SPARC suppresses lymph node metastasis by regulating the expression of VEGFs in ovarian carcinoma

Abstract

Lymph node metastasis is one of the most valuable determinants for the prognosis of ovarian cancer. However, the molecular mechanisms underlying lymphangiogenesis in ovarian cancer is still poorly understood. Secreted protein acidic and rich in cysteine (SPARC), a Ca2+-binding matricellular glycoprotein that modulates cell adhesion, migration and differentiation, is thought to play a decisive role in tumor metastasis. Vascular endothelial growth factor (VEGF)-C and VEGF-D contributes to tumor-associated lymphatic vessel growth, enhancing the metastatic spread of tumor cells to lymph nodes. The aim of the present study was to investigate the relationship among SPARC, VEGFs and lymph node metastasis in ovarian cancer. We found that SKOV3 cells expressed high-level SPARC, much more than SKOV3-PM4 cells (a subline with high directional lymphatic metastatic potentials established from the metastatic lymph node generated by human ovarian carcinoma cell line SKOV3 in nude mice) did at both mRNA and protein levels. A SPARC-overexpressed SKOV3-PM4 cell line was constructed and it was found that upregulation of SPARC expression suppressed the growth, migration and invasion of SKOV3-PM4 cells as well as markedly reduced the expression of VEGF-D at both mRNA and protein level by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assay. In 47 of ovarian malignant tissues, the expression of SPARC, VEGF-C and VEGF-D were determined by immunohistochemistry. Lymphatic microvessel density (LVD) and microvessel density (MVD) were evaluated by immunostaining with CD34 and D2-40 antibodies, respectively. We found that SPARC expression was significantly lower in tissues with lymph node metastasis as compared to tissues without lymph node metastasis. SPARC expression was inversely associated with the degree of malignancy and it had a negative correlation with VEGF-C expression, VEGF-D expression, LVD and MVD which were actually higher for advanced tumors than for non-advanced tumors. These results suggest SPARC might function as a tumor suppressor inhibiting angiogenesis and lymphangiogenesis in ovarian cancer by reducing the expression of VEGF-C and VEGF-D.

Overexpression of kinesin family member 20A is associated with unfavorable clinical outcome and tumor progression in epithelial ovarian cancer

“…LN metastasis is another valuable prognostic factor of EOC 25 and is also an important factor for doctors to select suitable treatments. Clinically, the 5-year survival rate of EOC is >90% when the tumor is limited to the ovary; however, it decreases to only 30% when the metastasis has happened.…”

SMAD specific E3 ubiquitin protein ligase�1 promotes ovarian cancer cell migration and invasion via the activation of the RhoA/ROCK signaling pathway

“…Vascular endothelial growth factor (VEGF)-C and VEGF-D were proposed to contribute to tumor-associated lymphatic vessel growth, enhancing the metastatic spread of tumor cells to lymph nodes. Secreted protein acidic and rich in cysteine functions as a tumor suppressor by inhibiting lymph node metastasis via the regulation of VEGF-C/D expression in OC cells (37). Formyl peptide receptor 2 (FPR2) expression levels were upregulated in OC cells.…”

Emerging Roles for VEGF-D in Human Disease

“…Hence, NSAIDs could exhibit an anti-cancer effect by restricting metastasis via lymphatics, potentially explaining the anti-cancer effects of the NSAID aspirin observed in randomized clinical trials and other studies [ 72 , 73 , 74 , 75 , 76 ]. VEGF-D, as well as VEGF-C, were recently shown to play a potential role in lymphangiogenesis in ovarian cancer as the secreted protein acidic and rich in cysteine (SPARC), a calcium-binding glycoprotein, appears to function as a tumor suppressor in this disease by inhibiting angiogenesis and lymphangiogenesis by reducing expression of both VEGF-C and VEGF-D [ 77 ]. While the source of VEGF-D in the animal models referred to above has typically been the tumor cell, VEGF-D has been associated with both tumor cells and infiltrating immune cells in human tumors [ 78 ].…”