Abstract C40: αvβ6 integrin promotes a TGFβ1-mediated cancer cell autonomous osteolytic program through upregulation of matrix metalloproteinase 2 (MMP2)

Abstract

Abstract Metastatic prostate cancer to the bone is associated with considerable morbidity and mortality. Because the molecular basis of this process is not completely understood, current treatment is largely palliative, aiming at reducing severe bone pain, nerve compression and pathological fractures. The molecular circuitries controlling osseous prostate metastasis are known to depend on the activity of a pro-metastatic cytokine, TGFβ1, and of matrix metalloproteinases (MMPs). MMP2 is known to enhance prostate cancer-mediated bone degradation and has been reported to be induced by TGFβ1. Various studies show that the αvβ6 integrin activates and is induced by TGFβ1, thus potentiating TGFβ1 responses in the sites where it is expressed. However, a role for αvβ6 in regulating TGFβ1—induced MMP2 has not been described before. Here, we demonstrate that the αvβ6 integrin is upregulated in human prostate cancer bone metastasis and promotes osteolysis as observed by μ–computed tomography (μ–CT) in an in vivo model of metastatic bone disease. Using immunoblotting and real-time PCR analysis, we provide evidence that the αvβ6 integrin sustains TGFβ1—dependent upregulation of MMP2 mRNA and protein levels by associating with TGFβ receptor II. We also show that αvβ6 contributes to upregulation of MMP2 by TGFβ1 through a highly specific transcriptional program mediated by Smad3, and promotes osteolysis in vivo through upregulation of MMP2 in cancer cells. In conclusion, we have identified a novel role of the αvβ6 integrin in directing, in vivo, a cell-autonomous osteolytic program through activation of MMP2. These mechanistic studies will support the development of novel molecular strategies for prostate cancer bone metastasis through inhibition of the TGFβ1\αvβ6\MMP2 signaling pathway. Acknowledgments: This work was supported by the following grants: NIH — RO1 CA89720 to Dr. Lucia R. Languino and NIH — PO1 CA140043 to Drs. Lucia R. Languino, Gary S. Stein, Jane B. Lian. Drs. Dutta and Li share the first authorship. Citation Format: Anindita Dutta, Jing Li, Huimin Lu, Jacqueline Akech, Jitesh Pratap, Tao Wang, Thomas J. FitzGerald, Zhong Jiang, Shelia M. Violette, Gary S. Stein, Jane B. Lian, Lucia R. Languino. αvβ6 integrin promotes a TGFβ1-mediated cancer cell autonomous osteolytic program through upregulation of matrix metalloproteinase 2 (MMP2). [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C40.