The respiratory epithelium expresses the
cholinergic system including
nicotinic receptors (nAChRs). It was reported that normal human bronchial epithelial cells (BEC), which are the precursor for
squamous cell carcinomas, and small airway epithelial cells (SAEC), which are the precursor for
adenocarcinomas, have slightly different repertoires of nAChRs. Studies shown that nAChRs expressed on lung
carcinoma or
mesothelioma form a part of an autocrine-proliferative network facilitating the growth of neoplastic cells; others demonstrated that
nicotine can promote the growth of colon, gastric, and
lung cancers.
Nicotine and structurally related
carcinogens like NNK [4-(methylnitrosoamino)- 1-(3-pyridyl)-1-butanone] and NNN (
N'-nitrosonornicotine) could induce the proliferation of a variety of
small cell lung carcinoma cell lines and endothelial cells and
nicotine in non-neuronal tissues -including lung- induces the secretion of
growth factors (bFGF,
TGF-alpha,
VEGF and PDGF), up regulation of the
calpain family
proteins, COX-2 and
VEGFR-2, causing the eventual activation of Raf/
MAPK kinase/ERK (Raf/MEK/ERK) pathway contributing to the growth and progression of
tumors exposed to
nicotine through tobacco
smoke or cigarette substitutes. It has been demonstrated that
nicotine promotes the growth of solid
tumors in vivo, suggesting that might induce the progression of
tumors already initiated. While tobacco
carcinogens can initiate and promote
tumorigenesis, the exposure to
nicotine could confer a proliferative advantage to early
tumors but there is no evidence that
nicotine itself provokes
cancer. This is supported by the findings that
nicotine can prevent apoptosis induced by various agents - such as chemotherapeutic in NSCLC, conferring a survival advantage as well.