Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis.
The matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) possesses multifaceted roles in modulation of cell-matrix interactions, as well as tumor growth and metastasis. To investigate the influence of host-derived SPARC on peritoneal dissemination of ovarian cancer, we established a murine model that faithfully recapitulates advanced human disease by intraperitoneal injection of syngeneic ID8 ovarian cancer cells into SPARC-null and wild-type mice. Compared to wild-type mice, SPARC-null mice showed significantly shorter survival and developed extensive nodular peritoneal dissemination with hemorrhagic ascitic fluid accumulation. Ascitic fluid collected from SPARC-null mice showed significantly augmented levels and activity of vascular endothelial growth factor and gelatinases. Immunohistochemical analysis of tumor nodules from SPARC-null mice revealed higher proliferation and lower apoptosis indices with minimal staining for major extracellular matrix constituents. In vitro, SPARC significantly suppressed adhesion to and invasion of various peritoneal extracellular matrix constituents by murine and human ovarian cancer cell lines. Our findings suggest that SPARC ameliorates ovarian peritoneal carcinomatosis through abrogation of the initial steps of disease pathogenesis, namely tumor cell adhesion and invasion, inhibition of tumor cell proliferation, and induction of apoptosis. Thus, SPARC represents an important therapeutic candidate in ovarian cancer.
Said
Neveen
N
Department of Pathology, Medical College of Georgia, Augusta, 30912, USA.
Motamed
Kouros
K
D000818:Animals; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015676:Osteonectin / Q000172:deficiency*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control; D010534:Peritoneal Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D015676:Osteonectin; D042461:Vascular Endothelial Growth Factor A