TY - JOUR
T1 - Cabozantinib reverses renal cell carcinoma-mediated osteoblast inhibition in three-dimensional coculture in vitro and reduces bone osteolysis in vivo
AU - Pan, Tianhong
AU - Martinez, Mariane
AU - Hubka, Kelsea M.
AU - Song, Jian H.
AU - Lin, Song Chang
AU - Yu, Guoyu
AU - Lee, Yu Chen
AU - Gallick, Gary E.
AU - Tu, Shi Ming
AU - Harrington, Daniel A.
AU - Farach-Carson, Mary C.
AU - Lin, Sue Hwa
AU - Satcher, Robert L.
N1 - Funding Information:
This work was supported by grants from MDACC Institutional Start-up Fund, Institutional Research Grant (IRG) Program, and Bridge Funding at the MD Anderson Cancer Center (to R. Satcher), the NIH RO1 CA174798, P50 CA140388, Cancer Prevention and Research Institute of Texas (CPRIT RP110327, RP150179, RP190252; to S.H. Lin), RP150282 (to G. Gallick), core grant P30 CA016672 (to MDACC), P01CA098912 (to M. Farach-Carson), F31DE025179 (to K. Hubka), NSF IRISE 0966303, and NSF GRFP DGE-1450681 (to M. Martinez).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Renal cell carcinoma bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFBI), secreted by 786-O renal cell carcinoma, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed three-dimensional (3D) hydrogels to coculture bone-derived 786-O (Bo-786) renal cell carcinoma cells with MC3T3-E1 pre-OSBs. Culturing pre-OSBs in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-OSBs were cocultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Furthermore, treatment with bone morphogenetic protein 4, which stimulates OSB differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the coculture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 renal cell carcinoma cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D coculture system is an effective tool for screening osteoanabolic agents for further in vivo studies.
AB - Renal cell carcinoma bone metastases (RCCBM) are typically osteolytic. We previously showed that BIGH3 (beta Ig-h3/TGFBI), secreted by 786-O renal cell carcinoma, plays a role in osteolytic bone lesion in RCCBM through inhibition of osteoblast (OSB) differentiation. To study this interaction, we employed three-dimensional (3D) hydrogels to coculture bone-derived 786-O (Bo-786) renal cell carcinoma cells with MC3T3-E1 pre-OSBs. Culturing pre-OSBs in the 3D hydrogels preserved their ability to differentiate into mature OSB; however, this process was decreased when pre-OSBs were cocultured with Bo-786 cells. Knockdown of BIGH3 in Bo-786 cells recovered OSB differentiation. Furthermore, treatment with bone morphogenetic protein 4, which stimulates OSB differentiation, or cabozantinib (CBZ), which inhibits VEGFR1 and MET tyrosine kinase activities, also increased OSB differentiation in the coculture. CBZ also inhibited pre-osteoclast RAW264.7 cell differentiation. Using RCCBM mouse models, we showed that CBZ inhibited Bo-786 tumor growth in bone. CBZ treatment also increased bone volume and OSB number, and decreased osteoclast number and blood vessel density. When tested in SN12PM6 renal cell carcinoma cells that have been transduced to overexpress BIGH3, CBZ also inhibited SN12PM6 tumor growth in bone. These observations suggest that enhancing OSB differentiation could be one of the therapeutic strategies for treating RCCBM that exhibit OSB inhibition characteristics, and that this 3D coculture system is an effective tool for screening osteoanabolic agents for further in vivo studies.
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U2 - 10.1158/1535-7163.MCT-19-0174
DO - 10.1158/1535-7163.MCT-19-0174
M3 - Article
C2 - 32220969
AN - SCOPUS:85085904493
SN - 1535-7163
VL - 19
SP - 1266
EP - 1278
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -