Beyond the cancer cell: progression-level determinants highlight the multiscale nature of carcinogenesis risk

Over the last several decades, improved awareness of the prevalence of carcinogens in the environment, along with a growing appreciation of the complexity of the carcinogenesis process, has shifted policy on cancer risk from one of strict avoidance of carcinogens to one of adherence to exposure limits deemed "safe" based on quantitative risk estimation. Meanwhile, given the mutagenic nature of most carcinogens, attention has gravitated to developing a genetic rationale for measuring and comparing risks. This focus has culminated in the now well-established multistage mutational paradigm, which holds that a stepwise sequence of mutations drives cell "initiation" and the subsequent "transformation" of an initiated cell into a cancer cell, and that, once created, a cancer cell will inevitably undergo "progression" to become overt disease. Unanticipated by this paradigm is the effect progression-phase population- and tissue-level bottleneck events may have on this process. Attesting to this is the prevalence of tumor dormancy, a state of arrested growth of an otherwise fully malignant, often microscopic cancer mass, maintained by interactions among cancer cells and between cancer and host cells. The proper inclusion of such progression-modifying influences would clearly behoove risk estimation and improve our understanding of the natural history of cancer by accounting for the less-than-certain risk of eventual cancer disease even when cancer cells are present. Such an improved understanding, in turn, stands to better inform policy-making and influence such clinical practice decisions as whether to treat the increasingly smaller tumors detectable with advancing technologies.