Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone
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Kai-Jie Yu1,5,6,*, Jeffrey K. Li1,*, Yu-Chen Lee1,*, Guoyu Yu1, Song-Chang Lin1, Tianhong Pan7, Robert L. Satcher7, Mark A. Titus2, Li-Yuan Yu-Lee4, Wen Hui Weng6, Gary E. Gallick2,3 and Sue-Hwa Lin1,2,3
1Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
2Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
3The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA
4Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
5Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
6Department of Chemical Engineering and Biotechnology and Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan
7Department of Orthopedic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*Authors have contributed equally to this work
Sue-Hwa Lin, email: [email protected]
Keywords: cabozantinib, osteoblast, secretome, anchorage-independent growth, migration
Abbreviations: CM: conditioned medium; PCa: prostate cancer; PMOs: primary mouse osteoblasts; real-time RT-PCR: reverse transcription followed with real-time polymerase chain reaction; ELISA: enzyme-linked immunosorbent assay
Received: May 25, 2017 Accepted: July 14, 2017 Published: August 24, 2017
Therapies that target cancer cells may have unexpected effects on the tumor microenvironment that affects therapy outcomes or render therapy resistance. Prostate cancer (PCa) bone metastasis is uniquely associated with osteoblastic bone lesions and treatment with cabozantinib, a VEGFR-2 and MET inhibitor, leads to a reduction in number and/or intensity of lesions on bone scans. However, resistance to cabozantinib therapy inevitably occurs. We examined the effect of cabozantinib on osteoblast differentiation and secretion in the context of therapy resistance. We showed that primary mouse osteoblasts express VEGFR2 and MET and cabozantinib treatment decreased osteoblast proliferation but enhanced their differentiation. A genome-wide analysis of transcriptional responses of osteoblasts to cabozantinib identified a set of genes accounting for inhibition of proliferation and stimulation of differentiation, and a spectrum of secreted proteins induced by cabozantinib, including pappalysin, IGFBP2, WNT 16, and DKK1. We determined that these proteins were upregulated in the conditioned medium of cabozantinib-treated osteoblasts (CBZ-CM) compared to control CM. Treatment of C4-2B4 or PC3-mm2 PCa cells with CBZ-CM increased the anchorage-independent growth and migration of these PCa cells compared to cells treated with control CM. These results suggest that the effect of cabozantinib on the tumor microenvironment may increase tumor cell survival and cause therapy resistance.
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