The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways

Courter, Donald; Cao, Hongbin; Kwok, Shirley; Kong, Christina S.; Banh, Alice; Kuo, Peiwen; Bouley, Donna M.; Vice, Carmen; Brustugun, Odd Terje; Denko, Nicholas C.; Koong, Albert C.; Giaccia, Amato J.; Le, Quynh Thu

doi:10.1371/journal.pone.0009633

Cited by 48 publications

(44 citation statements)

References 62 publications

(71 reference statements)

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“…As previously reported on the distinct adhesive properties of murine osteopontin that result from cell specific post-translational modifications, 38 we show that iSPP1 and sSPP1 are differentially expressed by tumor cells, with the former preventing TRP53 stabilization and apoptosis, and the latter signaling to host CCR2 receptors via CCL2 to promote lung homing. Our results corroborate previous work on the inhibition of apoptosis 39 and the involvement of TRP53 in iSPP1-dependent anti-apoptotic signaling 40 and show for the first time that the pro-survival effects of osteopontin in cancer cells are conditional on wild-type TRP53. Our findings imply that targeting of human iSPP1 in clinical trials may be selectively effective against TRP53 wild-type tumors and provide a rationale for stratification of patients by TRP53 status.…”

Section: Discussionsupporting

confidence: 91%

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

et al. 2016

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The lungs are ubiquitous receptacles of metastases originating from various bodily tumors. Although osteopontin (SPP1) has been associated with tumor dissemination, the role of its isoforms in lung-directed metastasis is incompletely understood. We employed syngeneic mouse models of spontaneous and induced lung-targeted metastasis in C57BL/6 mice competent and deficient in both Spp1 alleles. Tumorderived osteopontin expression was modulated using either stable anti-Spp1 RNA interference, or forced overexpression of intracellular and secreted Spp1 isoforms. Identified osteopontin's downstream partners were validated using lung adenocarcinoma cells conditionally lacking the Trp53 gene and Ccr2-deficient mice. We determined that host-derived osteopontin was dispensable for pulmonary colonization by different tumor types. Oppositely, tumor-originated intracellular osteopontin promoted tumor cell survival by preventing tumor-related protein 53-mediated apoptosis, while the secretory osteopontin functioned in a paracrine mode to accelerate lung metastasis by enhancing tumor-derived C-C-motif chemokine ligand 2 signaling to cognate host receptors. As new ways to target osteopontin signaling are becoming available, the cytokine may constitute an important therapeutic target against pulmonary involvement by cancers of other organs. KEYWORDSC-C-motif chemokine ligand 2; inflammation and cancer; secreted phosphoprotein 1; spontaneous lung metastasis; tumor-related protein 53

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Section: Discussionsupporting

confidence: 91%

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

et al. 2016

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“…In addition to the direct function of OPN on tumor cells, 20 we demonstrate for the first time that the OPN expressed by tumor cells can regulate immune cell activation. By coculture system, we found that supernatant from tumors overexpressing OPN significantly inhibited the proinflammatory cytokine TNF-a and increased anti-inflammatory IL-10 levels from monocytes ( Figure 3).…”

Section: Discussionmentioning

confidence: 74%

“…Courter et al have shown that the overexpression of either OPN-a or OPN-b promoted local tumor growth and lung metastasis in SCID mouse xenografts. 20 However, in that study, they did not examine the function of OPN-c. Most recently, it has been reported that OPN-c specifically activated ovarian tumor cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo.…”

Section: Discussionmentioning

confidence: 96%

Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Sun¹,

Feng²,

Chen³

et al. 2013

Cell Mol Immunol

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Osteopontin (OPN), a multifunctional glycoprotein, has three transcripts that have distinct roles in tumors in vitro. Whether OPN transcripts have different functions in tumor processes in vivo is unclear. It has been reported that immune cell-derived OPN can promote tumor formation. We propose a hypothesis that tumor-derived OPN may facilitate tumor immune escape by affecting immune cell differentiation and function. In this study, we constructed lentiviral expression vectors of OPN transcripts and transfected them into the MCF-7 cell line. MCF-7 cells transfected with OPN transcripts were injected into the armpit of nude mice, and tumor growth was monitored. The results showed that all OPN transcripts promoted local tumor formation, but that there was no significant difference among transcripts. We also investigated the effect of the OPN expressed by tumor cells on monocyte differentiation by coculturing monocytes with tumor supernatant. We found OPN-c upregulated CD163 levels compared with OPN-a and OPN-b; however, none of the transcripts affected HLA-DR and CD206 levels. All OPN transcripts significantly inhibited TNF-a and enhanced IL-10 production by monocytes. Furthermore, we found that the overexpression of OPN transcripts significantly upregulated TGF-b1 and MCP-1 production by tumor cells. Using neutralizing antibody and recombinant cytokines, we found that OPN overexpressed by tumor cells regulates the production of TNF-a and IL-10 by monocytes partly via MCP-1 and TGF-b1, respectively. Collectively, our results show that OPN transcripts have no distinct role in breast cancer formation in vivo. We also demonstrate that OPN regulates the alternative activation of monocytes via TGF-b1 and MCP-1, which may represent an additional mechanism for tumor immune escape.

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“…Ovarian malignant transformation is caused by genetic modifications that disrupt the regulation of proliferation, programmed cell death and senescence, but the specific genetic pathways involved in these processes are poorly understood (34,35). Alternative pre-mRNA splicing is an important molecular mechanism associated with tumorigenesis and cancer progression (36) and has been shown to be one of the mechanisms by which cancer cells alter the structure and function of OPN (16)(17)(18)(19)37). Based on these assumptions, we believe that describing the functional significance of OPN splicing isoforms in ovarian cancer would improve the understanding of signaling pathways involved in the progression of this complex neoplasic disease.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

Tilli

Franco²,

Robbs³

et al. 2011

Molecular Cancer Research

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Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression. Mol Cancer Res; 9(3); 280-93. Ó2011 AACR.

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The RGD Domain of Human Osteopontin Promotes Tumor Growth and Metastasis through Activation of Survival Pathways

Cited by 48 publications

References 62 publications

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

Tumor-derived osteopontin isoforms cooperate with TRP53 and CCL2 to promote lung metastasis

Osteopontin splice variants expressed by breast tumors regulate monocyte activation via MCP-1 and TGF-β1

Osteopontin-c Splicing Isoform Contributes to Ovarian Cancer Progression

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