Sunitinib Acts Primarily on Tumor Endothelium rather than Tumor Cells to Inhibit the Growth of Renal Cell Carcinoma

Abstract

Sunitinib is a broad-spectrum small-molecule inhibitor of receptor tyrosine kinases (RTK) that serves as the present standard of care for first-line therapy of advanced clear cell renal cell carcinoma (ccRCC). A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete. In this study, we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK(s) may specifically contribute to its therapeutic effects. Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets, only platelet-derived growth factor receptor-β and vascular endothelial growth factor receptor-2 (VEGFR-2) were overexpressed in ccRCCs relative to normal tissues. Sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (∼0.1 μmol/L) that inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing VEGFR-2 signaling. Moreover, whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment, sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment. Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells.

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

“…Renal cancers are highly angiogenic and sunitinib is proposed to suppress the growth of these tumours mainly through inhibition of angiogenesis (Faivre et al, 2007;Huang et al, 2010a). As our data identified FGF2 as a potent suppressor of sunitinib's anti-angiogenic activity, we assessed the expression of FGF2 in human renal cancer samples.…”

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

“…3 Kruskal-Wallis was used to examine associations between plasma proteins and patient characteristics. 4 Risk groups according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria [based on the five risk factors: low-Karnofsky performance status (<80%), high LDH (>1.5 times the upper limit of normal), low serum hemoglobin, high corrected serum calcium (>10 mg/dL), and time from initial diagnosis to treatment of less than 1 year]. 25 The median sVCAM-1 levels increased from 762 ng/mL (range, 325-3,458 ng/mL) at baseline to 931 ng/mL (range, 335-3,095 ng/mL) on C1D14 (p ¼ 0.022) and to 994 ng/mL (range, 507-2,336 ng/mL) on C1D28 (p ¼ 0.002).…”

“…3 Among these receptors, VEGFR on tumor associated-endothelium is considered to be a relevant target for sunitinib in RCC. 4 In the majority of RCC tumors, high levels of VEGF are being produced as a result from a defective function of the von Hippel-Lindau tumor suppressor gene. 5 VEGF is a potent angiogenic factor which plays a key role in tumor vascularization 6 and is involved in proliferation, migration and tube formation of endothelial cells as well as endothelial cell survival.…”

Vascular Endothelial Cell-specific MicroRNA-15a Inhibits Angiogenesis in Hindlimb Ischemia

“…It has been well established that stimulation of angiogenesis can be therapeutic in ischemic heart disease, cerebrovascular disease, peripheral arterial disease, and wound healing (3)(4)(5). However, inhibition of angiogenesis can also be therapeutic in cases of cancer, ophthalmic conditions, rheumatoid arthritis, and other diseases (2,6).…”