Seemingly the concept that assigns to cancer genes the primary role in carcinogenesis was in no conflict with the concept attributing site specific metastasis to the outcome of interactions between the seed (the tumor) and the soil (the TME). None the less, armed with cutting edge and sophisticated technologies the cancer geneticists established themselves as strong and influential policy makers while the microenvironmentalists, generating “uninteresting” data and describing “epiphenomena”

were not part of the main stream of cancer research at that time. The nineties of last century marked a change in this attitude. The contribution of the TME to cancer progression started to be recognized by an increasing number Nutlin-3a concentration of cancer researchers. A primary factor responsible for this development was the revolution in biomedicine brought about by the identification and functions of molecules involved in signal transduction and

the elucidation of signaling pathways [87–105]. Armed with novel knowledge and technologies it was demonstrated that gene expression in tumor cells as well as in non-tumor cells residing in the TME, is regulated by microenvironmental factors [e.g., 106, 107]. Assessment of the relative PCI-32765 in vitro contribution of microenvironmental factors versus genetic lesions to the shaping of the malignancy phenotype of tumor cells indicated that the latter are not the sole and exclusive driver of malignancy. For example, it was demonstrated that oncogenes and a microenvironmental factor (hypoxia) synergistically modulated VEGF expression in tumor cells and impacted angiogenesis [108]. Another study,

performed in my lab, showed that the microenvironment played an important role in tumorigenesis. The tumorigenicity of polyoma virus-transformed BALB/C 3T3 cells in syngeneic mice depended on the microenvironment in which these cells were grown rather than on the content of the polyoma middle T oncogene [109]. Another important factor that helped to bring TME to the fore front of AMP deaminase cancer research was that notable scientists from other domains of cancer research joined the ranks of the tumor microenvironmetalists. Mina Bissell, a noted developmental biologist was early in realizing that similarly to the dependence of developmental processes on the microenvironment, also tumor progression is dependent upon the microenvironment [110]. In another article Bissell’s group wrote “Several lines of evidence now support the contention that the pathogenesis of breast cancer is determined (at least in part) by the dynamic interplay between the ductal epithelial cells, the microenvironment, and the tissue structure (acini). Thus, to understand the mechanisms involved in carcinogenesis, the role of the microenvironment (ECM as well as the Epigenetics inhibitor stromal cells) with respect to tissue structure should be considered and studied” [111].