An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers were noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression.
Antitumor activity was evaluated in athymic nude mice bearing subcutaneous DLD1 xenograft tumors and treated with anti-VEGF (B20), anti-Ang-2 (LC06) and anti-VEGF/Ang-2 (CrossMab) antibodies.
Ang II stimulation increased the expression of Ang II receptor 1 (AT1), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), tumor growth factor-β (TGF-β) mRNA, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and the levels of hydrogen peroxide (H₂O₂) and superoxide anion (•O₂<sup>-</sup>) and reduced anti-oxidant enzyme activity.
We measured disease activity (weight loss, stool consistency, fecal occult blood) during the study and at sacrifice, collected blood for cytokine/biomarker (Ang2, interleukin [IL] 1-β, IL-6, tumor necrosis factor α [TNFα], and VEGF-C) enzyme-linked immunosorbent assay analysis, measured colon length, and assessed tumor burden.
The expression levels of genes relevant for angiogenesis [angiopoietin (ANGPT)1, ANGPT2, fibroblast growth factor (FGF)1, FGF2, epidermal growth factor, placental growth factor, VEGFA and DLL4] were detected by reverse transcription‑quantitative PCR using RNA extracted from the frozen tissues of four tumors with low and four tumors with high NICD expression.
This corresponds with a decrease in Vegfa-stimulated response, but an increase in Vegfa+Ang2- or conditioned medium from tumor cell-stimulated cellular/angiogenic responses, mimicking responses in end-stage tumors with elevated Ang2 levels.
Total incidence of Ang-2 expression in the cancerous tissues was up to 91.8 % (112 of 122) with significantly higher (χ<sup>2</sup>=103.753, <i>P</i><sup>2</sup>=7.883, <i>P</i>=0.005), differentiation degree (χ<sup>2</sup>=4.554, <i>P</i>=0.033), tumor node metastasis (TNM) staging (χ<sup>2</sup>=5.039, <i>P</i>=0.025), and 5-year survival rate (χ<sup>2</sup> =11.220, <i>P</i><sup>2</sup>=18.881, <i>P</i><sup>2</sup>=0.81, <i>P</i>=0.776) or III & IV (χ<sup>2</sup>=1.845, <i>P</i>=0.174).
In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME.
Compared with control samples, the Ang1 expression of the transplanted tumor in both the hyperplasia and proliferative phases was stably low (p<0.05), while expressions of Ang2 and Tie2 were both stably high (p<0.05).
Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68<sup>+</sup> and CD163<sup>+</sup> macrophages, respectively.
We previously reported that Kaposi's sarcoma-associated herpes virus (KSHV) infection of endothelial cells induces the cytokine angiopoietin-2 (Ang-2) to promote migration of monocytes into tumors.
The results showed that the expression levels of vascular endothelial growth factor A (VEGFA), angiopoietin-2 (ANGPT2), and tissue plasminogen activator (PLAT) were suppressed in ADAM9-silenced cells, which in turn leads to decreases in angiogenesis, vascular remodeling, and tumor growth in vivo.
Ang-2 expression was significantly associated with the tumor grade and stage, as well as the MIB-1, Bcl-2, and VEGFR3 expression (P = .042, P = .019, P = .039, P = .013, and P = .005, respectively).
For lenvatinib-treated patients, interaction-term analyses revealed that low baseline Ang2 level was predictive of tumour shrinkage (P<sub>interaction</sub> = 0.016) and PFS (P<sub>interaction</sub> = 0.018).
The initial step in the metastasis and transition of tumors is epithelial-mesenchymal transition (EMT)-induced angiogenesis, which can be mediated by angiopoietin 2 (ANG2), a key regulatory factor in angiogenesis.