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

In vitro transformation of primary cultures of chick embryo fibroblasts 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 extracellula r matrix that is thought to regulate cell-matrix interaction during develop ment, wound repair, and carcinogenesis. Its precise function remains unclea r. To estimate the contribution of SPARC down-regulation to the major aspec ts of the transformed phenotype, we have reexpressed this protein from a se lf-replicating retrovirus Rcas, designated R-SPARC, in the transformed cult ures. These R-SPARC-infected cultures display the following main properties : (i) they accumulate the SPARC protein to a level identical to or only sli ghtly higher than the level in normal chick embryo fibroblasts; (ii) they r etain the main phenotypic properties characteristic of in vitro transformed cells, that is, altered morphology, capacity to grow in a reduced amount o f serum, and capacity to develop colonies from single cells in agar; (iii) they display a clearly reduced capacity to develop local fibrosarcomas in v ivo. Taken together, these data strongly suggest that down-regulation of SP ARC contributes to the transformed phenotype triggered by vSrc and vJun in primary avian fibroblasts, by facilitating in vivo tumorigenesis.