SPARC enhances tumor stroma formation and prevents fibroblast activation

Abstract

Tumor growth is influenced by interactions between malignant cells and the tumor stroma. Although the normal host microenvironment is nonpermissive for neoplastic progression, tumor-reactive stroma, characterized by the presence of activated fibroblasts, promotes neoplastic growth and metastasis. Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that is capable of inhibiting the growth of several different types of cancer. Recently, we reported that SPARC also impairs the growth of xenografts comprised of 293 cells. In this study, we show that in addition to enhancing stroma formation, SPARC prevents fibroblast activation in 293 xenografts, suggesting that the anticancer effects of SPARC may be due, at least in part, to the formation of tumor stroma that is not supportive of tumor growth. In vitro, 3T3 fibroblasts cocultured with SPARC-transfected 293 cells remain negative for a-smooth muscle actin, whereas wild-type 293 cells induce fibroblast activation. Moreover, activation of 3T3 cells and primary fibroblasts by transforming growth factor b is blocked by SPARC treatment. We also demonstrate that SPARC significantly increases basic fibroblast growth factor-induced fibroblast migration in vitro, indicating that it may recruit host fibroblasts to the tumor stroma. Taken together, our results suggest that in addition to blocking angiogenesis, SPARC may inhibit tumor growth by promoting the assembly of stroma that is nonpermissive for tumor progression.

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

“…When Sparc +/+ and Sparc -/-macrophages were stimulated with H 2 O 2 , which is the prototypical ROS encountered in many tumor microenvironments including that of bladder cancer, the production of inflammatory cytokines by macrophages of either genotype was significantly increased over the nonstimulated controls (Supplemental Figure 5F) Figure 3A). Consistent with earlier reports (38,(40)(41)(42), under basal conditions, Sparc -/-NF exhibited 3.2-fold more proliferation, whereas Sparc -/-CAFs exhibited 0.9-fold more proliferation than Sparc +/+ counterparts: an effect that was reversed by exogenous SPARC (20 μg/ml; Supplemental Figure 6A). Next, we determined the expression of SPARC protein in Sparc +/+ NF during their differentiation in response to H 2 O 2 and CM from 72-hour murine bladder cancer cells (MB49).…”

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…Interestingly, the quality and quantity of mature collagen bundles reported in tumor stroma were positively correlated with levels of both tumor cell SPARC (32,33) and host SPARC (19,25,34). Thus, it was hypothesized that SPARC-induced changes in the tumor microenvironment were responsible, at least in part, for its anticancer effects (32).…”

“…As a tumor suppressor, effect of SPARC in different cancers was attributed not only to its counteradhesive, antiproliferative functions but also to its role in modulating angiogenesis as well as regulation of the production, assembly, and organization of the structural extracellular matrix proteins including type I collagen and fibronectin (23,25,(29)(30)(31)(32). Interestingly, the quality and quantity of mature collagen bundles reported in tumor stroma were positively correlated with levels of both tumor cell SPARC (32,33) and host SPARC (19,25,34). Thus, it was hypothesized that SPARC-induced changes in the tumor microenvironment were responsible, at least in part, for its anticancer effects (32).…”

The role of SPARC in the TRAMP model of prostate carcinogenesis and progression

“…The suppressive effects of SPARC on prostate cancer reported herein may, in part, be attributed to its negative effect on the constituents of the tumor microenvironment. Moreover, the enhanced proteolytic activity observed in the T þ /SP À/À prostate tumors may lead to increased tumor angiogenesis by increasing the bioavailability of angiogenic growth factors and proangiogenic inflammatory cytokines such as VEGF (and bFGF), IL-6, and MCP-1, as well as making the ECM more permissive for neovascular growth and sprouting (Chlenski et al, 2006(Chlenski et al, , 2007.…”

“…High expression of SPARC in malignant cells is associated with enhanced tumor growth and metastasis, and is correlated with poor survival for patients with melanoma, esophageal cancer, glioma, and head and neck cancers (Ledda et al, 1997;Schultz et al, 2002;Yamashita et al, 2003;Chin et al, 2005;Kato et al, 2005). In contrast, stromal SPARC inhibits angiogenesis and limits tumor growth in ovarian cancer and glioblastoma (Said and Motamed, 2005;Chlenski et al, 2006Chlenski et al, , 2007Said et al, 2007a, b). Although stromal SPARC was correlated with poor prognosis in pancreatic and small cell lung cancer (Podhajcer et al, 2008), tumor cell SPARC expression was lost due to promoter hypermethylation in pancreatic (Sato et al, 2003), non-small cell lung (Suzuki et al, 2005;Pan et al, 2008), colon (Tai et al, 2005;Yang et al, 2007;Cheetham et al, 2008), cervical (Sova et al, 2006;Kahn et al, 2008), endometrial (Rodriguez-Jimenez et al, 2007) and ovarian cancers (Socha et al, 2009).…”