Forced Expression of MMP9 Rescues the Loss of Angiogenesis and Abrogates Metastasis of Pancreatic Tumors Triggered by the Absence of Host SPARC

Abstract

Pancreatic adenocarcinoma is characterized by desmoplasia, local invasion, and metastasis. These features are regulated in part by MMP9 and SPARC. To explore the interaction of SPARC and MMP9 in cancer, we first established orthotopic pancreatic tumors in SPARC-null and wild-type mice with the murine pancreatic adenocarcinoma cell line, PAN02. MMP9 expression was higher in tumors from wild-type compared to SPARC-null mice. Coincident with lower MMP9 expression, tumors grown in SPARC-null mice were significantly larger, had decreased ECM deposition and reduced microvessel density compared to wild-type controls. In addition, metastasis was enhanced in the absence of host SPARC. Therefore, we next analyzed the orthotopic tumor growth of PAN02 cells transduced with MMP9 or a control empty vector. Forced expression of MMP9 by the PAN02 cells resulted in larger tumors in both wild-type and SPARC-null animals compared to empty vector controls and further diminished ECM deposition. Importantly, forced expression of MMP9 within the tumor reversed the decrease in angiogenesis and abrogated the metastatic potential displayed by control tumors grown in SPARC-null mice. Finally, contrary to the in vivo results, MMP9 increased cell migration in vitro, which was blocked by the addition of SPARC. These results suggest that SPARC and MMP9 interact to regulate many stages of tumor progression including ECM deposition, angiogenesis and metastasis.

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

“…ECM forms part of the tumor microenvironment and is secreted by cancer and stromal cells. Murine pancreatic cancer cells injected orthotopically into SPARC-null mice grow larger and metastasize more frequently than those in wild-type mice, thus highlighting the importance of SPARC function and ECM composition in tumor progression (Arnold et al, 2008). The fact that the tumor cells, but not the infiltrating stroma cells, express and secrete SPARC in the aforementioned studies also supports the observation that the effect of SPARC on tumorigenesis is context-and cell-type dependent (Brekken et al, 2003;Puolakkainen et al, 2004).…”

Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell lines

“…In these mice, enhanced growth of pancreatic tumors was observed following both subcutaneous and orthotopic tumor cell implantation in comparison to wild-type mice. 68,73 All these observations point to antitumorigenic properties of ON in PDAC.…”

“…67 Furthermore, ON has been reported to induce activation of MMP2 and to regulate MMP9 expression in vivo. 20,68 Clearly, in our model extravasation of pancreatic cancer cells is a step which precedes their growth in the liver of nude rats. Therefore it is surprising that no correlation was found between this property and the expression of MMPs which are known to destroy the extracellular matrix and to be a prerequisite to invasion and extravasation.…”

The role of MMP-9 in the anti-angiogenic effect of secreted protein acidic and rich in cysteine

“…The SPARC and MMP-9 are known to interact to regulate many stages of tumour progression including ECM deposition, angiogenesis and metastasis (Arnold et al, 2008). In addition, as mentioned above, the RT 2 Profiler PCR Array for angiogenesis and western blot analysis showed that SPARC overexpression led to decreased expression of MMP-9 and VEGF ( Figure 3B).…”