Down-regulation of the extracellular matrix protein SPARC in vSrc- and vJun-transformed chick embryo fibroblasts contributes to tumor formation in vivo

Abstract

In vitro transformation of primary cultures of chick embryo ®broblasts by the membrane-bound vSrc or the nuclear vJun oncoproteins is correlated with a downregulation of the secreted glycoprotein SPARC (also called BM-40 or osteonectin). This protein is a nonstructural component of the extracellular matrix that is thought to regulate cell ± matrix interaction during development, wound repair, and carcinogenesis. Its precise function remains unclear. To estimate the contribution of SPARC down-regulation to the major aspects of the transformed phenotype, we have reexpressed this protein from a self-replicating retrovirus Rcas, designated R-SPARC, in the transformed cultures. These R-SPARC-infected cultures display the following main properties: (i) they accumulate the SPARC protein to a level identical to or only slightly higher than the level in normal chick embryo ®broblasts; (ii) they retain the main phenotypic properties characteristic of in vitro transformed cells, that is, altered morphology, capacity to grow in a reduced amount of serum, and capacity to develop colonies from single cells in agar; (iii) they display a clearly reduced capacity to develop local ®brosarcomas in vivo. Taken together, these data strongly suggest that down-regulation of SPARC contributes to the transformed phenotype triggered by vSrc and vJun in primary avian ®broblasts, by facilitating in vivo tumorigenesis.

Endogenous Osteonectin/SPARC/BM-40 Expression Inhibits MDA-MB-231 Breast Cancer Cell Metastasis

“…The promoting or inhibiting effects of osteonectin in different cancers seem dependent upon the cell type, the concentration, and the presence of full-length or proteolytic fragments of osteonectin (9). Although osteonectin promotes melanoma and squamous cell tumor growth (10,11) and glioma invasion (12), there are reports that decreased osteonectin expression is associated with increased tumorigenicity and metastasis of human ovarian carcinoma cells (13) as well as transformed fibroblasts (14,15). In neuroblastomas, expression of osteonectin is inversely correlated with malignant progression, and treatment of these tumors with osteonectin results in impaired tumor growth in vivo (16).…”

Decorin Evokes Protracted Internalization and Degradation of the Epidermal Growth Factor Receptor via Caveolar Endocytosis

“…During quiescence, decorin expression is markedly up-regulated in most normal diploid cells, whereas its expression is nearly abolished in most transformed cells (2, 18 -20). For example, transformation induced by the activating transcription factor-3 and the nuclear v-Src and v-Jun oncoproteins cause a marked suppression of decorin gene expression (21)(22)(23). Lack of decorin expression is permissive for tumor development insofar as mice with a targeted ablation of both decorin and the tumor suppressor gene p53, develop lymphomas at accelerated rates as compared with the p53 null animals (24).…”

Decorin Binds to a Narrow Region of the Epidermal Growth Factor (EGF) Receptor, Partially Overlapping but Distinct from the EGF-binding Epitope

“…Most of the biological functions of decorin are mediated by the protein core's unique organization of 10 tandem leucine-rich repeats (LRR) 1 which fold into an arch-shaped structure (9) whose concave surface is well suited to bind both globular and nonglobular proteins (2,10,11) as well as metal ions (12). Decorin expression is markedly suppressed in most transformed cells derived from primary malignant tumors (13)(14)(15) or in cells transformed by oncogenes such as vSrc (16), vJun (17), and ATF3 (18). On the contrary, decorin expression is markedly up-regulated during quiescence (19,20), and its levels can reach ϳ40-fold in post-confluent fibroblasts (21).…”