Increase, Inflammation leads to Increase, angiogenesis

Likewise, two studies evaluated the specific continuum AhR activation – increased inflammation – increased angiogenesis (Pontillo et al., 2015 Nov 19, Zárate et al., 2020 Aug). As previously mentioned, the AhR activation increases inflammation, notably through an increase in COX 2 (Bekki et al., 2015, Miller et al., 2005, Degner et al., 2009 Jan, Pontillo et al., 2015 Nov 19, Zárate et al., 2020 Aug).

COX-2 can promote angiogenesis through an increase in VEGF (Vascular endothelial growth factor) (Harris et al., 2014 Oct 10, Kirkpatrick et al., 2002). In a pathologic study characterizing 46 breast cancer specimen using immunochemistry, it was found that the density of microvessels was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03) (Costa et al., 2002 Jun). The relationship between COX-2 and angiogenesis has also been shown in gastric and colorectal cancer (Tsujii et al., 1998 May 29, Uefuji et al., 2000 Jan). Indeed, colon carcinoma cells overexpressing COX-2 produce proangiogenic factors (VEGF, bFGF, TBF-β, PDGF, and endothelin-1), and stimulate endothelial migration and the formation of tube vessels. These effects were reversed by an inhibitor (NS-398). In vivo, Diclofenac, a COX-2 inhibitor, decreased angiogenesis in mice presenting a colorectal cancer (Seed et al., 1997 May 1). Likewise, in a murine model of breast cancer, celecoxib (a selective COX-2 inhibitor) reduced metastasis and tumor burden through a decrease of micro vessel density and VEGF (Yoshinaka et al., 2006 Dec, Zhang et al., 2004 Sep). In clinical studies, patients with inflammatory breast cancers have increased levels of genes involved in angiogenesis such as VEGF (Van der Auwera et al., 2004 Dec 1). Patients with an inflammatory breast cancer benefit the most from anti-angiogenic treatment bevacizumab (Pierga et al., 2012 Apr).

The evidence was classified as “moderate” due to the lack of dose response studies.