Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells

Abstract

Acquisition of invasive/metastatic potential is a key event in tumor progression. Cell surface glycoproteins and their respective matrix ligands have been implicated in this process. Recent evidence reveals that the secreted glycoprotein SPARC (secreted protein, acidic and rich in cysteine) is highly expressed in different malignant tissues. The present study reports that the suppression of SPARC expression by human melanoma cells using a SPARC antisense expression vector results in a significant decrease in the in vitro adhesive and invasive capacities of tumor cells, completely abolishing their in vivo tumorigenicity. This is the first evidence that SPARC plays a key role in human melanoma invasive-metastatic phenotype development.

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

“…In the tumour microenvironment, both neoplastic and neighbouring stromal cells can produce SPARC, thereby imparting a complexity of action for SPARC in cancer. 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.…”

“…We identify the matricellular SPARC protein, as a critical tumour-secreted permeability factor and a novel paracrine mediator of endothelium permeability during melanoma metastatic dissemination to lungs. Abnormal expression of SPARC has been reported in various cancer cell types including melanoma 13 , in which SPARC was shown to play a key role in melanoma cell tumorigenicity [14][15][16] . However, its role as a paracrine mediator of haematogenous metastasis during extravasation remains unclear.…”

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

“…In addition, FAK, ILK and AKT inhibitors may display combinatorial efficacy owing to the joint activities of these kinases in tumor cells expressing SPARC. Finally, targeting SPARC expression has already been demonstrated to be useful in the control of melanomas (Ledda et al, 1997;Alvarez et al, 2005), which further suggests that decreasing SPARC expression in some other cancer types, such as gliomas, may be beneficial for patient therapy.…”

“…Increased SPARC expression levels have been linked to poor glioma patient survival (Rich et al, 2005), which suggests that the reduction of SPARC expression may have therapeutic benefit. Indeed, expression of antisense oligonucleotides against SPARC in melanoma cells blocked tumor formation (Ledda et al, 1997).…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…SPARC is involved in cell-matrix interactions during tissue remodeling, wound healing and embryonic development [108,109]. Expression of SPARC in tumor cells, CAFs and stromal endothelial cells can lead to an EMT-like phenotype, including loss of cell-cell adhesion and induction of MMPs and has been shown to increase tumorigenicity [110][111][112]. Expression of SPARC in the tumor stroma is correlated independently with poor prognosis and increased mortality in NSCLC and pancreatic cancers [113,114] and leads to increased invasion and metastasis in melanoma, glioma and NSCLC [95][96][97]115].…”