PostDoc Journal Journal of PostDoctoral Research Vol. 1, No. 5, May 2013 www.postdocjournal.com Adapt or Dye: Tumor Microenvironment, A Powerful Regulator of Cancer Progression María Apellániz-Ruiz 1 , Zafira Castaño, PhD 2,3 1 Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, 28029, Spain 2 Heŵatology DiǀisioŶ, Brighaŵ & WoŵeŶ’s Hospital, BostoŶ, MassaĐhusetts, ϬϮϭϭϱ, U“A 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA Correspondence should be addressed to: Zafira Castaño: zcastano-corsino@partners.org Abstract Tumorigenesis is a complex multistep process in which a plethora of tumor and stromal cells play important roles. From this point of view, the biology of a tumor can be elucidated by focusing on the crosstalk between tumor cells and the tumor microenvironment, comprised by stromal cells of different origins. Several lines of evidence demonstrate essential contributions of tumor stromal cells, which influence the growth, survival, invasiveness, and metastatic ability of neoplastic epithelial cells within these tumors. This review describes the role of the microenvironment during tumor progression, and suggests possible new therapeutic avenues. Introduction Arguably one of the most well-known and widely studied aspects of cancer biology is the genetic mutations that underlie primary tumor formation. Tumor initiation is the result of mutations in oncogenes and tumor-suppressor genes. Often these genes directly affect the rate of cell growth or cell death. These mutations are inherited by daughter cells and the expansion of these populations give rise to tumors that have the uncontrolled rates of proliferation that are typical of cancer (1). Although clearly carcinomas arise from mutations in the epithelial cells that comprise the cancer, there is also evidence that the tumor microenvironment (TME) can play an important role in both initiation and promotion of cancer. The tumor microenvironment encompasses all of the components that surround and support tumor cells, including the extracellular matrix, and a milieu of distinct cell-types, including endothelial cells of the blood and lymphatic circulation, pericytes, fibroblasts, myofibroblasts, adipocytes, and a variety of bone marrow- derived cells. Tumor cells can alter the microenvironment, and reciprocally, the microenvironment can affect how tumor cells grow and spread (2, 3). The relevance of the TME was proposed almost 200 years ago, when in 1863 Virchow hypothesized that cancer may originate at sites of chronic inflammation. He based his hypothesis on the fact that some classes of irritants, which he Đalled proŵoters, eŶhaŶĐe epithelial Đell proliferation in response to tissue injury (reviewed by (4)). When tissues are wounded or