ATRA AS A POTENTIAL ANTIMETASTATIC AGENT IN COLORECTAL ADENOCARCINOMA

Abstract

The family of Retinoic acid compounds have long been the subject of intense study and interest as chemo prophylactic agents. This dates back to their therapeutic effect in leukoplakia Where ATRA was shown to lead to the reversal of premalignant lesions and Subsequent reports on their use in metastatic colorectal adenocarcinoma and a vast array of other malignant disorders as well as adjuvant treatment of loco regional head and neck and colorectal adenocarcinoma. All-trans retinoic acid has transformed the treatment and outcome of patients with acute promyelocytic leukemia by differentiating leukemic promyelocytes into mature cells. Retinoid Receptor knock out mouse models also serve as excellent proof for the critical role of retinoids in embryogenesis, specifically their vital role in heart and blood vessel development, CNS specification, fetal lung development and proper limb morphogenesis. Here we show the results of our first phase of in vitro studies of the interaction of ATRA with the Gut homing Receptor, CCR9. Hypoxia up regulates CCR9 expression in CCIC, while ATRA down regulates CCR9 expression in hypoxic CCIC. In contrast, HT29 cells express significantly less CCR9 which is up regulated by hypoxia and further enhanced by ATRA treatment. We conclude that CCIC (representing a colon cancer stem-like line) respond differently to ATRA treatment Vs. a less stem-like, more differentiated cancer cell line such as HT-29. These results support a potential clinical use of ATRA early in the natural history of CRC in order to abort or slow down the process of metastasis in colorectal adenocarcinoma which is the ultimate killer of such patients. They also signify the critical significance of the time window and intratumoral heterogeneity in the final outcome of our intervention with ATRA in the treatment of CRC.