Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

Sandeep Singh; Smitha Pillai; Srikumar Chellappan

doi:10.1155/2011/456743

Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

Singh, Sandeep;Pillai, Smitha;Chellappan, Srikumar 2011-03-30 00:00:00 Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 456743, 11 pages doi:10.1155/2011/456743 Review Article Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis Sandeep Singh, Smitha Pillai, and Srikumar Chellappan Department of Tumor Biology, H. Lee Moﬃtt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Correspondence should be addressed to Srikumar Chellappan, srikumar.chellappan@moﬃtt.org Received 19 December 2010; Accepted 28 January 2011 Academic Editor: Venkateshwar Keshamouni Copyright © 2011 Sandeep Singh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneﬁcial eﬀects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These eﬀects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Speciﬁc signal transduction cascades that emanate from diﬀerent nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor eﬀects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent eﬀorts to target the nicotinic acetylcholine receptors to combat cancer. 1. Introduction agents form DNA adducts and cause mutations in vital genes like Rb, p53, and K-Ras in smokers [7–9]. Smoking is a major risk factor associated with the develop- While the induction of these cancers is mediated by ment and progression of a variety of cancers [1]. Smoking is tobacco-speciﬁc nitrosamines as well as other carcinogens estimated to account for approximately 4-5 million deaths present in the tobacco smoke, it is becoming clear that worldwide and approximately 443,000 deaths each year in signaling through the nicotinic acetylcholine receptors con- the United States alone [2, 3]. Suﬃcient evidence has accu- tribute to the growth, progression, and metastasis of a mulated to conclude that tobacco smoking caused cancers variety of cancers. Nicotine, which is the major addic- not only of the lung, but also of the lower urinary tract tive component of tobacco smoke, acts through nicotinic including the renal pelvis and bladder, upper aero-digestive acetylcholine receptors (nAChR) [9–11], but is not thought tract including oral cavity, pharynx, larynx, and esophagus, to be carcinogenic. The expression of nAChRs in central and pancreas [2, 4]. Recent lines of evidence have showed and peripheral nervous system is associated with smoking that smoking tobacco can also cause cancers of the nasal dependence and addiction [12]. It was generally believed cavity, paranasal sinus, nasopharynx, stomach, liver, kidney, that nAChRs are only expressed in nervous system and at cervix, uterus, breast, adenocarcinoma of the esophagus, neuromuscular junctions (muscle type nAChRs). However, andmyeloidleukemia [2]. Of the thousands of chemicals the discovery of widespread expression of nAChRs in in tobacco smoke, polycyclic aromatic hydrocarbons and mammalian cells, including cancers, suggested its direct nicotine-derived nitrosamines have been identiﬁed as the role in cancer progression [13–15]. This paper deals with major and potent carcinogens [5, 6]. The metabolites of these certain aspects of nicotinic receptor signaling in nonneuronal 2 Journal of Oncology cells that lead to increased cell proliferation and survival, of CHRNA1, CHRNA5, and CHRNA7 subunit genes was angiogenesis, tumor growth, and metastasis. correlated with short-term exposure to nicotine [30]. Nico- tine stimulation contributed towards the growth of human mesothelioma cells. Human biopsies of mesothelioma as 2. Nicotinic Acetylcholine Receptor Expression well as of normal pleural mesothelial cells were found to in Nonneuronal Cells express functional α7-nAChR [31, 32]. Studies from the nAChRs are a complex of ﬁve subunits forming hetero- or Russo laboratory have shown that inhibition of nAChRs homopentamers to form a central ion channel [16, 17]. The by α-cobratoxin (α-CBT) can inhibit the growth of A549 tumors in immunocompromised mice [33]. These ﬁndings neuronal nAChRs can be homomeric composed of α7, α8, or α9 subunits or with the combinations of α2–α6or α10 strengthen the hypothesis that modulation of nAChRs subunits with β2–β4 subunits (heteromeric nAChRs). The upon chronic exposure to tobacco may contribute to the muscle type nAChRs may be comprised of combinations development and progression of cancer. In the following of α1 subunits with β1, γ, δ,or ε subunits [18]. Both sections, we will summarize the ﬁndings to support the neuronal as well as muscle nAChR families are found to hypothesis. be expressed in cancer cells [19]. Nicotine mimics acetyl- choline by binding as an agonist to α subunit of nAChRs 3. nAChRs Signaling in [10]. Nicotine binds with higher aﬃnity to heteromeric Tumor Growth and Survival α4β2-nAChRs than to α7-nAChRs [20]. Higher binding to α4β2-nAChRs results in desensitization of the receptor, Attempts have been made to elucidate the molecular events which could be the reason that α7-nAChR is the major that mediate nicotine-induced cell proliferation. Activation stimulator of cancer development and progression in vivo. of nAChR through nicotine or NNK has been found In addition to nicotine, tobacco-speciﬁc nitrosamines such to activate protein kinase C (PKC), the serine/threonine as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) kinase Raf-1, the mitogen-activated kinases ERK1 and can also bind to α7-nAchR, and N -nitrosonornicotine ERK2,and the transcription factors FOS,JUN,and MYC (NNN) binds to heteromeric αβ-nAChRs [21]. The aﬃnity through the selective activation of α7-nAChR in SCLC of NNK for the α7-nAChR was found to be 1,300 times [34]. Studies also demonstrated the stereospeciﬁcity of higher than nicotine, whereas the aﬃnity of NNN for nAChRs towards (−)-nicotine. It has been reported that heteromeric αβ-nAChRs was 5,000 times higher than that of (−)-nicotine stimulated tumor cell proliferation via secre- nicotine [21, 22]. tion of the neurotransmitter serotonin, and the growth Since the discovery of ubiquitous presence of nAChRs in stimulatory eﬀect of nicotine or NNK could be blocked mammalian cells, studies from many laboratories have linked by selective serotonergic receptor antagonists [27, 35, 36]. nAChRs with various pathological conditions including In a recent report, the eﬀects of acute and repetitive tumor growth and angiogenesis [13, 23]. In earlier studies, exposure to nicotine was shown to induce a neuronal- nicotine was found to stimulate endothelial-cell proliferation like appearance in N417 SCLC cell line, which produced via nAChR at concentrations lower than those obtained in bigger and more vascularized tumors in mice through blood after smoking [24]. As described in the later part activation of CXCR4/CXCL12 axis. A prominent increase in of this paper, many studies have correlated the exposure the expression of CXCR4 was observed in nAChR-dependent of nicotine or other tobacco smoke components with manner in nicotine-treated cells [37]. NSCLC cell lines induction of pathological neovascularization through the from large-cell carcinoma, squamous-cell carcinoma, and activation of nAChR [23, 25]. Studies from our laboratory adenocarcinoma, all showed the activation of PI3K-AKT have suggested that nicotine can enhance the growth and pathway and NF-κB activation in response to nicotine or metastasis of pre-established lung tumors [26]. Altogether, NNK treatment [38, 39]. In addition, frequent loss of the these studies proposed the involvement of tobacco smoke tumor suppressor gene FOXO3a was reported in carcinogen- components in various aspects