Selective targeting of M3 muscarinic receptors: an opportunity for improved treatment of upper gastrointestinal carcinomas

Upper Gastrointestinal (GI) Carcinomas are one of the most morbid forms of cancers that are inherently resistant to chemotherapeutic regimens. The G-protein coupled receptors (GPCRs) are the largest family of cell surface receptors that have recently emerged as significant modulators of cancer cell growth, survival, and metastasis. Owing to the normal physiologic role of muscarinic receptors, a major sub-class of GPCRs, many epithelial cells undergoes proliferation when exposed to acetylcholine. Since majority of the cancers are epithelial in origin, cancer cells frequently take over the philological machinery associated with muscarinic receptors and undergo uncontrolled proliferation, avoid cell death, and exhibit invasion and migration. The M 3 sub-type of muscarinic receptors is over expressed in tumors of different types. In this review we focus on the oncogenic signaling mechanisms activated by the M 3 receptors. The manuscript highlights the importance of M 3 receptor as a potent therapeutic target for selective treatment of Upper GI Carcinomas. We also reported, for the very first time, that M 3 receptor mRNA is significantly over expressed in Upper GI Carcinoma tissue samples. In addition, we also showed that M 3 -specific anti-muscarinic agents have considerable anticancer activity in Upper GI Cancer cells. This review serves as foundation for future studies delineating the anti-tumor effect of M 3 -specific anti-muscarinic agents as single agents or in combination in Upper GI Carcinoma.