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The ???? integrin is a metastasis suppressor in mouse models and human cancer.

ABSTRACT: Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that ?1 integrins may stimulate metastasis of a number of cancers, expression of the ?1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the ?2?1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of ?2?1 integrin in normal breast epithelium and loss of ?2?1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding ?2 integrin, but not genes encoding ?1, ?3, or ?1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of ?2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the ?2?1 integrin functionally inhibits breast tumor metastasis, and ?2 expression may serve as an important biomarker of metastatic potential and patient survival.

SUBMITTER: Ramirez NE

PROVIDER: S-EPMC3007139 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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The α₂β₁ integrin is a metastasis suppressor in mouse models and human cancer.

Ramirez Norma E NE Zhang Zhonghua Z Madamanchi Aasakiran A Boyd Kelli L KL O'Rear Lynda D LD Nashabi Abudi A Li Zhengzi Z Dupont William D WD Zijlstra Andries A Zutter Mary M MM

The Journal of clinical investigation 20101206 1

Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that β1 integrins may stimulate metastasis of a number of cancers, expression of the β1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the α2β1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data ...[more]

PMID: 21135504

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Project description: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.

Project description:BackgroundThe motif RXDLXXL-based nanoprobes allow specific imaging of integrin αvβ6, a protein overexpressed during tumorigenesis and tumor progression of various tumors. We applied a novel RXDLXXL-coupled cyclic arginine-glycine-aspartate (RGD) nonapeptide conjugated with ultrasmall superparamagnetic iron oxide nanoparticles (referred to as cFK-9-USPIO) for the application of integrin αvβ6-targeted magnetic resonance (MR) molecular imaging for breast cancer.MethodsA novel MR-targeted nanoprobe, cFK-9-USPIO, was synthesized by conjugating integrin αvβ6-targeted peptide cFK-9 to N-amino (-NH2)-modified USPIO nanoparticles via a dehydration esterification reaction. Integrin αvβ6-positive mouse breast cancer (4 T1) and integrin αvβ6 negative human embryonic kidney 293 (HEK293) cell lines were incubated with cFK-9-AbFlour 647 (blocking group) or cFK-9-USPIO (experimental group), and subsequently imaged using laser scanning confocal microscopy (LSCM) and 3.0 Tesla magnetic resonance imaging (MRI) system. The affinity of cFK-9 targeting αvβ6 was analyzed by calculating the mean fluorescent intensity in cells, and the nanoparticle targeting effect was measured by the reduction of T2 values in an in vitro MRI. The in vivo MRI capability of cFK-9-USPIO was investigated in 4 T1 xenograft mouse models. Binding of the targeted nanoparticles to αvβ6-positive 4 T1 tumors was determined by ex vivo histopathology.ResultsIn vitro laser scanning confocal microscopy (LSCM) imaging showed that the difference in fluorescence intensity between the targeting and blocking groups of 4 T1 cells was significantly greater than that in HEK293 cells (P < 0.05). The in vitro MRI demonstrated a more remarkable T2 reduction in 4 T1 cells than in HEK293 cells (P < 0.001). The in vivo MRI of 4 T1 xenograft tumor-bearing nude mice showed significant T2 reduction in tumors compared to controls. Prussian blue staining further confirmed that αvβ6 integrin-targeted nanoparticles were specifically accumulated in 4 T1 tumors and notably fewer nanoparticles were detected in 4 T1 tumors of mice injected with control USPIO and HEK293 tumors of mice administered cFK-9-USPIO.ConclusionsIntegrin αvβ6-targeted nanoparticles have great potential for use in the detection of αvβ6-overexpressed breast cancer with MR molecular imaging.

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The ???? integrin is a metastasis suppressor in mouse models and human cancer.

Publications

The α₂β₁ integrin is a metastasis suppressor in mouse models and human cancer.

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