Changes in Circulating Pro-Angiogenic Cytokines, other than VEGF, before Progression to Sunitinib Therapy in Advanced Renal Cell Carcinoma Patients

Abstract

Objectives: This study included a cohort of advanced renal cell carcinoma patients treated with sunitinib. Since resistance to sunitinib may be mediated through angiogenic cytokines other than VEGF, we measured the circulating levels of three pro-angiogenic cytokines: basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and interleukin (IL)-6. Methods: Cytokines were measured at baseline and on the first day of each treatment cycle until progression in 85 advanced kidney cancer patients treated with sunitinib using a quantitative sandwich enzyme immunoassay (ELISA) technique. Results: Even though no statistically significant differences in the titers of the three cytokines were observed between baseline and the time of progression in the whole patient cohort, in 45.3, 46.6, and 37.3% of the patients a more than 50% increase between baseline and the time of progression was shown in circulating IL-6, bFGF, and HGF, respectively. Furthermore, this increase was more than 100% in 37.3, 44, and 30.6% of the patients, respectively. We also demonstrated that, in these patients, cytokines tended to increase and to remain high immediately before progression. Conclusions: In a large percentage of kidney cancer patients, progression is preceded by a significant increase in pro-angiogenic cytokines other than VEGF.

The Effect of VEGF-Targeted Therapy on Biomarker Expression in Sequential Tissue from Patients with Metastatic Clear Cell Renal Cancer

“…FGF-2 may mediate resistance to VEGF-targeted therapy by providing an alternative proangiogenic signal for endothelial cells (6,9). Increased circulating concentrations of FGF-2 have been reported in patients progressing on VEGFtargeted therapy (29). However, the relevance of this circulating pool is not clear, because FGF-2 exerts a paracrine effect to promote angiogenesis and tumor cell proliferation (30).…”

Phase II Results of Dovitinib (TKI258) in Patients with Metastatic Renal Cell Cancer

“…Indeed, FGF is another pathway shown to play a role in tumor angiogenesis (7,8). Highly vascularized tumors often contain high levels of FGFs and FGF receptors (FGFR) after treatment with VEGF pathway inhibitors (9,10). In addition, dysregulated expression of FGFs or FGFRs has been described in several cancers, including RCC (11).…”

Essential Role for Endocytosis in the Growth Factor-stimulated Activation of ERK1/2 in Endothelial Cells

“…Hepatocyte growth factor (HGF) can also stimulate angiogenesis by signaling through the MET receptor expressed on endothelial cells (17,18). Both FGF2 and HGF can mediate resistance to VEGF receptor inhibition by providing an alternative pro-angiogenic signal for endothelial cells (18 -20), and increased tumor expression of both FGF2 and HGF has been linked with resistance to VEGF pathway inhibitors in both preclinical and clinical studies (21)(22)(23)(24). Therefore, drugs that are designed to inhibit multiple pro-angiogenic growth factors may prove to be more effective than anti-angiogenic agents that block the VEGF pathway alone (13)(14)(15).…”