Figure 6.

Outline of the metastatic process according to the proposed model. Tumor cells leave the primary tumor as single cells and seed the distant tissue, where they may lodge for some time in a quiescent state or go on proliferating. In the latter occurrence, the growth will result in avascular micrometastases. A further growth phase implies the absence (or removal) of angiogenesis inhibitors in order to release those capable of inducing neovascularization, or else the switch to an angiogenic phenotype of a subset of tumor cells within hitherto nonangiogenic micrometastases. Only after the start of the vascular phase may micrometastases grow until overt clinical recurrence ensues. It may be hypothesized that the presence of the primary tumor exerts some kind of homeostatic effect upon distant metastases, resulting in inhibited proliferation and/or enhanced apoptosis. In the presurgical condition, the primary tumor somewhat restrains transitions, causing the dormancy of single cells and avascular micrometastases. Primary tumor surgical removal (per se or due to the surgical manoeuvre) might concur to enhance transitions and then to fuel the metastatic process, the dynamics of which is described by the hazard rate. During the follow-up, orderly transitions between cellular and micrometastatic dormant states will result in a progressive enrichment of the avascular micrometastatic dormant phase, from which overt metastases will successively emerge, as described by the hazard rate pattern, peaking during the second year. The IBTR surgical removal is a new perturbing factor of this on-going process, firing up a sudden growing phase for tumor foci most of which, otherwise, would have reached the clinical level according to their own dynamics