The in vivo effect of integrin α11-deficiency and PDGFR inhibition in breast cancer
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Background: The tumor microenvironment is a major contributor to breast cancer progression. The abnormal composition of the extracellular matrix and its deregulated interactions with stromal cells, which is characterizing features in breast cancer, promotes tumor progression and poses an obstacle cancer therapy through increased interstitial fluid pressure. The aim of this study was to evaluate the effect of stromal integrin α11-deficiency and PDGFR-inhibition on tumor growth, interstitial fluid pressure, angiogenesis, and collagen density using the murine E0771 triple-negative breast cancer model. Methods: SCID mice with and without integrin α11-deficiency were injected with the murine E0771 cell line into the mammary fat pad. The mice were randomly divided into four groups, where two groups received treatment with the PDGFR-inhibitor Gleevec (100 mg/kg) by gavage once a day over a four-day period. The two remaining groups received water by gavage. The tumor growth was measured by caliper, the interstitial fluid pressure was measured with the wick-in-needle technique, microvessel density by immunohistochemical anti-CD31 staining, and the collagen density by picrosirius red staining. Results: Integrin α11-deficiency significantly reduced the interstitial fluid pressure, microvessel density, and collagen density. Gleevec significantly reduced the interstitial fluid pressure, and microvessel density. No effects were seen on tumor growth by either integrin α11-deficiency, or PDGFR-inhibition by Gleevec. No synergistic or additive effect was observed in response to inhibition of PDGF/PDGFR signalling in the α11- deficient groups. Conclusion: This study show the importance of integrin α11β1 in the regulation of the interstitial fluid pressure, angiogenesis and collagen density in the murine E0771 triplenegative breast cancer model. All these features are critical features in tumor progression, thus indicating that integrin α11 may represent an attractive therapeutic target in adjuvant settings. Gleevec was found to significantly reduce the interstitial fluid pressure, and the microvessel density. Suggesting that PDGF/PDGFR signalling is important in the regulation of pressure homeostasis and angiogenesis.