Journal of Cellular Biochemistry 104:721–732 (2008) A Prototypic Matricellular Protein in the Tumor Microenvironment—Where There’s SPARC, There’s Fire Clancy J. Clark 1 and E. Helene Sage 2 * 1 Department of General Surgery, Virginia Mason Medical Center, Seattle, Washington 2 Benaroya Research Institute at Virginia Mason, Seattle, Washington Abstract Within the tumor microenvironment is a dynamic exchange between cancer cells and their surrounding stroma. This complex biologic system requires carefully designed models to understand the role of its stromal components in carcinogenesis, tumor progression, invasion, and metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a prototypic matricellular protein at the center of this exchange. Two decades of basic science research combined with recent whole genome analyses indicate that SPARC is an important player in vertebrate evolution, normal development, and maintenance of normal tissue homeostasis. Therefore, SPARC might also play an important role in the tumor microenvironment. Clinical evidence indicates that SPARC expression correlates with tumor progression, but tightly controlled animal models have shown that the role of SPARC in tumor progression is dependent on tissue and tumor cell type. In this Prospectus, we review the current understanding of SPARC in the tumor microenvironment and discuss current and future investigations of SPARC and tumor–stromal interactions that require careful consideration of growth factors, cytokines, proteinases, and angiotropic factors that might influence SPARC activity and tumor progression. J. Cell. Biochem. 104: 721 – 732, 2008. ß 2008 Wiley-Liss, Inc. Key words: tumor microenvironment; SPARC; matricellular protein; angiogenesis; desmoplasia Within the tumor microenvironment, the stromal response through the production of growth factors, cytokines, and proteinases can determine tumor progression, invasion and metastasis [Witz and Levy-Nissenbaum, 2006; Albini and Sporn, 2007; Li et al., 2007; Potter, 2007]. In the setting of an established tumor, the network of extracellular and cellular com- ponents surrounding a tumor can facilitate or hinder tumor progression. Recent evidence also indicates that non-malignant, normal mesenchymal stromal cells (fibroblasts and myofibroblasts) can sufficiently alter the micro- environment of normal epithelial cells to pre- dispose them to malignant transformation or carcinogenesis [Olumi et al., 1999; Hu et al., 2005; Kalluri and Zeisberg, 2006]. Despite the wealth of information gained from tumor models that manipulate processes within tumor cells, we can no longer ignore the fact that tumor cells grow, not only in a highly inter- active environment, but also in discretely dif- ferent microenvironments. For example, a host response is undoubtedly divergent when human glioblastoma cells are injected into the relatively hypoxic, nutrient-poor dermis of a mouse, as opposed to implantation of these cells into the nutrient-rich, immune-privileged brain parenchyma of a syngeneic host. Due to the complexity of interactions at the stroma–tumor interface, two distinct approaches are currently employed. First, sys- tems biologists, using in silico analyses based on high throughput technologies that include whole genome single nuclear polymorphism (SNP) arrays, serial analysis of gene expression (SAGE), phage display, DNA microarray, tan- dem mass spectrometry proteomics, and tissue microarrays, are modeling tumor–host inter- actions to identify key, ‘‘rate-limiting’’ players in the tumor microenvironment [Kitano, 2002; Anderson et al., 2006]. Although terabytes of ß 2008 Wiley-Liss, Inc. Grant sponsor: Frederick A. Coller Society Surgical Fellow- ship; Grant sponsor: National Cancer Institute; Grant number: CA109559; Grant sponsor: National Inst. of Gen. Med. Sciences; Grant number: GM40711. *Correspondence to: E. Helene Sage, PhD, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue Seattle, WA 98101. E-mail: hsage@benaroyaresearch.org Received 7 December 2007; Accepted 10 December 2007 DOI 10.1002/jcb.21688