of tumorigenesis and vas- induced lung adenocarcinoma. In NNK-treated lung cancer cular dysfunctions in smokers. Extensive research by many cells, restoration of FOXO3a in FOXO3a-deﬁcient cells groups has successfully associated the physiological eﬀect increases sensitivity to apoptosis caused by a DNA-damaging of nicotine and its derivatives with the direct activation intermediate of NNK. This study proposed that FOXO3a of nAChRs. Small cell lung carcinoma (SCLC) pulmonary might play a role in lung adenocarcinoma suppression neuroendocrine cells (PNECs) and SCLC cells express high by providing a protective response to carcinogenic stress levels of the α7-nAChR, whereas heteromeric nAChRs were [40]. undetectable [27, 28]. At the same time, both hetero- and Experiments from our laboratory have shown that homomeric nAChRs are found to be expressed in nonsmall nicotine stimulation aﬀects various components of cell cell lung carcinoma cells of diﬀerent histologic subtypes cycle regulatory machinery [26, 29, 41]. Exposure to nico- [19, 29]. Recently, diﬀerential expression pattern of ACHR tine resulted in activation of Raf-1, induction of cyclin subunit gene was studied in NSCLC patients who were D and cyclin E-associated kinase activity as well as Rb smokers or never smokers. Higher expression of CHRNA6 phosphorylation, which led to the dissociation of E2F1 and CHRNB3 combination was correlated with NSCLCs from Rb. Further, it was observed that stimulation with in nonsmokers, whereas lower expression was correlated nicotine caused the dissociation of Rb from E2F-responsive with NSCLCs in smokers. Additionally, increased expression proliferative promoters (cdc6 and cdc25A), while there were Journal of Oncology 3 increased amounts of E2F1 bound to them. These molecular A centrosomal protein CEP55 as well as a DNA helicase events were correlated with increased proliferative eﬀects of and putative stem cell marker HELLS, were found to be nicotine in NSCLC cell lines A549 (human bronchioalveolar novel targets of nicotine-induced FOXM1 expression and carcinoma), NCI-H23, NCI-H441 (lung adenocarcinoma), correlated with oral cancer progression [45]. and NCI-H226 (pleural eﬀusion squamous cell carcinoma) A role of nAChR has been demonstrated in breast cancer as well as on primary normal human bronchial epithelial progression as well. Experiments with human mammary cells (NHBEs), small airway epithelial cells (SAECs), human epithelial-like MCF10A or cancerous MCF7 cells revealed aortic endothelial cells (HAECs), and human microvascular that treatment of these cells with nicotine enhances the endothelial cells from lung (HMEC-Ls). The mitogenic activity of protein kinase C (PKC) alpha with cdc42 as a eﬀects of nicotine were abrogated by α7 subunit antagonists, downstream target for nicotine-induced proliferation and α-bungarotoxin, and methylallyl aconitine (MAA), whereas migration [46]. It has also been suggested that nicotine- it was unaﬀected by α-lobeline (α4β2 subunit inhibitor) induced proliferation of human breast cancer cell is depen- or dihydro β-erythoidine (DHβE; α3β2and α4β2 subunit dent on α9-nAChR and cyclin D3 expression [47]. The inhibitor), suggesting that α7 subunits primarily mediated eﬀects of nicotine on a population of cancer stem cells in the mitogenic eﬀects of nicotine in NSCLC cells. We MCF-7 human breast cancer cells were examined, using have further illustrated that upon nicotine stimulation, the aldehyde dehydrogenase (ALDH) as a stem cell marker. This scaﬀolding protein β-arrestin-1 forms a complex with nonre- study found that nicotine increases the stem cell population ceptor tyrosine kinase-Src and gets recruited to the nAChRs. via α7-nAChR and the PKC-Notch dependent pathway Depletion of β-arrestin-1 or Src prevented nicotine-induced [48]. cell proliferation. These results suggested that α7-nAChR- Apart from direct responses through nAChRs, indirect mediated stimulation of cell proliferation is through a signaling events may also contribute to nicotine-induced β-Arrestin-1-Src signaling axis in NSCLC [41]; (see also tumor growth and survival. Since nAChRs are cation chan- Figure 1). nels, it can stimulate signaling cascades by the inﬂux of Ca2+ Other than lung cancer, activation of α7-nAChR and through the opened α7-nAChR [49]. Ca2+ channel blockers heteromeric nAChRs expressing α3and α5 subunits have are shown to signiﬁcantly reduce DNA synthesis in response been reported in oral and esophageal keratinocytes [22]. to nicotine or NNK in SCLCs [49]. Also, nAChR-mediated Similar to lung cancer cells, NNK was found to bind with systemic increase in stress neurotransmitters, adrenaline, high aﬃnity to α7-nAChR, whereas NNN was found to bind and noradrenaline, which are β-adrenergic agonists, are also to heteromeric nAChRs with higher aﬃnity [22]. Esophageal shown to stimulate β-adrenergic receptor-initiated cAMP cancer-Het-1A cells stimulated with NNK or NNN showed signaling and transactivation of EGFR cascade through increased mRNA transcripts and expression of PCNA and EGF secretion in NNK-treated small airway epithelial cells Bcl-2, and transcription factors GATA3, NF-κB, and STAT1. [50, 51]. Nicotine is found to induce systemic or cellular However, induction of Ras-Raf-ERK1-ERK2 cascade, the increase in noradrenaline and signiﬁcantly enhance the JAK2-STAT3 pathway and NF-κB activation was associated growth and angiogenesis of pancreatic, gastric, and colon with enhanced cell proliferation through these nitrosamines cancer-xenografts with increased expression of ERK1-ERK2, in immortalized oral epithelial cells [22]. In addition, chronic COX2, prostaglandin E2, VEGF, and transactivation of exposure of nicotine or environmental tobacco smoke on β-adrenergic as well as EGFR signaling in colon cancer oral keratinocytes selectively upregulated α5- and α7-nAChR cells [52–55]. Activation of ERK1-ERK2 and STAT3 in subunits, resulting in intensiﬁed signaling responses to response to nicotine has also been reported in bladder cancer nicotine [42]. cells downstream of nAChRs and β-adrenergic receptors The secreted mammalian Ly-6/urokinase plasminogen [56]. Importantly, apart from nAChRs, direct interaction activator receptor-related protein-1 (SLURP-1) is recently of NNK with β-adrenergic receptor has been proposed identiﬁed as an endogenous ligand for the α7 subunit of as a novel mechanism, which may signiﬁcantly enhance the nicotinic acetylcholine receptor (nAChR). The expres- the high cancer-causing potential of these nitrosamines sion levels of SLURP1 and SLURP2 (secreted mammal- [50, 57]. Similar to the activation via neurotransmitters, ian Ly-6/urokinase plasminogen activator receptor-related NNK binding to β-adrenergic receptor was also found protein-2) were reduced in NNK-treated cells. Transfection to activate adenylyl cyclase-cAMP-PKA-CREB cascade and of the cells with SLURP1 or SLURP2 cDNA reduced the transactivation of EFGR [58]. Additionally, an additive eﬀect nitrosamine-induced colony formation in soft agar while of estrogen receptors and nAChRs was also demonstrated inhibiting the growth of NNK-transformed keratinocytes in promoting the growth of A549 tumors in athymic nude in mouse xenografts. SLURP1 bound to α7-nAChR and mice. Cotreatment of nicotine and estradiol resulted in SLURP2 bound to nAChRs expressing the α3 subunit [22, increased cell proliferation as well as VEGF secretion from 43]. Similar results were demonstrated recently where HT- cancer cells, leading to increased tumor growth as well 29 human colon cancer cells treated with nicotine resulted as microvascular density within the tumor [59]. Recently, in increased cell proliferation and a marked reduction in the chronic exposure to estrogen and NNK was shown the protein expression of SLURP1 via α7-nAChRs acti- to have synergistic eﬀects on cell proliferation and pro- vation [44]. Recently, nicotine mediated upregulation of duction of noradrenaline and adrenaline, by upregulating FOXM1 expression was found in primary oral keratinocytes α7-nAChRs in immortalized small airway epithelial cells which was associated with induction of genomic instability. [60]. 