Abstract B32: TGF-β blockade improves the distribution and efficacy of chemotherapeutic agent in breast carcinoma

Abstract

Abstract In its journey from blood vessels to cancer cells, a therapeutic agent must overcome the transport barrier posed by the interstitial matrix. In contrast to our understanding of blood vessels, our understanding of the formation and function of the tumor interstitial matrix is still in its infancy. A primary component of the interstitial matrix, collagen type I, has been shown to inversely correlate with diffusive transport in solid tumors. TGF-β can stimulate production of collagen by stromal cells in tumors. Thus, we studied the effect of blocking TGF-β pathway in breast carcinoma progression and response to chemotherapy. To this end, we used a soluble Fc:TGF-β type II receptor fusion protein (sTβRII) to block TGF-β pathway in two breast cancer models (human MDA-MB-231 cells and mouse 4T1 cells). TGF-β blockade significantly impaired the growth and metastasis of orthotopic tumors in both tumor models. The recruitment of myofibroblasts and interstitial matrix content was determined by immunohistochemistry, TGF-β blockade significantly decreased the recruitment of myofibroblast and the level of collagen I. Next, to determine the effect of TGF-β blockade on interstitial transport, we injected fluorescent doxorubicin into the tail vein of mice and observed the intratumoral distribution of doxorubicin autofluorescence by confocal microscopy. We found that TGF-β blockade increased the transvascular flux of fluorescent doxorubicin. As a result, doxorubicin liposome (DOXIL) treatment was significantly more effective in inhibiting tumor progression in TGF-β blocked tumors compared to parental tumors. In summary, our study characterized the functional role of TGF-β in modulating tumor interstitial matrix in breast cancer xenografts and suggested that blocking TGF-β signaling pathway may represent a testable therapeutic approach to be combined with conventional chemotherapy in breast cancer treatment. Citation Information: Clin Cancer Res 2010;16(14 Suppl):B32.