Angiopoietin‐2 drives lymphatic metastasis of pancreatic cancer

Abstract

Lymphatic metastasis constitutes a critical route of disease dissemination, which limits the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). As lymphangiogenesis has been implicated in stimulation of lymphatic metastasis by vascular endothelial growth factor-C (VEGF-C) and VEGF-D, we studied the effect of the angioregulatory growth factor angiopoietin-2 (Ang-2) on PDAC progression. Ang-2 was found to be expressed in transformed cells of human PDAC specimens, with corresponding Tie-2 receptors present on blood and lymphatic endothelium. In vitro in PDAC cells, Ang-2 was subject to autocrine/paracrine TGF-β stimulation (2-fold induction, P=0.0106) acting on the -61- to +476-bp element of the human Ang-2 promoter. In turn, Ang-2 regulated the expression of genes involved in cell motility and tumor suppression. Orthotopic PDAC xenografts with forced expression of Ang-2, but not Ang-1, displayed increased blood and lymphatic vessel density, and an enhanced rate of lymphatic metastasis (6.7- to 9.1-fold, P<0.01), which was prevented by sequestration of Ang-2 via coexpression of soluble Tie-2. Notably, elevated circulating Ang-2 in patients with PDAC correlated with the extent of lymphatic metastasis. Furthermore, median survival was reduced from 28.4 to 7.7 mo in patients with circulating Ang-2 ≥ 75th percentile (P=0.0005). These findings indicate that Ang-2 participates in the control of lymphatic metastasis, constitutes a noninvasive prognostic biomarker, and may provide an accessible therapeutic target in PDAC.

Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma

“…Of note, similar results were observed when the median value was used as a cutoff value. A value of 5 ng/mL was then chosen considering results provided by previous publications (17,20) regarding that 98% of healthy volunteers have baseline plasmatic levels of Ang-2 below 5 ng/mL. In consequence, to investigate a cutoff value for clinical use, a level of 5 ng/mL seemed to be a relevant choice (Fig.…”

“…18). Other exploratory studies pointed out its potential prognostic value by the description of an association between Ang-2 and OS or PFS, in small cohorts of patients (19,20). However, the independent and additional Ang-2 prognostic value for OS, among the conventional prognostic factors and prognostic scores used in clinical practice, is not yet established.…”

Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy

“…Angpt2 levels are increased in many human cancers, and its blockage inhibits tumor growth and angiogenesis (12)(13)(14). Blocking Angpt2 also inhibits tumor metastasis via hematogenous and lymphatic routes (13,15).…”

Molecular Regulation of Lymphangiogenesis in Development and Tumor Microenvironment

“…It is possible that activation of TIE-2 signaling pathway by ANGPT1 promotes the normalization of tumor-associated lymphatic vessels so that tumor cell could spread efficiently via lymphatics and establish metastatic foci in lymph nodes. Furthmore, ANGPT2 was also shown to promote tumor lymphangiogenesis and lymphatic metastasis (Schulz et al 2011). ANGPT2-blocking antibodies were shown to suppress tumor lymphangiogenesis and lymph node metastasis (Holopainen et al 2012).…”