4 Journal of Oncology NNN, NNK, nicotine Epithelial markers EMT Angiogenesis c-Src β-arrestin metastasis Mesenchymal markers Adrenaline and nAChRs β-ARs noradrenline PI3K EGF-release β-arrestin EGFR AKT c-Src Ras PI3K pRb pRb Raf XIAP Raf NF-κB cdc6 AKT E2F1 E2F1 cdc25a Survivin ERK Proliferation Survival Figure 1: A schematic of nAChR-mediated regulation of diverse tumorigenic processes. nAChRs are activated by tobacco smoke components like NNN, NNK, and nicotine with diﬀerent aﬃnity. Induced nAChRs activate several downstream signaling pathways involved in cell proliferation, inhibition of apoptosis, metastasis, and angiogenesis in a variety of cancer and primary cells. Agonist binding to nAChR forms complex with β-arrestin and Src and results in Raf-1 activation. Activated Raf-1 phosphorylates and inactivates Rb tumor-suppressor- function. These in turn results in E2F-1-mediated transcriptional upregulation of target genes involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Downstream eﬀect of nAChR activation is also indirectly supported by the activation of β-adrenergic receptor (β-AR) signaling. Nicotine exposure directly results in metastatic dissemination of primary tumor by inducing epithelial to mesenchymal transition (EMT) in cancer cells. 4. nAChRs Signaling in Cell Survival and Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or speciﬁc depletion of AKT was Resistance to Apoptosis shown to block both nicotine-induced Bax phosphorylation In addition to the eﬀect on tumor growth, epidemiological and cisplatin resistance in NSCLC cells [64]. and clinical data implicate that in patients with cancer, In addition to these signaling events, results from our continued smoking causes resistance to therapy by blocking laboratory revealed a signiﬁcant role for the IAP pro- the induction of apoptosis. Various studies have linked the teins XIAP and survivin in nicotine-mediated chemoresis- activation of nAChR resulting in inhibition of apoptotic tance in NSCLCs in vitro. Chromatin immunoprecipitation pathways. In SCLC cells, NNK was shown to phosphorylate assays demonstrated that nicotine stimulation caused an Bcl-2 at Ser70 which promoted its interaction with c-Myc increased recruitment of E2F1 and concomitant dissociation that signiﬁcantly enhanced the half-life of the c-Myc protein of retinoblastoma tumor suppressor protein (Rb) from [61]. This functional cooperation of Bcl2 and c-Myc resulted survivin promoter in NSCLC cells [65]. Moreover, ablation in promoting cell survival and proliferation. This eﬀect of E2F1 levels caused abrogation of survivin expression could be blocked by the PKC inhibitor staurosporin, the and protective eﬀects of nicotine against cisplatin-induced ERK1-ERK2 inhibitor PD98059 or silencing of MYC [61, apoptosis in A549 cells. In the above study, chemoprotective 62]. Additionally, mesothelioma cells also showed nicotine- eﬀect of nicotine was found to be mediated through α3/β4- 2+ stimulated proliferation through α7-nAChR-mediated Ca - nAChR activation and could be abrogated by agonists of dependent activation of the ERK1-ERK2 cascade and inhib- these subunits. It was also found that nicotine stimulation ited apoptosis by induction of NF-κB and phosphorylation enhanced the levels of XIAP at the protein level. Nicotine of BAD at Ser112 (Bcl-2 antagonist of cell death) [32]. In induces the activation of Akt, which is known to phosphory- NSCLCs, constitutive activation of AKT is associated with late XIAP and prevent its proteasome-mediated degradation lung cancer cell survival and resistance to chemotherapy [66]. In agreement with this, an Akt inhibitor could abrogate and radiation [63]. Similarly, nicotine or NNK exposure the antiapoptotic eﬀects of nicotine in A549 cells [65]. displayed AKT-mediated growth and NF-κB-mediated resis- In other studies, the cooperative eﬀect of nicotine and tance to apoptosis in human airway epithelial cells as well NNK was investigated for their transforming ability in vari- as lung cancer cells [38, 39]. Further, activated AKT could ous lung epithelial or cancer cells. Exposure to nicotine or the directly phosphorylate Bax in vitro in nicotine treated cells. combination of nicotine and NNK for one week augmented Journal of Oncology 5 Bcl-2 expression, accompanied by an increased resistance in vivo. In a mouse model of hind-limb ischemia, nicotine to cisplatin-induced apoptosis [67]. This study also showed increased capillary and collateral growth, and enhanced that the combination treatment promoted cell prolifera- tissue perfusion. These eﬀects of nicotine were mediated tion and anchorage-independent growth as compared to through nicotinic acetylcholine receptors at nicotine concen- NNK exposure alone [67]. In another study, nicotine was trations that are pathophysiologically relevant and suggested demonstrated to mediate prosurvival activity by Mcl-1 a possible role for the endothelial production of nitric oxide, phosphorylation. Nicotine-induced Mcl-1 phosphorylation prostacyclin, and vascular endothelial growth factor [70– signiﬁcantly enhanced the half-life of Mcl-1, which conferred 74]. Nicotine has been demonstrated to stimulate postnatal long-term survival potential [68]. Speciﬁc depletion of Mcl-1 angiogenesis, having an antiapoptotic eﬀect on endothelial by RNA interference blocked nicotine-stimulated survival cells. It was observed that nicotine stimulated postnatal vas- and enhanced apoptotic cell death [67]. Nicotine-mediated culogenesis on endothelial progenitor cells (EPCs) [75]. The activation of α7-nAChR has also been linked with the eﬀect of nicotine on EPC survival was signiﬁcantly enhanced expression of PPARβ/δ protein by inhibiting AP-2α protein under serum starvation. Furthermore, the antiapoptotic expression and DNA binding activity to the PPARβ/δ gene eﬀect of nicotine was blocked completely by nicotinic promoter [69]. Sp1 was found to modulate this process. α7- acetylcholine receptor (nAChR) antagonist hexamethonium nAChR antagonist and short interfering RNA against α7- bromide [75]. nAChR as well as inhibitors of phosphatidylinositol 3-kinase Recent studies have shown that apart from cigarette (PI3K; wortmannin and LY294002) and mammalian target smoking, exposure to secondhand smoke also could induce of rapamycin (mTOR; rapamycin) blocked the expression angiogenesis. A positive correlation between secondhand of PPARβ/δ protein demonstrating a novel mechanism by smoke exposure and concentrations of nicotine in the body which nicotine could promote human lung carcinoma cell was established after analyzing twenty-two studies measuring growth [69]. These studies show that signaling through the biological eﬀects of nicotine [76]. Further, it was found the nAChRs could promote cell proliferation and survival, that the levels of nicotine exposure from secondhand smoke utilizing multiple signaling cascades. were comparable to those of active smokers. In a mouse model where Lewis lung cancer cells were implanted subcu- taneously into mice, which were then exposed to sidestream 5. nAChRs and Tumor Angiogenesis smoke (SHS) or clean room air and administered vehicle or mecamylamine (an inhibitor of nAChR); SHS