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SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated
Author(s) -
Haber Cynthia López,
Gottifredi Vanesa,
Llera Andrea S.,
Salvatierra Edgardo,
Prada Federico,
Alonso Leonardo,
E. Helene Sage,
Podhajcer Osvaldo L.
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23216
Subject(s) - osteonectin , cell growth , stromal cell , extracellular matrix , melanoma , cancer research , cell culture , cancer cell , microbiology and biotechnology , cell adhesion , endogeny , chemistry , cell , biology , cancer , biochemistry , genetics , enzyme , alkaline phosphatase , osteocalcin
Cell interaction with the extracellular matrix (ECM) has profound influence in cancer progression. The s ecreted p rotein, a cidic and r ich in c ysteine (SPARC) a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. This apparent paradox might result either from the biochemical properties of the different SPARC sources or from differential responses of malignant and stromal cells to SPARC. To test these hypotheses, we purified SPARC secreted by melanoma cells (hMel‐SPARC) and compared its activity with different recombinant SPARC preparations, including a new one produced in insect cells. All 5 SPARC species were effective in inhibiting bovine aortic endothelial cell proliferation, adhesion and migration. We then used the melanoma‐derived protein to assess SPARC effect on additional cell types. hMel‐SPARC greatly impaired the proliferation of both normal and transformed human endothelial cells and exerted a moderate biphasic effect on human fetal fibroblasts proliferation, irrespective of their endogenous SPARC levels. However, SPARC had no effect on the proliferation of several human cancer cell lines regardless of their endogenous levels of SPARC expression. Importantly, downregulation of SPARC levels in melanoma cells using either an antisense RNA or a shRNA against SPARC sensitized them to hMel‐SPARC addition in proliferation and migration assays, suggesting that malignant cells developed a SPARC‐resistance mechanism. This was not a general resistance to growth suppressing agents, as melanoma cells with restricted SPARC expression were more resistant to chemotherapeutic agents. Thus, malignant cells expressing or not expressing SPARC developed alternative mechanisms that, in contrary to stromal cells, rendered them SPARC‐insensitive. © 2007 Wiley‐Liss, Inc.