Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis

Department of Experimental Oncology, Immunotherapy and Gene Therapy Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Universita degli Studi di Milano, Milan, Italy.
Cancer Research (Impact Factor: 9.33). 12/2008; 68(21):9050-9. DOI: 10.1158/0008-5472.CAN-08-1327
Source: PubMed


Other than genetic imprinting and epithelial to mesenchymal transition, cancer cells need interaction with the nearby stroma toward metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) deposition and cell-ECM interaction. Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through alpha(v)beta(5) integrin. Indeed, RNA interference knockdown of beta(5) integrin expression reduces cell migration in vitro and metastasis in vivo. Together these results show that macrophage-derived SPARC takes part in metastasis, acting at the step of integrin-mediated migration of invasive cells.

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    • "Similar results were found by Condeelis and Pollard (2006), implicating macrophages for tumour cell migration and invasion. Moreover, macrophages are capable of producing SPARC/osteonectin, which is essential in forming metastasis (Sangaletti et al, 2008). This evidence suggests a protumorous potential of monocytes due to formation of different macrophage phenotypes that promote the malignant process (Swann et al, 2008). "
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    ABSTRACT: Background: Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients. Methods: Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan–Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS). Results: Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29–0.76, P=0.002; HR: 0.51, 95%CI: 0.31–0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22–0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28–1.66, P=0.397). When the subgroup of patients with ‘high-risk' LMR⩽2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60–1.63; P=0.953). Conclusion: The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.
    British Journal of Cancer 12/2013; 110(2). DOI:10.1038/bjc.2013.785 · 4.84 Impact Factor
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    • ") targeting the b1-(HMb1-1) and the b3-subunit (HM beta 3.1), both of which block ligand binding of integrins in functional assays (Piali et al., 1995; Ridger et al., 2001; Sangaletti et al., 2008). As shown earlier in this study, both antibodies recognized the corresponding integrin subunit of the mouse fibroblasts. "
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    • "Since dSparc is a component of the ECM it could feasibly facilitate remodeling of the BM, preventing soluble factors to reach loser cells, or blocking delamination and making them more resistant to apoptosis. Such remodeling of ECM by SPARC has been described (Sangaletti et al., 2008). "
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