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Figure 3 from Antiangiogenic Tyrosine Kinase Inhibitors have Differential Efficacy in Clear Cell Renal Cell Carcinoma in Bone

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posted on 2024-10-08, 11:40 authored by Stefan Maksimovic, Nina C. Boscolo, Ludovica La Posta, Sergio Barrios, Mohammad Jad Moussa, Emanuela Gentile, Pedro I. Pesquera, Wenjiao Li, Jianfeng Chen, Javier A. Gomez, Akshay Basi, Jared K. Burks, Christopher Alvarez-Breckenridge, Jianjun Gao, Matthew T. Campbell, Eleonora Dondossola

In vitro and in vivo effects of TKIs on blood vessels. A, Dose–response curve of axitinib, cabozantinib, and lenvatinib treatment of HUVECs, mean ± SD, n = 4. B, Schematic representation of the experimental approach. C and D, Impact of TKIs on vascularization of RENCA VHL tumors in bone evaluated by IF analysis; representative images acquired by confocal microscopy (green, GFP; blue, DAPI; yellow, endomucin; red, laminin; C) and quantification are shown (D); dotted line, tumor area; mean ± SEM, n = 4–10/group; bar, 100 μm. E and F, Impact of TKIs on vascularization of RENCA VHL tumors in lungs; representative images acquired by confocal microscopy (green, GFP; blue, DAPI; red, CD31; E) and quantifications are shown; dotted line, tumor area; mean ± SEM, n = 4–10/group; ar, 100 μm. P values by one-way ANOVA with Tukey honestly significant difference post hoc test; *, P < 0.05; **, P < 0.01; ***, P < 0.001. A, axitinib; BV, blood vessel; C, cabozantinib; Endo/Endom, endomucin; L, lenvatinib; Lam, laminin; RV, RENCA VHL; V, vehicle.

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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.

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