Over a century of cancer research: “inconvenient truths” and promising leads

Despite more than a century of intensive research, including the “great gains” promised by the “War on Cancer” (in 1971), our understanding of the fundamental etiology of this complex disease is still incomplete. Authors [see attached essay] analyze the “lack of progress” since 1999, in explaining and “curing” cancer — by examining the merits of the premises that determine how cancer is understood and treated. Authors propose to “clarify the sources of misunderstandings at the root of the cancer puzzle”, while providing a plausible and comprehensive biomedical perspective, as well as a new theory of carcinogenesis that is compatible with evolutionary theory. Herein the authors explain how this new theory, the tissue-organization-field theory (TOFT), “might help chart a path to progress for cancer researchers by explaining features of cancer that remain inexplicable from the perspective of the (still dominant) somatic mutation theory (SMT) and its variants.” Authors suggest that “the premises underlying the TOFT can offer new perspectives” on basic biological phenomena.

The SMT is anchored at the cellular level of biological organization. If “a cell” is the crucial target of carcinogens, the research strategy to be followed highlights events to be found inside cells. Adequate models for this strategy can then be adopted — as exemplified by experiments using a single cell-type in a 2-dimensional cell culture. In contrast, the TOFT is anchored at the tissue level of biological organization; thus, carcinogenesis is explored as a relational problem, whereby the reciprocal interactions among diverse cell-types of the morphogenetic field (i.e. development of normal form or structure especially as controlled by the growth, differentiation, and movement of cells and tissues) take place. The TOFT focuses not on a single cell-type but (as in organogenesis) on the interactions among different cell types and compartments.

The difference between these theories can be summarized as “the renegade cell” of the SMT versus “development gone wrong” of the TOFT. Equally important, these two theories adopt distinctive premises regarding inherent cell behavior: [a] the cell-centered theory implicitly adopts the principle that quiescence is the constitutive (default) state of all cells, and therefore cells require intrinsic or extrinsic stimulation by either “oncogenes” or “growth factors,” respectively, in order to proliferate; [b] the TOFT postulates that proliferation is the default state of all cells, and therefore only inhibitory constraints prevent them from entering the cell cycle. Thus, according to the TOFT, cells constitutively proliferate and generate movement, whereas tissues in which they reside constrain their ability to proliferate and move. When a carcinogen relaxes these tissue constraints, cells regain their default state and proliferate again, eventually forming a tumor mass — also allowing cells to migrate, invade tissues, and metastasize to other sites in the body. Hence, the relevant question is not what drives proliferation and motility, but rather what tissue constraints inhibit both processes and how they operate in the altered morphogenetic field.

For the sake of future credibility in the fields of biology at large and cancer in particular — authors believe that “a rigorous critical assessment of the odd situation that biologists and cancer researchers are facing is needed.” Cancer researchers’ long-term analysis of the theoretical bases under which cancer research has been conducted — and the empirical evidence collected after more than a century of detailed research — indicates that the reductionist cell-based SMT should be abandoned and replaced by the tissue-based TOFT that adopts principles relevant to the theories of evolution and organogenesis. Switching theories will have profound effects on biology at large and, critically, on how researchers design their experiments and interpret observations in normal vs cancer states.


PLoS Biol Apr 2020; 18: e3000670

COMMENT: The more I read of this review, the more I felt it was a “nothingburger,” “lots of eloquent words summarizing everything and signifying nothing…”


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