Abstract 4924: Adh1b low/ Cyp26b1 high activity of CD90+ (myo)fibroblasts supports tumor-promoting inflammation in colorectal cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.4924-4924
• Main Authors: Villeger, Romain, Uribe, Gabriella, Trieu, Judy A., Johnson, Paul, Qiu, Suimmin, Powell, Don W., Beswick, Ellen J., Pinchuk, Iryna V.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4924

Introduction. Retinol (RO) and its active metabolite, all-trans retinoic acid (atRA), have been widely studied as cancer chemotherapeutic agents. atRA is a critical immunoregulatory molecule reported to decrease cancer cell proliferation and inhibit tumor-promoting inflammation. However, recent studies report a loss of efficacy of atRA treatment to counteract colorectal cancer (CRC) progress, and the mechanisms underlying this failure are not fully understood. Alcohol dehydrogenase 1B (ADH1B), a major isoform of alcohol dehydrogenase expressed in normal colon, is responsible for the conversion of RO to atRA. We recently reported that stromal (myo)fibroblasts are major ADH1B expressers in normal colonic mucosa and that this expression is lost during the neoplastic transformation process of CRC. Thus, we hypothesized that aberrant retinoid signaling in cancer-associated fibroblasts (CAFs) is among key processes supporting tumor-promoting inflammation in CRC. Methods. Real-time PCR, confocal microscopy and cytokine luminex arrays were used to evaluate alterations in retinoid pathway gene expression and activity to define its relevance to the tumor-associated inflammation in human normal and CRC colonic tissues, and in normal primary (myo)fibroblasts (N-CMFs) and CAFs. Results. We observed a strong downregulation of ADH1B expression in CAFs in situ and in culture along with an increased expression of the tumor growth promoting inflammatory cytokine IL-6. Addition of the ADH1B substrate, RO, or its metabolite, atRA, to N-CMF cultures decreased the LPS-inducible IL-6 expression by N-CMFs. No downregulation of LPS-inducible IL-6 expression by RO was observed in CAFs, while atRA treatment partially inhibits IL-6 expression. Silencing of adh1b gene in N-CMFs led to the increased production of the LPS-inducible IL-6. This suggests that lack of ADH1B expression in CAFs prevents conversion of RO into atRA, resulting in the disruption of the negative regulation of IL-6. A decrease in downstream enzyme ALDH1A expression, which converts ADH1B’s byproduct retinaldehyde, to atRA, was also observed in CAFs. Finally, only a partial inhibition of IL-6 production by exogenous atRA was observed in CAFs. When compared to N-CMFs, CAFs expressed higher levels of CYP26B1, a cytochrome that is responsible for atRA degradation. Treatment of CAFs with atRA resulted in an eight fold higher upregulation of CYP26B1 expression than in N-CMFs. Conclusions. Taken together, our data suggests