Editorial [Hot Topic:Targeting Tumor Stroma (Guest Editors: Marc G. Achen and Steven A. Stacker)]

Many of the currently available anti-cancer therapeutics are based on the concept of targeting tumor cells. However, the tumor stroma has also become a major focus of attention as a therapeutic target. An early attempt to target stromal components, in the 1990s, involved the matrix metalloproteinases (MMPs), that can be expressed by various cell types in the tumor stroma. MMPs were targeted in human cancer with synthetic inhibitors, however, these compounds failed in clinical trials, in part because the complex mechanisms-of-action of MMPs, and the biology of the tumor stroma, were not well understood. Typically, the tumor stroma can consist of extracellular matrix as well as a range of cell types, including fibroblasts, the endothelial cells of blood vessels and lymphatic vessels, and immune cells such as monocytes and macrophages. The cells of the tumor stroma can be important for sustaining or promoting the growth and metastatic spread of solid tumors. For example, tumor angiogenesis, that gives rise to tumor blood vessels, promotes tumor growth and presumably facilitates metastatic spread via the bloodstream. Moreover, tumor lymphangiogenesis, that increases the abundance and possibly the size of peritumoral or intratumoral lymphatics, may facilitate metastatic spread of tumor cells to regional lymph nodes and possibly to more distant sites in the body. Recent studies have indicated that components of inflammatory infiltrate in solid tumors, particularly macrophages, can play a role in recruiting blood vessels thereby facilitating tumor growth. The communication between tumor cells and stromal components is facilitated by a range of growth factors, growth factor receptors and proteases. Members of the VEGF family of glycoproteins are important for recruitment of tumor blood vessels and lymphatics, Wnt signaling pathways are involved in signaling between epithelial cells and stromal cells, TGF-β is thought to play a role in the tumor-promoting activities of cancer-associated fibroblasts, and the Eph receptors and their ephrin ligands may be important for migration of stromal cells associated with tumors. Each of these signaling systems is examined by an article in this issue. The growth factors and receptors that are essential for such signaling pathways are potential therapeutic targets in cancer - some, including VEGF-A and VEGF receptors, have already been exploited for development of anti-cancer therapeutics. The emerging technologies of “systems biology” will surely prove useful for defining the circuitry of biological signal transduction pathways that control the interaction of tumor cells with components of the tumor stroma. This information will be essential for understanding how distinct signaling pathways can influence each other to determine outcomes in terms of tumor biology. The targeting of the tumor stroma will undoubtedly become a more prominent theme for anti-cancer therapeutics in future. We trust that this issue, which explores i) the biology of the tumor stroma, ii) specific signaling pathways involved in communication between tumor cells and stromal components, and iii) therapeutic strategies for targeting stromal components, will provide a useful overview of current activities in this rapidly developing area.