Effects of TKIs on blood vessels in RENCA VHL- bone and lung tumors. A) Visual representation of the experimental approach. B,C) Bone tumors: representative pictures captured at the confocal microscope and quantification of blood vessel area in tumor (green, GFP), nuclei (blue, DAPI); blood vessels (yellow, endomucin; red, laminin); dotted line, tumor edge; single channel endomucin is shown. A quantification of % blood vessels on tumor area is shown, mean + SEM, n=3-4/group; Bar, 100 µm. D,E) Lung tumors: representative pictures captured at the confocal microscope and quantification (C) of blood vessel area in tumor (green, GFP), nuclei (blue, DAPI); blood vessels (red, CD31); dotted line, tumor edge; single channel CD31 is shown. A quantification of % blood vessels on tumor area is shown, mean + SEM, n=3-4/group; Bar, 100 µm P values by one-way ANOVA with Tukey’s HSD post hoc test; p < 0.05 = *, p < 0.01 = **. BV- blood vessels. Endo-endomucin; Lam-laminin; BV-blood vessels; V-vehicle, A-axitinib, C-cabozantinib, L-lenvatinib;
ARTICLE ABSTRACT
Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel–Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies.
TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution.
