Increase, Inflammation leads to Increased, Invasion

In the specific setting of AhR activation, only 2 studies showed the continuum between AhR activation – increased inflammation – increased invasion (Miller et al., 2005, Yamashita et al., 2018 May 1). However, in general, there is extensive knowledge on the relationship between cell inflammation and organ invasion. First, COX-2 is expressed at higher levels in triple negative invasive breast cancers than in less aggressive ER-positive cancers (Gilhooly and Rose, 1999 Aug, Liu and Rose, 1996 Nov 15). COX-2 catalyzes the conversion of arachidonic acid into prostaglandin H2, a pro-inflammatory factor, and is therefore considered as a prognosis factor in breast cancer (Ristimäki et al., 2002 Feb 1, Parrett et al., 1997 Mar). Transfection with COX-2 triple negative MDA-MB-435 cells increased cell migration 2-fold compared to control cells in a transwell-Matrigel® assay. Antagonism of COX-2 through an inhibitor (NS-398) reversed this action in a dose-dependent way (Singh et al., 2005 May). Second, in vivo, the use of anti-inflammatory treatments such as celecoxib (COX-2 inhibitor) can reduce tumor growth and spread (Harris et al., 2000 Apr 15). Finally, epidemiologic evidence suggests that inflammatory breast cancers have the worse prognosis. Indeed, the median overall survival of patients with inflammatory breast cancer compared with those with non-inflammatory breast cancer tumors is 4.75 years versus 13.40 years for stage III disease and 2.27 years versus 3.40 years for stage IV disease (Schlichting et al., 2012 Aug, Fouad et al., 2017 Apr).

The mechanism of action of COX-2 are consensual. COX-2 promotes cell invasion through upregulation of MMPs (notably 2 and 9) (Takahashi et al., 1999 Oct 22, Sivula et al., 2005 Feb, Larkins et al., 2006 Jul). Moreover, COX-2 could also activate the urokinase plasminogen activator (uPA) which degrades the basal membrane of epithelia (Singh et al., 2005 May, Takahashi et al., 1999 Oct 22, Larkins et al., 2006 Jul, Guyton et al., 2000 Mar).

The relationship between inflammation and invasion is well document therefore the evidence was classified as “strong”.