Research Papers:

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

Kai-Jie Yu, Jeffrey K. Li, Yu-Chen Lee, Guoyu Yu, Song-Chang Lin, Tianhong Pan, Robert L. Satcher, Mark A. Titus, Li-Yuan Yu-Lee, Wen Hui Weng, Gary E. Gallick and Sue-Hwa Lin _

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Oncotarget. 2017; 8:74987-75006. https://doi.org/10.18632/oncotarget.20489

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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

Correspondence to:

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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