Pushing tumor cells towards a malignant phenotype: stimuli from the microenvironment, intercellular communications and alternative roads.

The tumor microenvironment produces different types of stimuli capable of endowing tumor cells with an aggressive behavior that is characterized by increased motility, invasiveness and propensity to metastasize, gain of a tumor-initiating phenotype, and drug resistance. The following classes of stimuli have been reported to promote such a malignant phenotype: (i) solid- or fluid-induced stress; (ii) altered composition of the extracellular matrix; (iii) hypoxia and low pH; (iv) innate and adaptive immune responses; (v) antitumor drugs. The simultaneous presence of more than one of these stimuli, as likely occurs in vivo, may lead to synergistic interactions in the induction of malignant traits. In many cases, the gain of a malignant phenotype is not the result of a direct effect of the stimuli on tumor cells but, rather, a stimulus-promoted cross-talk between tumor cells and other cell types within the tumor microenvironment. This cross-talk is mainly mediated by two classes of molecules: paracrine factors and adhesion receptors. Stimuli that promote a malignant phenotype can promote additional outcomes in tumor cells, including autophagy and cell death. We summarize here the available evidence about the variables that induce tumor cells to take one or the other of these roads in response to the same stimuli. At the end of this review, we address some unanswered questions in this domain and indicate future directions of research.