Abstract
Abstract Bone microenvironment and tumor-stromal interactions are critical for the initiation and development of metastasis. The aim of this study was to delineate the role of VEGFR/PDGFR axes in bone metastatic homing and colonization using a multi-tyrosine kinase inhibitor (SU11248). SU blocks 7 different receptors, including VEGFRs and PDGFRs, resulting in the blockade of many biological functions. Here we show that SU blocks lung cancer metastasis to the bone through different mechanisms. Incubation of bone metastatic lung A549M1 cells with SU in vitro had no effect on cell proliferation whereas a potent effect on bone marrow (BM) stromal ST2 cells, and BM-derived endothelial cells (BMEC) was seen. The inhibitory effects of SU over ST2 cells were mediated through PDGFRbeta, which was highly expressed by ST2 cells. Direct heterotypic adhesion of tumor cells to a ST2 monolayer was significantly decreased by SU, whereas no effects were found in BMEC or HUVEC monolayers. SU markedly impaired invasion in vitro. Furthermore, SU inhibited the adhesion of A549M1 cells to collagen I. To evaluate these effects in an in vivo model of bone homing, we pretreated mice with SU two days before intracardiac (i.c.) inoculation of luciferase expressing A549M1 cells. Dramatic inhibition of bioluminescence was observed in SU treated mice 4 days post-inoculation. Quantification of A549M1 colony forming units after BM flushing revealed identical results suggesting an effect of SU in bone homing. To test SU effects in bone metastasis colonization, we used SU alone or in combination with the zoledronic acid (ZA) daily, starting from 6 days after i.c. of A549 M1 cells. As expected, ZA treatment slightly increased survival, whereas SU or combination led to a double lifespan. Bioluminescence imaging showed a moderate decrease in skeletal tumor burden in single ZA and SU treated mice, whereas marked reduction in osteolytic lesions assessed by X-Ray imaging and microCT scans was only evident in ZA treated mice. However, combination abrogated tumor burden and severely prevented the development of osteolytic lesions as compared to SU treated mice, which correlated with the number of TRAP positive cells at tumor-bone interphase. Treatment of tumor-free mice with SU revealed a potent proapoptotic effect on BM stromal PDGFRbeta+ compartment, as seen by extensive active Caspase-3 immunoreactiviy 24h after treatment. This effect over stroma leads to severe haemorrhage after 4 days of treatment, indicating a severe disruption of the BM microenvironment by SU. These data suggest that disruption of VEGFR/PDGFR axes alters heterotypic tumor-stromal cell and tumor-matrix interactions during bone homing preventing osseous colonization. We suggest that SU in combination with ZA could be suitable for the treatment of osteolytic bone metastasis. 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 289.
Published Version
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