The traditional interpretation of cancer progression is that tumor cells accumulate multiple genetic alterations, resulting in the capability to surmount a variety of obstacles including detachment from the primary tumor, intravasation into blood or lymphatic vessels, survival into circulation, extravasation and growth at a secondary site, lymph node and/or distant organ (Vogelstein and Kinzler, Nat Med 10:789-799, 2004). The hypothesis of a hierarchical organization of cells within at least certain tumors in which a subset of tumor cells has the property to self-renew, hence defined stem-like or cancer stem cells (CSC), and to generate and sustain the wide heterogeneity comprising the tumor is very attractive. However, the tumor cell-centered view of cancer progression ignores the contribution of the tumor microenvironment to the malignant phenotype. A tumor should be viewed as a complex dynamically evolving ecosystem where minor alterations may cause dramatic reorganization of the whole system and of the malignant versus benign behavior of cells. In fact, the tumor microenvironment is constantly changing and cancer cells, either CSC or more differentiated tumor cells, adapt, evolve, and survive during this process. Tumors grow in conducive microenvironments reminiscent of the normal stem cells niche concept. The tumor microenvironment is implicated in the transition from preinvasive to invasive growth and is regarded as a crucial participant in tumorigenesis promoting a more aggressive phenotype and has relevance also for therapeutical approaches.
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