Association of Angiopoietin-2 and Ki-67 Expression with Vascular Density and Sunitinib Response in Metastatic Renal Cell Carcinoma

Abstract

The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.

Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma

“…Arresting VEGFR2 on the cell surface through trans complex formation with NRP1 may also enhance efficient targeting of VEGFR2 using anti-angiogenic therapy through slower turn-over of the receptor; this scenario warrants further testing in mechanistic studies involving murine models of RCC. Furthermore, these data add to recent literature demonstrating prognostic impact of novel vascular and perivascular markers in RCC [32][33][34].…”

Potential suppressive effects of theophylline on human rectal cancer SW480 cells in�vitro by inhibiting YKL-40 expression

“…Angiopoietin-2, a member of the angiopoietin family, binds to the endothelium-specific receptor TEK tyrosine kinase (Tie2) and serves a notable role in maintaining normal vasculature through the modulation of vessel stability (31). High expression of angiopoietin-2 has been associated with several cancer types, including lung, oral, nasopharyngeal and kidney cancer (32)(33)(34)(35). The concentration of angiopoietin-2 was higher in patients with colon cancer and in colorectal mice models than in healthy patients or animals, and circulating angiopoietin-2 levels were reported to predict an unfavorable outcome in metastatic colorectal carcinoma (36,37).…”

Anti-angiogenic Targets: Angiopoietin and Angiopoietin Receptors

“…ANGPT2 expression has been shown in renal cell carcinoma (RCC) (Currie et al 2002;Rautiola et al 2016;Wang et al 2014). ANGPT2 expression was found specifically in the tumor endothelium with weaker or no expression in tumor cells (Currie et al 2002;Rautiola et al 2016). Specific endothelial expression was found to correlate with vascular density (Rautiola et al 2016).…”