SPARC Inhibits LPA-Mediated Mesothelial—Ovarian Cancer Cell Crosstalk

Said, Neveen; Najwer, Ida; Socha, Matthew J.; Fulton, David; Mok, Samuel C.; Motamed, Kouros

doi:10.1593/neo.06658

Cited by 61 publications

(78 citation statements)

References 34 publications

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“…The major identified component of these bioactive lipids was LPA, which influences almost every aspect of ovarian cancer progression (7,9). In agreement with our recent report (27), LPA was also shown to induce proliferation of ID8 cells directly in a concentration-dependent manner, and addition of exogenous SPARC (10 Amol/L) significantly diminished the proliferation induced by low concentrations (5-10 Amol/L) of LPA but had no significant effect when higher concentrations (>20 Amol/L) of LPA were used (Fig. 7D).…”

Section: Modulation Of the Activity Of Bioactive Lipids In The Ascitisupporting

confidence: 92%

“…We and others have recently shown that biologically active lipids, mainly lysophosphatidic acid (LPA), in the heatinsensitive fraction of mesothelial cell conditioned medium exert a chemotactic and proinvasive effect on human ovarian cancer cells in vitro (9,27). In the latter study, we also reported that exogenous SPARC significantly inhibited LPA-mediated invasiveness and proliferation of human ovarian cancer cells.…”

Section: Modulation Of the Activity Of Bioactive Lipids In The Ascitimentioning

confidence: 53%

“…Moreover, the mitogenic and prosurvival effects of LPA have been attributed to its direct effect on cell cycle progression, up-regulation of VEGF, transactivation of receptor tyrosine kinases (e.g., EGFR and VEGFRs), and induction of an inflammatory response (66). Our recent report on significant attenuation of the LPA-mediated crosstalk between mesothelial cells and human ovarian cancer cell lines by exogenous addition or ectopic overexpression of SPARC (27), as well as significant diminutions in proliferation, migration, and invasion of bioactive lipids in ascites of ovarian tumor -bearing SP +/+ mice, highlights the important role of SPARC in suppression of LPA-mediated events in ovarian carcinoma.…”

Section: Discussionmentioning

confidence: 97%

“…Up-regulation of potent prosurvival, proangiogenic, as well as proinflammatory cytokines and chemokines has been reported downstream of LPA activity in vivo and in vitro (6,7,65,66). LPA is constitutively produced by peritoneal mesothelial cells and has been shown to be crucial for the chemotactic activity of shed ovarian cancer cells (9,27). Moreover, LPA enhances motility and invasiveness of ovarian cancer cells, in part, through upregulation and activation of MMPs in ovarian cancer cells (67).…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports highlight the role of this molecule as a positive or negative modulator in the pathogenesis of different malignancies (18)(19)(20)(21)(22)(23)(24). We and others have shown that SPARC functions as a tumor suppressor in ovarian cancer (25)(26)(27)(28). As a tumor suppressor, effect of SPARC in different cancers was attributed not only to its counteradhesive, antiproliferative functions but also to its role in modulating angiogenesis as well as regulation of the production, assembly, and organization of the structural extracellular matrix proteins including type I collagen and fibronectin (23,25,(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 97%

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Normalization of the Ovarian Cancer Microenvironment by SPARC

Said¹,

Socha²,

Olearczyk³

et al. 2007

Molecular Cancer Research

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102

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Section: Modulation Of the Activity Of Bioactive Lipids In The Ascitisupporting

confidence: 92%

Section: Modulation Of the Activity Of Bioactive Lipids In The Ascitimentioning

confidence: 53%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

Normalization of the Ovarian Cancer Microenvironment by SPARC

Said¹,

Socha²,

Olearczyk³

et al. 2007

Molecular Cancer Research

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102

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SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated

