Development of a realistic in vivo bone metastasis model of human renal cell carcinoma.
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (μCT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.
Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Maija P
MP
Valta
Hongjuan
H
Zhao
Alexandre
A
Ingels
Alan E
AE
Thong
Rosalie
R
Nolley
Matthias
M
Saar
Donna M
DM
Peehl
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D002470:Cell Survival; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010014:Osteolysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays