The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host

Abstract

Tumor growth is essentially the result of an evolving cross-talk between malignant and surrounding stromal cells (fibroblasts, endothelial cells and inflammatory cells). This heterogeneous mass of extracellular matrix and intermingled cells interact through cell-cell and cell-matrix contacts. Malignant cells also secrete soluble proteins that reach neighbor stromal cells, forcing them to provide the soil on which they will grow and metastasize. Different studies including expression array analysis identified the matricellular protein SPARC as a marker of poor prognosis in different cancer types. Further evidence demonstrated that high SPARC levels are often associated with the most aggressive and highly metastatic tumors. Here we describe the most recent evidence that links SPARC with human cancer progression, the controversy regarding its role in certain human cancers and the physiological processes in which SPARC is involved: epithelial-mesenchymal transition, immune surveillance and angiogenesis. Its relevance as a potential target in cancer therapy is also discussed.

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

“…Our results from GeneChip analysis and quantitative evaluation of SPARC mRNA expression in 110 CaP patients are consistent with the literature that indicates a role for SPARC, 22,23 and a high expression of SPARC protein 20 , in metastasis. Therefore, we hypothesized that high SPARC expression (likely at protein level as SPARC is functionally linked to metastasis) in primary prostate tumors may predict a higher chance of later metastasis.…”

“…Of note, there was conservation of NKXH_NKXH_HOX composite regulatory elements in the promoters of the genes in this network suggestive of the biological significance of this gene-expression regulatory mechanism in CaP progression. As SPARC has a role 22,23 and high protein levels 20 in metastasis, we hypothesized that high SPARC expression in primary tumor may predict future metastasis. Indeed, further analysis revealed that high SPARC protein expression in malignant prostate cells at the time of RP is associated with an increased risk of tumor metastasis (see study flow chart in Supplementary Figure 2).…”

“…SPARC plays an important role in cell-matrix interactions, tissue remodeling, wound repair, cellular differentiation, morphogenesis, cell migration and angiogenesis. 21,[23][24][25] In this study, the transcriptome of laser capture-microdissected tumor cells with poorly differentiated (PD) and with well differentiated (WD) phenotype were analyzed for gene expression and biochemical pathway alterations significantly associated with aggressive CaP. SPARC, a gene linked to bone metastasis, was identified as a potential early marker of less favorable outcome associated with poor differentiation of CaP.…”

Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis

“…Although endothelial cells in the tumour microenvironment are known to produce high levels of SPARC, we found that endothelial-derived SPARC did not influence melanoma cell transmigration, further supporting the notion that tumour-and host-derived SPARC have different biological activities and that the origin of SPARC participates to the complexity of SPARC in metastasis 44,47 .…”

“…In melanoma, we and others have previously identified an autocrine role for SPARC in regulating invasiveness, epithelial-mesenchymal-like transition and melanoma survival [14][15][16]42 . Although SPARC expression has been clearly linked to cancer progression through cell-autonomous and non-autonomous actions in cell invasion and survival 20,43,44 , its function as a paracrine factor has remained poorly characterized. Paracrine functions attributed so far to SPARC in melanoma were related to inhibition of polymorphonuclear leukocyte recruitment 43 , and inhibition of proliferation and migration capacities of endothelial cells in vitro 45 .…”