Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone

// Kai-Jie Yu 1, 5, 6, * , Jeffrey K. Li 1, * , Yu-Chen Lee 1, * , Guoyu Yu 1 , Song-Chang Lin 1 , Tianhong Pan 7 , Robert L. Satcher 7 , Mark A. Titus 2 , Li-Yuan Yu-Lee 4 , Wen Hui Weng 6 , Gary E. Gallick 2, 3 and Sue-Hwa Lin 1, 2, 3 1 Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA 2 Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA 3 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA 4 Department of Medicine, Baylor College of Medicine, Houston, Texas, USA 5 Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan 6 Department of Chemical Engineering and Biotechnology and Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan 7 Department of Orthopedic Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA * Authors have contributed equally to this work Correspondence to: Sue-Hwa Lin, email: slin@mdanderson.org 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 ABSTRACT 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.