for insisting that the human immunodeficiency virus does not cause acquired immunodeficiency syndrome; nevertheless, his theories on cancer dovetail with theories of other credible researchers.)6Duesberg resurrected an earlier hypothesis that posited carcinogens as a cause of abnormal chromosomal divisions that resulted in a mass of cells possessing a unique chromosomal profile—essentially a different species from the human they affected. In contrast with Duesberg, however, Vincent believes a genetic mutation may drive this parasitic process.7

Too Little Information or Too Much?

Another hypothesis gaining some support is cancer as a metabolic disease, a theory that originated with Otto Warburg in the 1930s before it fell out of favor. Thomas Seyfried, biology department, Boston College, Chestnut Hill, Massachusetts is a strong proponent of the metabolic theory of cancer and has expressed skepticism of the push to develop more targeted therapies.8Seyfried and colleagues wrote that mitochondria abnormalities impair cellular energy metabolism, causing mutations that further impair cellular respiration. They believe the metabolic theory satisfactorily explains many of the paradoxes observed with the somatic mutation theory.An element that unites most critics of the concept that genetic abnormalities are the primary cause of cancer is the lack of progress against cancer despite the amount of money poured into genomic research. Robert Weinberg, Whitehead Institute for Biomedical Research, MIT Department of Biology, Cambridge, Massachusetts, who has written extensively about the role of genetic mutations in cancer, has an explanation—the sheer amount of data collected and its complexity.

He recently wrote, "While data mining...occasionally flags one or another highly interesting gene or protein, the use of entire data sets to rationalize how and why a cancer cell behaves as it does is still beyond our reach…The data that we now generate overwhelm our abilities of interpretation…We lack the conceptual paradigms and computational strategies for dealing with this complexity.” Although technology has been a tremendous help in unraveling the mechanisms of various diseases, as the experience with cancer shows, it may also create as many questions as it answers—questions that will likely require more advanced technology to understand.

References

  1. American Cancer Society. Family cancer syndromes. http://www.cancer.org/cancer/cancercauses/geneticsandcancer/heredity-and-cancer. Updated June 25, 2014. Accessed February 1, 2015.
  2. Ted talk with Minea Bissell: experiments that point to a new understanding of cancer. http://www.ted.com/talks/mina_bissell_experiments_that_point_to_a_new_understanding_of_cancer/transcript?language=en. Published June 2012. Accessed February 1, 2015.
  3. Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression?Nat Med. 2011;17:320-329.
  4. Baker SG, Cappuccio A, Potter JD. Research on early-stage carcinogenesis: are we approaching paradigm instability?J Clin Oncol. 2010;28:3215-3218.
  5. Brücher BL, Jamall IS. Epistemology of the origin of cancer: a new paradigm.BMC Cancer. 2014;14:331.
  6. Tontonoz M. Do bacteria cause cancer? Cancer Research Institute website. http://cancerresearch.org/news-publications/our-blog/march-2014/do-bacteria-cause-cancer. Published March 10, 2014. Accessed February 1, 2015.
  7. Haederle M. Cancer wars: an outcast researcher’s new theory. http://www.psmag.com/health-and-behavior/cancer-wars-an-outcast-researchers-new-theory-40560. Published April 27, 2012. Accessed September 1, 2015.
  8. Seyfried TN, Flores RE, Poff AM, D’Agostinio DP. Cancer as a metabolic disease: implications for novel therapeutics.Carcinogenesis. 2014;35:515-527.
  9. Weinberg RA. Coming full circle-from endless complexity to simplicity and back again.Cell. 2014;157:267-271.