1. ¹Laboratory of Molecular and Cellular Therapy, Leloir Institute – CONICET – University of Buenos Aires, Patricias Argentinas 435, (C1405BWE), Buenos Aires, Argentina
2. ²Molecular Pathology Section, Eva Perón Hospital, Balcarce 900, (1650) Provincia de Buenos Aires, Argentina
3. ³Animal Facility, Faculty of Veterinary Sciences, University of La Plata, Calle 60 y 118, (B1094AVW), La Plata, Argentina

Correspondence: Dr Osvaldo L. Podhajcer, Instituto Leloir, Av. Patricias Argentinas 435, (C1405BWE) Ciudad de Buenos Aires, Argentina. E-mail: opodhajcer@leloir.org.ar

⁴Current address: Joint Centers for Systems Biology, Columbia University, New York, New York 10032, USA

Received 13 November 2006; Revised 24 April 2007; Accepted 13 May 2007; Published online 12 July 2007.

Abstract

SPARC (secreted protein acidic and rich in cysteine) is a matricellular protein whose overexpression in malignant or tumor-stromal cells is often associated with increased aggressiveness and bad prognosis in a wide range of human cancer types, particularly melanoma. We established the impact that changes in the level of SPARC produced by malignant cells and neighboring stromal cells have on melanoma growth. Melanoma cell growth in monolayer was only slightly affected by changes in SPARC levels. However, melanoma growth in spheroids was strongly inhibited upon SPARC hyperexpression and conversely enhanced when SPARC expression was downregulated. Interestingly, SPARC overexpression in neighboring fibroblasts had no effect on spheroid growth irrespective of SPARC levels expressed by the melanoma cells, themselves. Downregulation of SPARC expression in melanoma cells induced their rejection in vivo through a mechanism mediated exclusively by host polymorphonuclear cells. On the other hand, SPARC hyperexpression enhanced vascular density, collagen deposition, and fibroblast recruitment in the surrounding stroma without affecting melanoma growth. In agreement with the in vitro data, overexpression of SPARC in co-injected fibroblasts did not affect melanoma growth in vivo. All the data indicate that melanoma growth is not subject to regulation by exogenous SPARC, nor by stromal organization, but only by SPARC levels produced by the malignant cells themselves.