Secreted Protein Acidic and Rich in Cysteine Produced by Human Melanoma Cells Modulates Polymorphonuclear Leukocyte Recruitment and Antitumor Cytotoxic Capacity

Abstract

The expression of secreted protein acidic and rich in cysteine (SPARC) has been associated with the malignant progression of different types of human cancer. SPARC was associated with tumor cell capacity to migrate and invade, although its precise role in tumor progression is still elusive. In the present study, we show that SPARC produced by melanoma cells modulates the antitumor activity of polymorphonuclear leukocytes (PMN). Administration to nude mice of human melanoma cells in which SPARC expression was transiently or stably knocked down by antisense RNA (SPARC-sup cells) promoted PMN recruitment and obliterated tumor growth even when SPARC-sup cells accounted for only 10% of injected malignant cells. In addition, SPARC-sup cells stimulated the in vitro migration and triggered the antimelanoma cytotoxic capacity of human PMN, an effect that was reverted in the presence of SPARC purified from melanoma cells or by reexpressing SPARC in SPARC-sup cells. Leukotrienes, interleukin 8, and growth-related oncogene, in combination with Fas ligand and interleukin 1, mediated SPARC effects. These data indicate that SPARC plays an essential role in tumor evasion from immune surveillance through the inhibition of the antitumor PMN activity. (Cancer Res 2005; 65(12): 5123-32)

SPARC Oppositely Regulates Inflammation and Fibrosis in Bleomycin-Induced Lung Damage

“…35,36 An impaired ECM deposition or the absence of SPARC is associated with increased inflammatory infiltration and immune cell migration. 10,37,38 This finding has prompted the idea that SPARC might be involved in the regulation of inflammatory response as partially demonstrated in ovarian cancer, where SPARC normalizes the tumor microenvironment by regulating cytokine production. 12 In Sparc Ϫ/Ϫ mice inflammation is greater than in their WT counterparts.…”

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.…”

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

“…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 .…”

“…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 . Supported by previous evidence that elevated SPARC is associated with the occurrence of distant metastases and poor survival in melanoma patients 30,31 , our findings functionally demonstrate that SPARC mediates critical tumour cell-endothelium communications through a novel paracrine function on lung capillaries culminating in breaching vascular integrity during metastatic dissemination.…”