signiﬁcantly Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex multistep process increased tumor size, weight, capillary density, VEGF, and involved in a number of physiological processes such as MCP-1 levels, and circulating endothelial progenitor cells wound healing, embryogenesis and reproduction. In addi- (EPC). Mecamylamine partially inhibited the eﬀects of SHS tion, angiogenesis is necessary for the sustained growth on these angiogenic processes and nearly abolished the eﬀects of the primary tumor as well as metastatic dissemination. of SHS on tumor capillary density suggesting that nicotine Nicotine has been shown to enhance angiogenesis in many mediated the eﬀects of SHS on tumor angiogenesis and experimental systems and animal models. The proangiogenic growth [77]. Several recent studies have implicated that nicotine- activity of nicotine is mediated by nicotinic acetylcholine receptors, particularly α7 subunit. The pioneering study by induced angiogenesis could be mediated by growth stabi- Villablanca (1998) demonstrated the ability of nicotine to lization and transmigration of endothelial progenitor cells (EPC) [75, 78, 79]. Nicotine accelerated the growth of induce endothelial cell proliferation [24]. This observation was followed by the elegant studies from the John Cooke’s syngenic colon cancer CMT93 cells when grown subcuta- laboratory suggesting a cholinergic pathway for nicotine- neously in mice by inducing angiogenesis via bone marrow induced angiogenesis where they demonstrated complete derived EPCs [78]. To determine if the angiogenic eﬀects inhibition of endothelial network formation using nons- of nicotine is mediated by EPC mobilization, Heeschen et al. used a model of mouse parabiosis and found that elective nAChR antagonist mecamylamine in an in vitro angiogenesis model [25]. Although several nAChR isoforms nicotine enhances EPC mobilization into the vasculature of are expressed on endothelial cells, a similar inhibition was the ischemic tissue. This eﬀect may be due to the direct actions of nicotine on EPC proliferation, migration and/or obtained only with the selective α7-nAChR antagonist α- bungarotoxin, conﬁrming the speciﬁc involvement of α7- mobilization as suggested by in vitro models [80]and plasma nAChR. Further, in vivo pharmacological inhibition of markers used in the investigation [79]. They also noticed that in the absence of acute ischemia, nicotine did not stimulate nAChR and a genetic disruption of α7-nAChR expres- sion signiﬁcantly inhibited inﬂammatory angiogenesis and EPC mobilization. The activation of nAChRs in response to reduced ischemia-induced angiogenesis and tumor growth. ischemia induced the release of proangiogenic factors like They also provided anatomic and functional evidence for VEGF and stem cell derived factor-1, both of which are regu- nicotine-induced angiogenesis and arteriogenesis when they lated by hypoxia, which in turn facilitates EPC mobilization [81]. Evidence from another study also demonstrated that observed that nicotine accelerated the growth of tumor and atheroma in association with increased neovascularization nicotine promotes angiogenesis via stimulation of nAChR- [23]. dependent endothelial cell migration. nAChR antagonism not only abolished nicotine-induced human microvascular Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated ﬁbrovascular growth endothelial cells (HMVEC) migration but also abolished 6 Journal of Oncology migration induced by bFGF and attenuated migration studies from our laboratory demonstrated that nicotine can induced by VEGF. Transcriptional proﬁling identiﬁed gene induce invasion and migration in cell lines derived from lung expression programs which were concordantly regulated by cancer, breast cancer, and pancreatic cancer via α7-nAChR- all 3 angiogens (nicotine, VEGF, and bFGF), a notable feature mediated signal transduction pathways [90]. The proinvasive of which includes corepression of thioredoxin-interacting eﬀects of nicotine were mediated by α7-nAChR in lung protein (TXNIP), endogenous inhibitor of the redox regu- cancer cells while α7-nAChR and DhβEsensitive nAChRs lator thioredoxin. Furthermore, TXNIP repression by all 3 mediated invasion of breast cancer cells. Nicotine was also angiogens induced thioredoxin activity. Interestingly, nAChR found to inhibit anoikis in lung airway epithelial cells. antagonism abrogates growth factor (VEGF- and bFGF-) Further, nicotine could induce changes in gene expression mediated induction of thioredoxin activity suggesting the consistent with EMT. Long-term treatment of lung cancer requirement of nAChR activation in endothelial cell migra- and breast cancer cells with nicotine was found to diminish tion, a key angiogenesis event [82]. levels of epithelial markers namely β-catenin and E-cadherin The proangiogenic eﬀects of nicotine have been found and upregulate mesenchymal proteins like ﬁbronectin and to be mediated by α7-nAChR on endothelial cells by acti- vimentin, indicative of disruption of cell-cell contacts and vating ERK/MAP kinase pathway, PI3 kinase/Akt pathway, increased motility [90]. and NF-κB[23, 25, 83, 84]. Further, nicotine has been In addition to facilitating EMT, nicotine and NNK shown to induce the proangiogenic factors like VEGF have been shown to aﬀect various aspects of tumor cell and HIF-1α in NSCLC cell lines [85]. Pharmacologically invasion and migration. For example, both nicotine and blocking nAChR-mediated signaling cascades, including the NNK are shown to promote the invasion of NSCLC by Ca2+/calmodulin,Src,protein kinase C, PI3K/Akt, MAPK/ phosphorylation of μ and m-calpains [62]. Several lines of ERK1/2, mTOR pathways, signiﬁcantly attenuated nicotine- evidence show that calpain-mediated proteolysis mediates induced upregulation of HIF-1α. These proangiogenic and various aspects of cell physiology including cell migration invasive eﬀects of nicotine were partially abrogated by and invasion. Nicotine was found to induce phosphorylation depleting HIF-1α using siRNA techniques. Additionally, of both μ and m-calpains via α7-nAChR; the binding of nicotine could promote angiogenesis of gastric cancers nicotine to α7-nAChR in turn was found to activate Src by upregulating COX2 and VEGFR2 [86]. Nicotine also and PKC-iota, leading to enhanced invasion and migration enhanced the activity of matrix metalloproteinase 2 and 9 of NSCLC cell line H1299. Similarly, NNK also could and expression of plasminogen activators in a COX2 and promote invasion and migration through phosphorylation VEGFR2-dependent manner. The proangiogenic eﬀect of of μ and m-calpains in a α7-nAChR-dependent fashion nicotine has been shown to be dependent on Src activity by [62]. our laboratory [41]. The inhibition of Src, using chemical Several observations in patients suggest that those inhibitors or siRNA has been shown to inhibit endothelial exposed to tobacco carcinogens are more likely to develop cell proliferation, migration, and angiogenic tubule forma- larger, more vascularized tumors with a high propensity tion on matrigel. As mentioned earlier, studies from our for metastatic spread and resistance to chemotherapy [90]. laboratory suggest that the scaﬀolding protein β-arrestin-1 About 30% of lung cancer patients who are smokers continue causes the activation of Src. Oligomeric complex comprising to smoke after they have been diagnosed [91], which might of nAChR, β-arrestin-1, and Src is vital for nAChR signaling. result in increased adverse medical consequences such as In addition, depletion of β-arrestin-1 caused abrogation of increased tumor progression, development of a second endothelial cell proliferation and angiogenic tubule