Article in Seminars in Cancer Biology · April 2008 doi: 10. 1016/j semcancer

Conclusions

While providing extremely sophisticated, reliable details of processes happening inside cells,

the reductionist, gene-centered strategy of the SMT appears to be irrelevant, however, to the

resolution of the cancer puzzle. During the last three decades, the field of cancer research has

witnessed a slowly but relentless switch of emphasis in searching of explanations for

carcinogenesis. From a reductionist, bottom-up approach represented by the SMT the

consensus is moving toward an emergentist, top-down and bottom-up approach where the

centerpiece of the research effort is the tissue microenvironment. A rapidly growing body of

Sonnenschein and Soto

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data on stroma-epithelium interactions and the role of mechanical forces on tissue architecture

suggest that cancer is a developmental process, akin to organogenesis but gone awry, happening

at the tissue level of biological complexity. No amount of rhetorical fodder will resolve the

paradoxes emerging when explaining carcinogenesis and metastasis. Systems biologists now

have the tools at the in animal, in culture and the in silico levels and the ingenuity to devise

new methodologies aimed at unraveling this complex process. However, for this to be effective

it will be crucial to honor evolutionary principles; as not even organismal biology could be

understood outside the frame of evolution [17,67]. In our view, the questions we are left to

grapple with are the following: 1) is the default state of all cells proliferation or quiescence?

and 2) is the locus of carcinogenesis the tissular level of biological organization or, instead,

the cellular/subcellular one? The answers to these questions ought to enlighten the scientific

community on the merits of joining evolutionary thinking at levels of biological complexity

that have so far escaped its powerful influence. The overused mantra of “translational research”

would then make more sense and thus replace hype with substance.