Role of non-neuronal cholinergic system in breast cancer progression

We have previously reported the expression of functional muscarinic acetylcholine receptors (mAChR) in two different murine mammary adenocarcinoma cell lines LM2 and LM3. Activation of mAChR with carbachol (CARB) increased proliferation in both tumor cell lines in a concentration-dependent manner. In LM3 cells CARB promoted proliferation via M3 receptor activation by inositol 1,4,5-triphosphate and nitric oxide (NO) production. CARB-induced LM2 cells proliferation needed both M2 and M1 receptor activation increasing prostaglandin E2 liberation and arginase catabolism respectively. Our present results indicate that CARB stimulates LM2 and LM3-induced angiogenesis and tumor growth. This activation follows different patterns. In LM2 tumor, M1 and M2 receptors activation stimulates neovascularization by arginase II and cyclooxygenase-2 (COX-2)-derived products while M1 and M3 receptors mediate CARB-induced tumor growth by the same effector enzymes. In LM3 tumor, we observe that M1 and M2 receptors are involved in agonist-stimulated angiogenesis by COX and NOS1-derived products while tumor growth is stimulated by M3 and M2 receptors activation and COX-2-derived prostanoids. Taken together these data present, at least in part, a picture of the regulation that different mAChR subtypes activation exerts on angiogenesis and growth of two different murine mammary adenocarcinomas.