Haber

Gottifredi

Llera

et al. 2008

Intl Journal of Cancer

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Cell interaction with the extracellular matrix (ECM) has profound influence in cancer progression. The secreted protein, acidic and rich in cysteine (SPARC) a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. This apparent paradox might result either from the biochemical properties of the different SPARC sources or from differential responses of malignant and stromal cells to SPARC. To test these hypotheses, we purified SPARC secreted by melanoma cells (hMel-SPARC) and compared its activity with different recombinant SPARC preparations, including a new one produced in insect cells. All 5 SPARC species were effective in inhibiting bovine aortic endothelial cell proliferation, adhesion and migration. We then used the melanoma-derived protein to assess SPARC effect on additional cell types. hMel-SPARC greatly impaired the proliferation of both normal and transformed human endothelial cells and exerted a moderate biphasic effect on human fetal fibroblasts proliferation, irrespective of their endogenous SPARC levels. However, SPARC had no effect on the proliferation of several human cancer cell lines regardless of their endogenous levels of SPARC expression. Importantly, downregulation of SPARC levels in melanoma cells using either an antisense RNA or a shRNA against SPARC sensitized them to hMel-SPARC addition in proliferation and migration assays, suggesting that malignant cells developed a SPARC-resistance mechanism. This was not a general resistance to growth suppressing agents, as melanoma cells with restricted SPARC expression were more resistant to chemotherapeutic agents. Thus, malignant cells expressing or not expressing SPARC developed alternative mechanisms that, in contrary to stromal cells, rendered them SPARC-insensitive. ' 2007 Wiley-Liss, Inc.Key words: SPARC; osteonectin; cell proliferation; tumor heterogeneity; stromal cells Tumors grow as the result of crosstalk between the different cellular components of the tumor mass. Malignant cells secrete proteins that reach neighboring stromal nonmalignant cells (i.e., fibroblasts and endothelial cells) that in some cases induce them to provide the soil in which the tumor will grow.1 Nonmalignant stromal cells might also contribute to cancer progression, since the establishment of human cancer xenografts in mice depends on the presence of tumor-derived fibroblasts.2 This data therefore points toward a central role of extracellular matrix (ECM) in tumor progression.From the many proteins secreted by tumor and stromal cells, the secreted protein, acidic and rich in cysteine, SPARC (also known as BM40 and osteonectin), a nonstructural, matricellular component of the ECM, has been associated with tumor growth. In healthy tissues, SPARC production is largely restricted to areas undergoing repair or remodeling.4 SPARC is expressed at high levels in many tumors, and it was found to be associated with tumor progression in human melanoma, 5 properties on certain cell types have been associated with...

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Transforming growth factor‐beta‐induced protein secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells

Ween

Lokman

Hoffmann

et al. 2011

Intl Journal of Cancer

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Ovarian cancer metastasis is characterized by the shedding of malignant cells from the surface of the ovary and their implantation onto the peritoneal surface, which lines the abdominal cavity. As the factors promoting this process are poorly understood, we investigated the ovarian cancer–peritoneal interaction by means of in vitro coculture experiments with ovarian cancer (OVCAR‐5 and SKOV‐3) and peritoneal (LP‐9) cells. One of the proteins differentially expressed in the coculture secretome was identified by MALDI‐TOF/TOF mass spectrometry as the extracellular matrix protein transforming growth factor‐beta‐induced protein (TGFBIp, also known as βig‐H3). Immunohistochemistry showed high TGFBIp levels in normal surface ovarian epithelial and peritoneal cells, whereas TGFBIp levels in primary serous ovarian carcinomas and matching metastatic implants was very low. In functional in vitro experiments, treatment with recombinant TGFBIp significantly increased the motility and invasiveness of OVCAR‐5 and SKOV‐3 cells and significantly increased ovarian cancer cell (OVCAR‐5, OVCAR‐3 and SKOV‐3) adhesion to LP‐9 cells. TGFBIp was found to be processed at both the N‐ and C‐terminus in the secretome of the ovarian cancer–peritoneal cell coculture. Plasmin inhibitors blocked TGFBIp processing and significantly reduced OVCAR‐5 cell adhesion to peritoneal cells. We conclude that TGFBIp expressed by peritoneal cells increases the metastatic potential of ovarian cancer cells. TGFBIp is therefore a potential novel therapeutic target against ovarian cancer.

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SPARC Inhibits LPA-Mediated Mesothelial—Ovarian Cancer Cell Crosstalk

Cited by 61 publications

References 34 publications

Normalization of the Ovarian Cancer Microenvironment by SPARC

Normalization of the Ovarian Cancer Microenvironment by SPARC

SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated

Transforming growth factor‐beta‐induced protein secreted by peritoneal cells increases the metastatic potential of ovarian cancer cells

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