SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated.

CYNTHIA LÓPEZ HABER; VANESA GOTTIFREDI; ANDREA S. LLERA; EDGARDO SALVATIERRA; FEDERICO PRADA; LEONARDO ALONSO; E. HELENE SAGE; OSVALDO PODHAJCER

INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER.

JOHN WILEY & SONS INC

Año: 2008 vol. 122 p. 1465 - 1475

0020-7136

Cell interaction with the extracellular matrix (ECM) has profoundinfluence in cancer progression. The secreted protein, acidic andrich in cysteine (SPARC) a component of the ECM, impairs theproliferation of different cell types and modulates tumor cellaggressive features. This apparent paradox might result eitherfrom the biochemical properties of the different SPARC sourcesor from differential responses of malignant and stromal cells toSPARC. To test these hypotheses, we purified SPARC secreted bymelanoma cells (hMel-SPARC) and compared its activity with differentrecombinant SPARC preparations, including a new oneproduced in insect cells. All 5 SPARC species were effective in inhibitingbovine aortic endothelial cell proliferation, adhesion andmigration. We then used the melanoma-derived protein to assessSPARC effect on additional cell types. hMel-SPARC greatlyimpaired the proliferation of both normal and transformedhuman endothelial cells and exerted a moderate biphasic effect onhuman fetal fibroblasts proliferation, irrespective of their endogenousSPARC levels. However, SPARC had no effect on the proliferationof several human cancer cell lines regardless of their endogenouslevels of SPARC expression. Importantly, downregulationof SPARC levels in melanoma cells using either an antisenseRNA or a shRNA against SPARC sensitized them to hMel-SPARCaddition in proliferation and migration assays, suggesting that malignantcells developed a SPARC-resistance mechanism. This wasnot a general resistance to growth suppressing agents, as melanomacells with restricted SPARC expression were more resistantto chemotherapeutic agents. Thus, malignant cells expressing ornot expressing SPARC developed alternative mechanisms that, incontrary to stromal cells, rendered them SPARC-insensitive.