forma- cancer, greater recurrence, greater cancer-related mortality tion [29, 41]. These data suggest that nicotine behaves in a and reduced quality of life [92, 93]. While these studies manner analogous to growth factors and induces cell cycle demonstrate a role for tobacco carcinogens in the initiation, progression in endothelial cells. growth, and progression of cancers, the relative contribution of nicotine by itself to these processes is not well explored. A recent study from our laboratory demonstrated that 6. nAChRs in EMT and Tumor Metastasis nicotine by itself can induce the growth and metastasis Epithelial to mesenchymal transition (EMT) is a biolog- of tumors in immunocompetent mice, independent of other tobacco carcinogens [26]. Nicotine administered either ical process that allows a polarized epithelial cell, which normally interacts with the basement membrane through intraperitonially or by commercially available transdermal its basal surface, to undergo multiple biochemical changes patches could substantially promote tumor growth. Similar eﬀects were observed on implanted tumors as well as tumors with a signature of more advanced and less diﬀerentiated cancer that allow it to assume a mesenchymal phenotype. induced by tobacco carcinogen, NNK. Furthermore, mice This enhanced migratory capacity, invasiveness, resistance exposed to nicotine showed signiﬁcantly enhanced lung to apoptosis, and greatly increased production of ECM metastasis as well as tumor recurrence after surgical removal components [87–89]. This process results in degradation of of the primary tumor, indicating that nicotine can enhance the growth and metastasis of pre-established lung tumors basement membrane and the formation of a mesenchymal like cell, which can migrate away from the epithelial layer [26]. As mentioned earlier, repetitive exposure to nicotine on in which it originated [88]. Epithelial to mesenchymal SCLC-N417 cells resulted in neuronal-like appearance along with increased adhesion to the extracellular matrix. These transition (EMT) is involved in tumor progression from noninvasive tumor cells into metastatic carcinomas. Recent changes were accompanied by enhanced migration through Journal of Oncology 7 collagen matrices and adhesion to and transmigration across isoform, OPNc, is selectively inducible by nicotine and lymphatic endothelial cell monolayers [37]. is highly expressed in PDA tissues from smokers which Accumulating evidence from epidemiological studies induced the expression of monocyle chemoattractant protein suggest a strong association between smoking and pul- (MCP-1) indicating a proinﬂammatory role of nicotine monary metastatic disease in women with breast cancer [108]. Altogether, these results suggest that nicotine plays a [94]. In a murine model of metastatic mammary cell key role in the regulation of the complex cellular cascades cancer, cigarette smoke exposure was associated with an that modulate cell adhesion, invasion, and migration leading increase in the total pulmonary metastatic burden providing to metastasis. experimental support for an adverse eﬀect of smoking on the metastatic process and suggesting a possible mechanism for 7. Discussion and Conclusions smokers’ increased breast cancer mortality [95]. In addition, it was observed that cigarette smoking was correlated with Tobacco smoking is a well-documented risk factor for increased lymph node metastases at mastectomy in women many cancers. As summarized in Figure 1, nicotine, the older than 50 years of age suggesting that tobacco usage principal addictive component of tobacco smoke, as well may potentiate the early spread of malignant disease [96]. as other nitrosamines have been found to act through Although numerous studies have indicated the role of nico- nAChRs on nonneuronal cells to facilitate tumor growth, tine exposure in tumor promotion, little is known about the angiogenesis, metastasis, survival, and chemoresistance by molecular mechanisms by which nicotine promoted breast regulating diverse signaling pathways. Binding of agonist tumor development, especially on the metastatic process of to nAChR facilitates the complex formation between the breast cancer. At least four diﬀerent subunits of nAChRs receptor, scaﬀolding protein β-arrestin and tyrosine kinase including α5, α7, α9, and β4 are shown to be expressed in Src. Activation of Src was found to be important for cancer breast cancer cells [46]. It has been demonstrated that in as well as endothelial cell proliferation and angiogenic tube addition to proliferative eﬀect, nicotine promoted migration formation in vitro.Proliferative eﬀect of nAChR-activation of breast cell lines (mammary epithelial cell line MCF10A was also supported by indirect stimulation of β-adrenergic and breast cancer cell line MCF7) through a signaling cascade receptor (β-AR) signaling. Further, chemotherapy-induced involving PKC activation and its downstream eﬀector cdc42 apoptosis was found to be blocked by nicotine-induced [46]. Exposure to nicotine has shown to increase the survivin expression as well as NF-κB activation. Activation expression of α9-nAChR in breast cancer cells [47, 97]. of nAChR is also correlated with EMT-like changes and Studies using a soft agar transforming assay and a mouse metastatic dissemination of primary tumor cells. Given the xenograft model demonstrated that noncancerous human ability of nicotine to aﬀect various aspects of tumor growth breast epithelial cell line, MCF10A, could be neoplastically and metastasis, antagonists of nAChR signaling might be transformed by exposure to either a cigarette smoke con- beneﬁcial in controlling the growth and progression of densate or the tobacco speciﬁc carcinogen, NNK [98, 99]. tumors. Recently, alpha cobratoxin (α-CbT) has been shown In a recent study, α9-nAChR expression was silenced in to block the growth of a variety of NSCLC and mesothelioma MDA-MB-231 breast cancer cells which resulted in reduced cell lines both in vitro and in vivo [109, 110]. The most proliferation and tumorigenic potential in both in vitro and striking eﬀect of α-CbT was its ability to eﬀectively inhibit in vivo assays, indicating the role of α9-nAChR in breast the metastatic potential of lung cancer cells transplanted carcinogenesis [100]. into nude mice, indicating the possibility of using nAChR Cigarette smoking has recently been recognized as a risk antagonists as adjuvant therapy in preventing metastatic factor for gastric cancer [101] and long-term exposure of spread. At the same time, the potential side eﬀects of nicotine-induced EMT like changes in gastric cancer cell nAChR antagonists on the brain and central nervous system lines by activating Erk/5-Lox signaling pathway [102]. A need to be investigated before using them as a viable drug study on the association between cigarette smoking and for combating lung cancer. Moreover, the direct role of pancreatic cancer showed that smokers had a signiﬁcantly nicotine alone on several aspects of tumorigenesis raises higher risk (70%) of developing pancreatic cancer compared the need to revisit the potential tumor promoting eﬀects of to nonsmokers [103–105]. Accumulating evidence suggests nicotine-replacement therapy. Also, the modulation eﬀects of that nicotine induces expression of osteopontin, a secreted secondhand smoke on nAChRs require detailed investigation phosphoprotein that confers on cancer cells a migratory phe- in the future. notype and activates signaling pathways that induce cell sur- vival, proliferation, invasion, and metastasis. Rats exposed to cigarette smoke showed a dose-dependent increase in Acknowledgments pancreatic osteopontin expression. 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Publisher: Hindawi Publishing Corporation
