Retinoid Signaling in Cancer and Its Promise for Therapy

Abstract

Research ArticleOpen Access Coyle et al., J Carcinog Mutagen 2013, S7 http://dx. AbstractDeregulated signal transduction is a major facet of cancer development and progression. Herein, we review the current paradigm for retinoic acid signaling, its role in cancer and potential therapeutic applications and challenges. Retinoic acid is used with remarkable success in the treatment of one of the most high-risk leukemias, acute promyelocytic leukemia; however, extending its use in the treatment of other cancers has had limited success at best. Functional studies provide clues for the poor performance of retinoic acid as a general cancer therapeutic, connecting retinoic acid signaling to both cell growth arrest and proliferation with tumor suppression and cancer progression consequences. The dualistic role of the retinoic acid signaling pathway in cancer is revealed in its gene transcription targets, cross-talk with other transcription factors, mediation of apoptotic pathways, and influence in the immune system. If the greatest potential benefit of retinoid-based cancer therapeutics is to be achieved, the many physiological roles of retinoic acid need to be considered.

Reengineering Tumor Microenvironment with Sequential Interleukin Delivery

“…These suggest a potential impact on hematopoietic cell recruitment of both lymphocytic and mononuclear cells, aligning with the immune cell signature analyses. Common to the 27pepL groups were predicted reductions in retinol and triacylglycerolrelated pathways, and these could potentially promote or reduce tumor cell growth (via Treg inhibition), depending on the context [35]. Anti-tumor T-cell related pathways were predicted as activated in IL-18-and/or IL-27-containing groups, including Th1 and TCR signaling.…”

Epigenetics Territory and Cancer

“…Retinoic acid (RA), as a derivative of vitamin A or retinol, has a remarkable epigenetic regulatory role in gene transcription (Chambon 1996). Moreover, the "dualistic role" of the retinoic acid signaling pathway in cancer is reviewed (Coyle et al 2013). Retinoids and their products induce differentiation in various cell types as well.…”

Blockage of retinoic acid signaling via RARγ suppressed the proliferation of pancreatic cancer cells by arresting the cell cycle progression of the G1-S phase

“…RA signaling plays a role in the development and maintenance of homeostasis in various tissues [ 10 ] and exerts many biological effects, such as the induction of tumor suppressors in cancer [ 11 ]. Previous studies on PDAC attempted to activate RA signaling by adding all-trans RA (ATRA) based on data indicating attenuated signaling activity [ 12 , 13 ].…”

“…In PDAC cases, increased expression of RARα is reportedly associated with a better prognosis [ 13 ], suggesting that RARα is a tumor suppressor. RARβ is a well-documented tumor suppressor, and loss of RARβ expression or silencing of its regulatory regions by epigenetic mechanisms is found in many types of cancers, including PDAC [ 11 , 18 ]. The antitumor function of RARβ in PDAC has also been confirmed by its overexpression in vivo and in vitro [ 19 ].…”