Anticancer drug resistance is a multifactorial process that includes acquired and de novo drug resistances. Acquired resistance develops during treatment, while de novo resistance is the primary way for tumor cells to escape chemotherapy. Tumor microenvironment has been recently shown to be one of the important factors contributing to de novo resistance and called environment-mediated drug resistance (EMDR). Two forms of EMDR have been described: soluble factor-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR). Anthracyclines, among the most potent chemotherapeutic agents, are widely used in clinics against hematopoietic and solid tumors. Their main mechanism of action relies on the inhibition of topoisomerase I and/or II and the induction of apoptosis. Beyond this well-known antitumor activity, it has been recently demonstrated that anthracyclines may display potent anti-invasive effects when used at subtoxic concentrations. In this paper, we will describe two particular modes of EMDR by which microenvironment may influence tumor-cell response to one of these anthracyclines, doxorubicin. The first one considers the influence of type I collagen on the antimigratory effect of doxorubicin (CAM-DR). The second considers the protection of tumor cells by thrombospondin-I against doxorubicin-induced apoptosis (SFM-DR). 1. Tumor Cell Microenvironment and Drug Resistance In the last decade, the earlier point of view of tumors as a relatively homogeneous cancer cells has been totally changed into considering tumors as high complex organs. The autonomous properties of cancer cells are no longer sufficient to elucidate the multistep process of tumorogenesis. In fact, a better understanding of this process needs to take into consideration the stromal cells and the extracellular matrix (ECM) proteins that constitute the tumor microenvironment. These elements are known to contribute to the development and the expression of certain cancer hallmarks [1]. It is well documented that anticancer drug resistance represents a major obstacle for the successful treatment of various human malignancies. This process is multifactorial and can be subdivided into two broad categories: acquired and environment-mediated drug resistance (EMDR). Acquired resistance develops during treatment as a result of sequential genetic changes leading mainly to overexpression of drug transporters and alterations in drug targets [2]. Conversely, EMDR a form of de novo resistance allows cancer cells to tolerate the stress induced by therapies during the first
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