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Genetic depletion and pharmacological targeting of ?v integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models.

ABSTRACT: Increased expression of ?v integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which ?v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of ?v integrins in breast cancer also have yet to be investigated.We knocked down ?v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the ?v antagonist GLPG0187. The effects of ?v integrin depletion on mesenchymal markers, transforming growth factor-? (TGF-?)/Smad signaling and TGF-?-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of ?v integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis.Genetic interference and pharmacological targeting of ?v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of ?v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-?/Smad response. TGF-? induced ?v integrin mRNA expression and ?v integrin was required for TGF-?-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-? signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments.These findings show that ?v integrin is required for efficient TGF-?/Smad signaling and TGF-?-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting ?v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress ?v integrin.

SUBMITTER: Li Y

PROVIDER: S-EPMC4381510 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genetic depletion and pharmacological targeting of αv integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models.

Li Yihao Y Drabsch Yvette Y Pujuguet Philippe P Ren Jiang J van Laar Theo T Zhang Long L van Dam Hans H Clément-Lacroix Philippe P Ten Dijke Peter P

Breast cancer research : BCR 20150225

<h4>Introduction</h4>Increased expression of αv integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which αv integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of αv integrins in breast cancer also have yet to be investigated.<h4>Methods</h4>We knocked down αv integrin in MDA-MB-231 and MCF10A-M4 breast cancer cell ...[more]

PMID: 25849225

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Project description:BACKGROUND:Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. METHODS:tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. RESULTS:We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. CONCLUSION:We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.

Dataset Information

Genetic depletion and pharmacological targeting of ?v integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models.

Publications

Genetic depletion and pharmacological targeting of αv integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models.

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