Copyright: Copyright © 2011 Sandeep Singh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN: 1687-8450
eISSN: 1687-8469
DOI: 10.1155/2011/456743
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Abstract

Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 456743, 11 pages doi:10.1155/2011/456743 Review Article Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis Sandeep Singh, Smitha Pillai, and Srikumar Chellappan Department of Tumor Biology, H. Lee Moﬃtt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA Correspondence should be addressed to Srikumar Chellappan, srikumar.chellappan@moﬃtt.org Received 19 December 2010; Accepted 28 January 2011 Academic Editor: Venkateshwar Keshamouni Copyright © 2011 Sandeep Singh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneﬁcial eﬀects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These eﬀects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Speciﬁc signal transduction cascades that emanate from diﬀerent nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor eﬀects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent eﬀorts to target the nicotinic acetylcholine receptors to combat cancer. 1. Introduction agents form DNA adducts and cause mutations in vital genes like Rb, p53, and K-Ras in smokers [7–9]. Smoking is a major risk factor associated with the develop- While the induction of these cancers is mediated by ment and progression of a variety of cancers [1]. Smoking is tobacco-speciﬁc nitrosamines as well as other carcinogens estimated to account for approximately 4-5 million deaths present in the tobacco smoke, it is becoming clear that worldwide and approximately 443,000 deaths each year in signaling through the nicotinic acetylcholine receptors con- the United States alone [2, 3]. Suﬃcient evidence has accu- tribute to the growth, progression, and metastasis of a mulated to conclude that tobacco smoking caused cancers variety of cancers. Nicotine, which is the major addic- not only of the lung, but also of the lower urinary tract tive component of tobacco smoke, acts through nicotinic including the renal pelvis and bladder, upper aero-digestive acetylcholine receptors (nAChR) [9–11], but is not thought tract including oral cavity, pharynx, larynx, and esophagus, to be carcinogenic. The expression of nAChRs in central and pancreas [2, 4]. Recent lines of evidence have showed and peripheral nervous system is associated with smoking that smoking tobacco can also cause cancers of the nasal dependence and addiction [12]. It was generally believed cavity, paranasal sinus, nasopharynx, stomach, liver, kidney, that nAChRs are only expressed in nervous system and at cervix, uterus, breast, adenocarcinoma of the esophagus, neuromuscular junctions (muscle type nAChRs). However, andmyeloidleukemia [2]. Of the thousands of chemicals the discovery of widespread expression of nAChRs in in tobacco smoke, polycyclic aromatic hydrocarbons and mammalian cells, including cancers, suggested its direct nicotine-derived nitrosamines have been identiﬁed as the role in cancer progression [13–15]. This paper deals with major and potent carcinogens [5, 6]. The metabolites of these certain aspects of nicotinic receptor signaling in nonneuronal 2 Journal of Oncology cells that lead to increased cell proliferation and survival, of CHRNA1, CHRNA5, and CHRNA7 subunit genes was angiogenesis, tumor growth, and metastasis. correlated with short-term exposure to nicotine [30]. Nico- tine stimulation contributed towards the growth of human mesothelioma cells. Human biopsies of mesothelioma as 2. Nicotinic Acetylcholine Receptor Expression well as of normal pleural mesothelial cells were found to in Nonneuronal Cells express functional α7-nAChR [31, 32]. Studies from the nAChRs are a complex of ﬁve subunits forming hetero- or Russo laboratory have shown that inhibition of nAChRs homopentamers to form a central ion channel [16, 17]. The by α-cobratoxin (α-CBT) can inhibit the growth of A549 tumors in immunocompromised mice [33]. These ﬁndings neuronal nAChRs can be homomeric composed of α7, α8, or α9 subunits or with the combinations of α2–α6or α10 strengthen the hypothesis that modulation of nAChRs subunits with β2–β4 subunits (heteromeric nAChRs). The upon chronic exposure to tobacco may contribute to the muscle type nAChRs may be comprised of combinations development and progression of cancer. In the following of α1 subunits with β1, γ, δ,or ε subunits [18]. Both sections, we will summarize the ﬁndings to support the neuronal as well as muscle nAChR families are found to hypothesis. be expressed in cancer cells [19]. Nicotine mimics acetyl- choline by binding as an agonist to α subunit of nAChRs 3. nAChRs Signaling in [10]. Nicotine binds with higher aﬃnity to heteromeric Tumor Growth and Survival α4β2-nAChRs than to α7-nAChRs [20]. Higher binding to α4β2-nAChRs results in desensitization of the receptor, Attempts have been made to elucidate the molecular events which could be the reason that α7-nAChR is the major that mediate nicotine-induced cell proliferation. Activation stimulator of cancer development and progression in vivo. of nAChR through nicotine or NNK has been found In addition to nicotine, tobacco-speciﬁc nitrosamines such to activate protein kinase C (PKC), the serine/threonine as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) kinase Raf-1, the mitogen-activated kinases ERK1 and can also bind to α7-nAchR, and N -nitrosonornicotine ERK2,and the transcription factors FOS,JUN,and MYC (NNN) binds to heteromeric αβ-nAChRs [21]. The aﬃnity through the selective activation of α7-nAChR in SCLC of NNK for the α7-nAChR was found to be 1,300 times [34]. Studies also demonstrated the stereospeciﬁcity of higher than nicotine, whereas the aﬃnity of NNN for nAChRs towards (−)-nicotine. It has been reported that heteromeric αβ-nAChRs was 5,000 times higher than that of (−)-nicotine stimulated tumor cell proliferation via secre- nicotine [21, 22]. tion of the neurotransmitter serotonin, and the growth Since the discovery of ubiquitous presence of nAChRs in stimulatory eﬀect of nicotine or NNK could be blocked mammalian cells, studies from many laboratories have linked by selective serotonergic receptor antagonists [27, 35, 36]. nAChRs with various pathological conditions including In a recent report, the eﬀects of acute and repetitive tumor growth and angiogenesis [13, 23]. In earlier studies, exposure to nicotine was shown to induce a neuronal- nicotine was found to stimulate endothelial-cell proliferation like appearance in N417 SCLC cell line, which produced via nAChR at concentrations lower than those obtained in bigger and more vascularized tumors in mice through blood after smoking [24]. As described in the later part activation of CXCR4/CXCL12 axis. A prominent increase in of this paper, many studies have correlated the exposure the expression of CXCR4 was observed in nAChR-dependent of nicotine or other tobacco smoke components with manner in nicotine-treated cells [37]. NSCLC cell lines induction of pathological neovascularization through the from large-cell carcinoma, squamous-cell carcinoma, and activation of nAChR [23, 25]. Studies from our laboratory adenocarcinoma, all showed the activation of PI3K-AKT have suggested that nicotine can enhance the growth and pathway and NF-κB activation in response to nicotine or metastasis of pre-established lung tumors [26]. Altogether, NNK treatment [38, 39]. In addition, frequent loss of the these studies proposed the involvement of tobacco smoke tumor suppressor gene FOXO3a was