Role of non neuronal cholinergic system in breast cancer progresión

ESPAÑOL ALEJANDRO; DE LA TORRE EULALIA; RIMMAUDO LAURA; FISZMAN GABRIEL; SALES MARÍA

Mainz, Alemania

Simposio; Second International Symposium on Non-neuronal Acetilcholyne; 2006

In 1998 we began to study the expression and function of muscarinic acetylcholine receptors (mAchR) in murine mammary adenocarcinoma cell lines (LM2, LM3 and LMM3). We observed that mAchR expression was up regulated in the three tumor cell lines in comparison with cells from normal murine mammary gland, NmuMG. We probed that receptor were functional because they responded to the muscarinic agonist carbachol, increasing proliferation in a concentration dependent manner. We also observed that the agonist increased arginine metabolism through nitric oxide synthase/arginase pathways. In addition carbachol potentate angiogenesis induced by tumor cells, quantified as microvessel density in an in vivo assay. These results correlate with VEGF-A expression in the skin that surrounds the site of tumor cells inoculation. Extra neuronal mAchR are also expressed in peritoneal macrophages (Mps) from tumor bearers (TMps). These MPs potentated tumor cells induced angiogenesis/lymphangiogenesis and elicited angiogenesis/lymphangiogenesis “per se”. The activation of mAchR in TMps by carbachol triggers arginine metabolism, PGE2 synthesis and VEGF production, promoting neovascularization. We also detected autoantibodies (autoAbs) against mAchR in the sera of tumor bearers that exert pro tumor functions. In small tumor bearing mice (14 days) autoAbs stimulate tumor cell proliferation while in big tumor bearers (30 days) autoAbs potentated tumor cells induced neovascularization. In conclusion non-neuronal mAchR expression in tumor cells regulates not only growth itself but also prompt host immune system towards a pro tumor response.