Abstract 2332: Alphavbeta6 integrin, a downstream effector of TGFbeta, promotes prostate cancer osteolytic lesions

Abstract

Abstract Integrins and their extracellular matrix ligands are crucial regulators of cancer progression. We show in the present study that the alphaVbeta6 integrin is abundantly expressed in human bone metastasis and enhances metastatic bone disease, which occurs frequently in prostate and breast cancer patients. Our analysis shows that alphaVbeta6 is upregulated in prostate cancer cells via a pro-metastatic signaling pathway mediated by TGFbeta and SMAD3. Given alphaVbeta6 ability to act as a downstream effector of TGFbeta, we tested the ability of alphaVbeta6 to mediate metastatic cancer growth in bone in vivo. We injected PC3 cells stably transfected with alphaVbeta6 in the tibiae of SCID mice. Intraosseous growth of these cells results in extensive osteolytic lesions. Micro-computed tomographic reconstruction of the various bone lesions demonstrates that expression of alphaVbeta6 promotes the appearance of osteolytic lesions beginning at 2 weeks after injection of the tumor cells, further progressing to massive trabecular and cortical bone loss by 4 and 8 weeks. In contrast, intraosseous growth of cells expressing alphaVbeta5, another alphaV containing integrin known to promote metastasis, does not result in osteolytic lesions at the same time intervals and causes woven bone deposition in the medullary cavity. Intraosseous tumors produced by intratibial injection of alphaVbeta6- or alphaVbeta5-expressing prostate cancer cells grew with indistinguishable kinetics, thus ruling out that the enhanced formation of osteolytic lesions mediated by alphaVbeta6 was simply due to accelerated tumor growth. Further analysis shows that alphaVbeta6 contributes to osteolytic lesions by selective upregulation of MMP2 levels in PC3 tumors in vivo, which, in contrast, is not observed in alphaVbeta5- PC3 tumors. These findings show for the first time a mechanism that promotes alphaV integrin-mediated osteolysis in prostate cancer metastatic growth and suggest that the players involved are targets for future personalized therapies of prostate cancer. Grant support: NIH R01 CA089720 (LRL). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2332.