reported in carcinogen- components in various aspects of tumorigenesis and vas- induced lung adenocarcinoma. In NNK-treated lung cancer cular dysfunctions in smokers. Extensive research by many cells, restoration of FOXO3a in FOXO3a-deﬁcient cells groups has successfully associated the physiological eﬀect increases sensitivity to apoptosis caused by a DNA-damaging of nicotine and its derivatives with the direct activation intermediate of NNK. This study proposed that FOXO3a of nAChRs. Small cell lung carcinoma (SCLC) pulmonary might play a role in lung adenocarcinoma suppression neuroendocrine cells (PNECs) and SCLC cells express high by providing a protective response to carcinogenic stress levels of the α7-nAChR, whereas heteromeric nAChRs were [40]. undetectable [27, 28]. At the same time, both hetero- and Experiments from our laboratory have shown that homomeric nAChRs are found to be expressed in nonsmall nicotine stimulation aﬀects various components of cell cell lung carcinoma cells of diﬀerent histologic subtypes cycle regulatory machinery [26, 29, 41]. Exposure to nico- [19, 29]. Recently, diﬀerential expression pattern of ACHR tine resulted in activation of Raf-1, induction of cyclin subunit gene was studied in NSCLC patients who were D and cyclin E-associated kinase activity as well as Rb smokers or never smokers. Higher expression of CHRNA6 phosphorylation, which led to the dissociation of E2F1 and CHRNB3 combination was correlated with NSCLCs from Rb. Further, it was observed that stimulation with in nonsmokers, whereas lower expression was correlated nicotine caused the dissociation of Rb from E2F-responsive with NSCLCs in smokers. Additionally, increased expression proliferative promoters (cdc6 and cdc25A), while there were Journal of Oncology 3 increased amounts of E2F1 bound to them. These molecular A centrosomal protein CEP55 as well as a DNA helicase events were correlated with increased proliferative eﬀects of and putative stem cell marker HELLS, were found to be nicotine in NSCLC cell lines A549 (human bronchioalveolar novel targets of nicotine-induced FOXM1 expression and carcinoma), NCI-H23, NCI-H441 (lung adenocarcinoma), correlated with oral cancer progression [45]. and NCI-H226 (pleural eﬀusion squamous cell carcinoma) A role of nAChR has been demonstrated in breast cancer as well as on primary normal human bronchial epithelial progression as well. Experiments with human mammary cells (NHBEs), small airway epithelial cells (SAECs), human epithelial-like MCF10A or cancerous MCF7 cells revealed aortic endothelial cells (HAECs), and human microvascular that treatment of these cells with nicotine enhances the endothelial cells from lung (HMEC-Ls). The mitogenic activity of protein kinase C (PKC) alpha with cdc42 as a eﬀects of nicotine were abrogated by α7 subunit antagonists, downstream target for nicotine-induced proliferation and α-bungarotoxin, and methylallyl aconitine (MAA), whereas migration [46]. It has also been suggested that nicotine- it was unaﬀected by α-lobeline (α4β2 subunit inhibitor) induced proliferation of human breast cancer cell is depen- or dihydro β-erythoidine (DHβE; α3β2and α4β2 subunit dent on α9-nAChR and cyclin D3 expression [47]. The inhibitor), suggesting that α7 subunits primarily mediated eﬀects of nicotine on a population of cancer stem cells in the mitogenic eﬀects of nicotine in NSCLC cells. We MCF-7 human breast cancer cells were examined, using have further illustrated that upon nicotine stimulation, the aldehyde dehydrogenase (ALDH) as a stem cell marker. This scaﬀolding protein β-arrestin-1 forms a complex with nonre- study found that nicotine increases the stem cell population ceptor tyrosine kinase-Src and gets recruited to the nAChRs. via α7-nAChR and the PKC-Notch dependent pathway Depletion of β-arrestin-1 or Src prevented nicotine-induced [48]. cell proliferation. These results suggested that α7-nAChR- Apart from direct responses through nAChRs, indirect mediated stimulation of cell proliferation is through a signaling events may also contribute to nicotine-induced β-Arrestin-1-Src signaling axis in NSCLC [41]; (see also tumor growth and survival. Since nAChRs are cation chan- Figure 1). nels, it can stimulate signaling cascades by the inﬂux of Ca2+ Other than lung cancer, activation of α7-nAChR and through the opened α7-nAChR [49]. Ca2+ channel blockers heteromeric nAChRs expressing α3and α5 subunits have are shown to signiﬁcantly reduce DNA synthesis in response been reported in oral and esophageal keratinocytes [22]. to nicotine or NNK in SCLCs [49]. Also, nAChR-mediated Similar to lung cancer cells, NNK was found to bind with systemic increase in stress neurotransmitters, adrenaline, high aﬃnity to α7-nAChR, whereas NNN was found to bind and noradrenaline, which are β-adrenergic agonists, are also to heteromeric nAChRs with higher aﬃnity [22]. Esophageal shown to stimulate β-adrenergic receptor-initiated cAMP cancer-Het-1A cells stimulated with NNK or NNN showed signaling and transactivation of EGFR cascade through increased mRNA transcripts and expression of PCNA and EGF secretion in NNK-treated small airway epithelial cells Bcl-2, and transcription factors GATA3, NF-κB, and STAT1. [50, 51]. Nicotine is found to induce systemic or cellular However, induction of Ras-Raf-ERK1-ERK2 cascade, the increase in noradrenaline and signiﬁcantly enhance the JAK2-STAT3 pathway and NF-κB activation was associated growth and angiogenesis of pancreatic, gastric, and colon with enhanced cell proliferation through these nitrosamines cancer-xenografts with increased expression of ERK1-ERK2, in immortalized oral epithelial cells [22]. In addition, chronic COX2, prostaglandin E2, VEGF, and transactivation of exposure of nicotine or environmental tobacco smoke on β-adrenergic as well as EGFR signaling in colon cancer oral keratinocytes selectively upregulated α5- and α7-nAChR cells [52–55]. Activation of ERK1-ERK2 and STAT3 in subunits, resulting in intensiﬁed signaling responses to response to nicotine has also been reported in bladder cancer nicotine [42]. cells downstream of nAChRs and β-adrenergic receptors The secreted mammalian Ly-6/urokinase plasminogen [56]. Importantly, apart from nAChRs, direct interaction activator receptor-related protein-1 (SLURP-1) is recently of NNK with β-adrenergic receptor has been proposed identiﬁed as an endogenous ligand for the α7 subunit of as a novel mechanism, which may signiﬁcantly enhance the nicotinic acetylcholine receptor (nAChR). The expres- the high cancer-causing potential of these nitrosamines sion levels of SLURP1 and SLURP2 (secreted mammal- [50, 57]. Similar to the activation via neurotransmitters, ian Ly-6/urokinase plasminogen activator receptor-related NNK binding to β-adrenergic receptor was also found protein-2) were reduced in NNK-treated cells. Transfection to activate adenylyl cyclase-cAMP-PKA-CREB cascade and of the cells with SLURP1 or SLURP2 cDNA reduced the transactivation of EFGR [58]. Additionally, an additive eﬀect nitrosamine-induced colony formation in soft agar while of estrogen receptors and nAChRs was also demonstrated inhibiting the growth of NNK-transformed keratinocytes in promoting the growth of A549 tumors in athymic nude in mouse xenografts. SLURP1 bound to α7-nAChR and mice. Cotreatment of nicotine and estradiol resulted in SLURP2 bound to nAChRs expressing the α3 subunit [22, increased cell proliferation as well as VEGF secretion from 43]. Similar results were demonstrated recently where HT- cancer cells, leading to increased tumor growth as well 29 human colon cancer cells treated with nicotine resulted as microvascular density within the tumor [59]. Recently, in increased cell proliferation and a marked reduction in the chronic exposure to estrogen and NNK was shown the protein expression of SLURP1 via α7-nAChRs acti- to have synergistic eﬀects on cell proliferation and pro- vation [44]. Recently, nicotine mediated upregulation of duction of noradrenaline and adrenaline, by upregulating FOXM1 expression was found in primary oral keratinocytes α7-nAChRs in immortalized small airway epithelial cells which was associated with induction of genomic instability. [60]. 