Theories of Carcinogenesis: Cancer as Development Gone Awry
10:00 am US Eastern Time
Speaker presentation slides
Additional resources of interest
Listen to the first call in this series: Theories of Carcinogenesis: Assessing the Carcinogenic Potential of Low-Dose Exposures to Chemical Mixtures in the Environment
Soto/Sonnenschein Labratory: New Theory of Carcinogenesis: Tissue organization field theory of carcinogenesis (includes links to additional recommended readings)
Journal of the National Cancer Institute: Cancer Metastases: So Close and So Far
When CHE Partners explore environmental contributors to cancer, they often do so with limited scientific background in the competing theories of carcinogenesis. The CHE Cancer Working Group is undertaking a series of teleconferences to explore these theories because of their direct bearing on how environmental contributors to carcinogenesis are perceived and evaluated. On this call on Drs. Carlos Sonnenschein and Ana Soto discussed the tissue organization field theory (TOFT).
From Drs. Sonnenschein and Soto:
At the beginning of the 21st century, biology is facing an epistemological crisis which anticipates a paradigm change. Reductionism has failed to bring about an understanding of complex phenomena which resulted in reappraisals of old research concepts in embryology and cancer research. Objectively, the dominant view during the last fifty years has been that development is merely the unfolding of a genetic program. This view guided the construction of developmental genetics, “a discipline that explicitly treated phenotype as a direct ‘readout’ of the nuclear genome” (SF Gilbert, J. Biosci. 2005;30:65–74). This perception is now being challenged by two disciplines that are displacing the gene as privileged causal agents; those disciplines are ecological developmental biology and developmental systems theory.
Complementarily, the dominant theory of carcinogenesis, the somatic mutation theory (SMT), is being replaced by the tissue organization field theory (TOFT). The century-old, gene-centered and reductionist SMT views cancer as a cell-based disease. The premises of this theory are: 1) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations, 2) cancer is a disease of cell proliferation caused by mutations in genes involved in the cell cycle and/ or the control of cell proliferation, and 3) the default state of cell proliferation in metazoa is quiescence. The research program of the SMT adopted cell lines growing in 2-D cultures as the subject of research, thus reducing cancer to a 2D cellular phenomenon. Additionally, neoplasms, which are 3D structures, were reduced to “transformed” cells. Because lack-of-fits are increasingly challenging the predictions of this theory, a series of ad hoc explanations are being offered resulting in a field rife with contradictions. Partly due to these shortcomings, the TOFT that is centered at the tissue level of organization, has been gaining momentum.
The historical and conceptual roots of the TOFT date from the late nineteenth century when pathologists, using light microscopes, described the histological pattern of tumors and suggested that altered tissue organization was at the core of neoplasia, thus linking carcinogenesis to embryonic development. In contrast to SMT, TOFT postulates that: 1) carcinogenesis represents a problem of tissue organization, and 2) the default state of all cells is proliferation with variation and motility. A central motif in this theory is the persistence of morphogenetic fields throughout adult life; these fields orchestrate histogenesis and organogenesis before birth as well as tissue maintenance and regeneration throughout postnatal life. Carcinogens as well as teratogens, acting on those morphogenetic fields, would disrupt the normal dynamic interaction of neighboring cells and tissues. The TOFT posits that neoplasms result from a flawed interaction among cells and tissues and that, thus carcinogenesis is potentially reversible. Accordingly, explaining carcinogenesis requires the use of animal models and/or 3D cultures where cells can organize into tissues resembling the topology and cellular diversity observed in neoplasms in vivo. The development of the research program based on the TOFT will contribute to explaining carcinogenesis and will provide realistic therapeutic options to cancer patients.
Carlos Sonnenschein, MD, Professor of Integrative Physiology & Pathobiology at Tufts University. The Sonnenschein Lab's research concentration is on on three interrelated areas: the control of cell proliferation by estrogens and androgens; the impact of endocrine disruptors on organogenesis and the reproductive function; and, the role of stroma/epithelial interactions on rat and human mammary carcinogenesis. Dr. Sonnenschein has collaborated for several decades with Professor Ana M. Soto, M.D., his colleague at the Tufts University Medical School. Part of that collaboration led to the early discovery of the pernicious effect of endocrine disruptors (they coined the term). For their exceptional contribution to science through this work, Drs. Sonnenschein and Soto they received the 2012 Jacob Heskel Gabbey Award (with Dr. Patricia Hunt). Dr. Sonnenschein also co-authored with Dr. Soto The Society of Cells (Bios-Springer-Verlag, 1999) in which they proposed, based on exhaustive analysis of cancer research, that the so-called sporadic cancers (95 percent of all clinical cases) represent diseases specifically anchored at the tissue level of biological organization (tissue organization field theory, TOFT).
Ana Soto, MD, Professor of Integrative Physiology & Pathobiology at Tufts University. Dr. Soto's laboratory studies the regulation of cell proliferation by sex steroids.This work is based on the premise that proliferation is the default state of all living cells. The lab recently identified an androgen-induced gene that mediates the state of proliferative quiescence observed in normal adult prostate epithelium. In collaboration with Dr. Carlos Sonnenschein, Dr. Soto and her colleagues have proposed the tissue organization field theory of carcinogenesis. It posits that carcinogenesis is a tissue-based phenomenon, rather than a cell-based phenomenon caused by DNA mutations. In 2013 Dr. Soto selected by a scientific committee of the French government as one of four Blaise Pascal Chairs in residence at the Ecole Normale Superieure, in Paris. While in Paris, Soto explored what she terms a “crisis” in biology, namely the lack of an all-encompassing theory capable of directing and analyzing complex biological phenomena. “We are facing an explosion of data,” she wrote the Pascal committee in describing her proposed research project, “but do not yet have the theoretical bases or an adequate language to make sense of them.”
The call was moderated by Michael Lerner, President of Commonweal.