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In the airway tract acetylcholine (ACh) is known to be the mediator of the parasympathetic nervous system. However ACh is also synthesized by a large variety of non-neuronal cells. Strongest expression is documented in neuroendocrine and in epithelial cells (ciliated, basal and secretory elements). Growing evidence suggests that a cell-type specific Ach expression and release do exist and act with local autoparacrine loop in the non-neuronal airway compartment. Here we review the molecular mechanism by which Ach is involved in regulating various aspects of innate mucosal defense, including mucociliary clearance, regulation of macrophage activation as well as in promoting epithelial cells proliferation and conferring susceptibility to lung carcinoma onset. Importantly this non-neuronal cholinergic machinery is differently regulated than the neuronal one and could be specifically therapeutically targeted.

Cancer is a genetic disease and this concept has now been widely exploited by both biologists and clinicians to design new targeted therapeutical approaches. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patient treatment. Correlation between mutations in cancer alleles and drug response is a crucial point to identify drugs or drug combinations that match the genetic profile of individual tumors. On the other hand, experiences derived from receptor tyrosine kinases (RTKs) inhibition have pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to the genetic alterations responsible for receptors activation and continued expression of their signaling pathways. Therefore, switching off the oncogenic activity by specific inhibitors will trigger an “oncogenic shock” which eventually will lead tumor cell to die. Overall these observations provide a strong rationale for molecular-based diagnosis and cancer patients selection for targeted treatment. Understanding how the mutational status of oncogenic alleles affects sensibility or resistance to drugs represents the most potential strategy in identifying patients for effective personalized therapies. In consideration of the high incidence and the poor prognosis of affected patients, lung carcinoma has been considered and still identify major objective of the targeted therapeutic approach. Experiences derived from this disease, and mainly from non-small cell lung cancer (NSCLC), represent fundamental achievement of translational research. From this perspective, members of the EGFR signal transduction pathway play a key role in lung carcinogenesis and act as genetic markers predictive of response to anti-EGFR therapy. In unselected NSCLCs EGFR activating mutations are rarely present (10%); mutation frequency increases to over 50% in a restricted subset of NSCLC patients: East-Asian, women, non smokers, affected by ADC (mainly BAC variant). Moreover the incidence of EGFR mutations in NSCLCs increases up to 77% among EGFR TKIs responders, while it is 7% in unsensitive cases. This project aims to evaluate in a cohort of NSCLC patients the prevalence of activating mutations in EGFR and KRAS genes by analyzing tumor cells obtained through transthoracic biopsy by FNAC, which actually represents the most appropriate diagnostic tool for peripheral lesions, such as ADKs that actually account for 40% of NSCLC diagnosis. Validation of sequencing technology on tumor samples constituted by only few cells has two relevant implications. First it might allows routinary tumor molecular profiling as powerful integration of conventional histo-pathological diagnosis. Besides the clinical management of NSCLC will take advantages from the characterization of EGFR-KRAS mutational status in order to develop personalized and effective treatment strategies., Bollettino della Società Medico Chirurgica di Pavia, Vol 123, N° 2 (2010)