Nicotine: specific role in angiogenesis, proliferation and apoptosis

Abstract

Nowadays, tobacco smoking is the cause of ~5-6 million deaths per year, counting 31% and 6% of all cancer deaths (affecting 18 different organs) in middle-aged men and women, respectively. Nicotine is the addictive component of tobacco acting on neuronal nicotinic receptors (nAChR). Functional nAChR, are also present on endothelial, haematological and epithelial cells. Although nicotine itself is regularly not referred to as a carcinogen, there is an ongoing debate whether nicotine functions as a 'tumour promoter'. Nicotine, with its specific binding to nAChR, deregulates essential biological processes like regulation of cell proliferation, apoptosis, migration, invasion, angiogenesis, inflammation and cell-mediated immunity in a wide variety of cells including foetal (regulation of development), embryonic and adult stem cells, adult tissues as well as cancer cells. Nicotine seems involved in fundamental aspects of the biology of malignant diseases, as well as of neurodegeneration. Investigating the biological effects of nicotine may provide new tools for therapeutic interventions and for the understanding of neurodegenerative diseases and tumour biology.

Nicotinic receptor and tobacco-related cancer

“…Indeed, when cigarette smoke is inhaled, either directly or by second hand, more than 7000 chemicals are introduced; among these hundreds are hazardous and 69, at least, are known to cause cancer (Russo et al, 2011). Chemicals, that are rapidly absorbed by cells, induce specific disease processes, including impairment of the immune system, which ultimately leads to cancer and other diseases (reviewed in Cardinale et al, 2012;Catassi et al, 2008;Huxley and Woodward, 2011;Russo et al, 2011). Among the cancerogens present on tobacco there are two nicotine-specific metabolites namely: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), which bind to nicotinic receptor (nAChR) (reviewed in Schuller, 2009).…”

α7 nicotinic acetylcholine receptors in lung cancer (Review)

“…These carcinogens and their metabolites may induce the formation of DNA adducts which result in mutations of a number of key cancer suppressor genes, including retinoblastoma tumor suppressor protein (Rb), KRAS proto-oncogene, GTPase and tumor protein p53 (11) and eventually contributing to tumorigenesis in different ways. Accumulating evidences have suggested that nicotine not only contributes to tumorigenesis but may also increase the spread of cancer in the body (12)(13)(14). α7 nicotinic acetylcholine receptors in lung cancer (Review) SHENGCHAO …”

Functional properties of ion channels and transporters in tumour vascularization

“…The angiogenic effect of nAChR is exerted through MAPK, PI3K/Akt and NF-kB pathway; however, because nAChR-mediated angiogenesis is partially inhibited only in a7-nAChR-deficient mouse, other nAChR isoforms are presumably involved [41]. Nicotine triggers neo-angiogenesis in breast, colon and lung tumour cells implanted in chick chorioallantoic membranes and promotes b-FGF release through the recruitment of nicotinic receptor, v3 integrin and MAPK pathway [94][95][96]. The ability of nicotine to promote late EPCs proliferation, migration, adhesion and tubulogenesis strongly suggests that its role is not restricted to mature EC [43] (table 1 and figure 2) …”

“…ECs express most of the known mammalian nAChR subunits [41,55,94]. In particular, a7 nAChR mediates the main effects of nicotine on EC, such as proliferation, survival, migration, tube formation and intracellular signalling.…”