4 Journal of Oncology NNN, NNK, nicotine Epithelial markers EMT Angiogenesis c-Src β-arrestin metastasis Mesenchymal markers Adrenaline and nAChRs β-ARs noradrenline PI3K EGF-release β-arrestin EGFR AKT c-Src Ras PI3K pRb pRb Raf XIAP Raf NF-κB cdc6 AKT E2F1 E2F1 cdc25a Survivin ERK Proliferation Survival Figure 1: A schematic of nAChR-mediated regulation of diverse tumorigenic processes. nAChRs are activated by tobacco smoke components like NNN, NNK, and nicotine with diﬀerent aﬃnity. Induced nAChRs activate several downstream signaling pathways involved in cell proliferation, inhibition of apoptosis, metastasis, and angiogenesis in a variety of cancer and primary cells. Agonist binding to nAChR forms complex with β-arrestin and Src and results in Raf-1 activation. Activated Raf-1 phosphorylates and inactivates Rb tumor-suppressor- function. These in turn results in E2F-1-mediated transcriptional upregulation of target genes involved in cell proliferation, angiogenesis, and inhibition of apoptosis. Downstream eﬀect of nAChR activation is also indirectly supported by the activation of β-adrenergic receptor (β-AR) signaling. Nicotine exposure directly results in metastatic dissemination of primary tumor by inducing epithelial to mesenchymal transition (EMT) in cancer cells. 4. nAChRs Signaling in Cell Survival and Treatment of cells with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or speciﬁc depletion of AKT was Resistance to Apoptosis shown to block both nicotine-induced Bax phosphorylation In addition to the eﬀect on tumor growth, epidemiological and cisplatin resistance in NSCLC cells [64]. and clinical data implicate that in patients with cancer, In addition to these signaling events, results from our continued smoking causes resistance to therapy by blocking laboratory revealed a signiﬁcant role for the IAP pro- the induction of apoptosis. Various studies have linked the teins XIAP and survivin in nicotine-mediated chemoresis- activation of nAChR resulting in inhibition of apoptotic tance in NSCLCs in vitro. Chromatin immunoprecipitation pathways. In SCLC cells, NNK was shown to phosphorylate assays demonstrated that nicotine stimulation caused an Bcl-2 at Ser70 which promoted its interaction with c-Myc increased recruitment of E2F1 and concomitant dissociation that signiﬁcantly enhanced the half-life of the c-Myc protein of retinoblastoma tumor suppressor protein (Rb) from [61]. This functional cooperation of Bcl2 and c-Myc resulted survivin promoter in NSCLC cells [65]. Moreover, ablation in promoting cell survival and proliferation. This eﬀect of E2F1 levels caused abrogation of survivin expression could be blocked by the PKC inhibitor staurosporin, the and protective eﬀects of nicotine against cisplatin-induced ERK1-ERK2 inhibitor PD98059 or silencing of MYC [61, apoptosis in A549 cells. In the above study, chemoprotective 62]. Additionally, mesothelioma cells also showed nicotine- eﬀect of nicotine was found to be mediated through α3/β4- 2+ stimulated proliferation through α7-nAChR-mediated Ca - nAChR activation and could be abrogated by agonists of dependent activation of the ERK1-ERK2 cascade and inhib- these subunits. It was also found that nicotine stimulation ited apoptosis by induction of NF-κB and phosphorylation enhanced the levels of XIAP at the protein level. Nicotine of BAD at Ser112 (Bcl-2 antagonist of cell death) [32]. In induces the activation of Akt, which is known to phosphory- NSCLCs, constitutive activation of AKT is associated with late XIAP and prevent its proteasome-mediated degradation lung cancer cell survival and resistance to chemotherapy [66]. In agreement with this, an Akt inhibitor could abrogate and radiation [63]. Similarly, nicotine or NNK exposure the antiapoptotic eﬀects of nicotine in A549 cells [65]. displayed AKT-mediated growth and NF-κB-mediated resis- In other studies, the cooperative eﬀect of nicotine and tance to apoptosis in human airway epithelial cells as well NNK was investigated for their transforming ability in vari- as lung cancer cells [38, 39]. Further, activated AKT could ous lung epithelial or cancer cells. Exposure to nicotine or the directly phosphorylate Bax in vitro in nicotine treated cells. combination of nicotine and NNK for one week augmented Journal of Oncology 5 Bcl-2 expression, accompanied by an increased resistance in vivo. In a mouse model of hind-limb ischemia, nicotine to cisplatin-induced apoptosis [67]. This study also showed increased capillary and collateral growth, and enhanced that the combination treatment promoted cell prolifera- tissue perfusion. These eﬀects of nicotine were mediated tion and anchorage-independent growth as compared to through nicotinic acetylcholine receptors at nicotine concen- NNK exposure alone [67]. In another study, nicotine was trations that are pathophysiologically relevant and suggested demonstrated to mediate prosurvival activity by Mcl-1 a possible role for the endothelial production of nitric oxide, phosphorylation. Nicotine-induced Mcl-1 phosphorylation prostacyclin, and vascular endothelial growth factor [70– signiﬁcantly enhanced the half-life of Mcl-1, which conferred 74]. Nicotine has been demonstrated to stimulate postnatal long-term survival potential [68]. Speciﬁc depletion of Mcl-1 angiogenesis, having an antiapoptotic eﬀect on endothelial by RNA interference blocked nicotine-stimulated survival cells. It was observed that nicotine stimulated postnatal vas- and enhanced apoptotic cell death [67]. Nicotine-mediated culogenesis on endothelial progenitor cells (EPCs) [75]. The activation of α7-nAChR has also been linked with the eﬀect of nicotine on EPC survival was signiﬁcantly enhanced expression of PPARβ/δ protein by inhibiting AP-2α protein under serum starvation. Furthermore, the antiapoptotic expression and DNA binding activity to the PPARβ/δ gene eﬀect of nicotine was blocked completely by nicotinic promoter [69]. Sp1 was found to modulate this process. α7- acetylcholine receptor (nAChR) antagonist hexamethonium nAChR antagonist and short interfering RNA against α7- bromide [75]. nAChR as well as inhibitors of phosphatidylinositol 3-kinase Recent studies have shown that apart from cigarette (PI3K; wortmannin and LY294002) and mammalian target smoking, exposure to secondhand smoke also could induce of rapamycin (mTOR; rapamycin) blocked the expression angiogenesis. A positive correlation between secondhand of PPARβ/δ protein demonstrating a novel mechanism by smoke exposure and concentrations of nicotine in the body which nicotine could promote human lung carcinoma cell was established after analyzing twenty-two studies measuring growth [69]. These studies show that signaling through the biological eﬀects of nicotine [76]. Further, it was found the nAChRs could promote cell proliferation and survival, that the levels of nicotine exposure from secondhand smoke utilizing multiple signaling cascades. were comparable to those of active smokers. In a mouse model where Lewis lung cancer cells were implanted subcu- taneously into mice, which were then exposed to sidestream 5. nAChRs and Tumor Angiogenesis smoke (SHS) or clean room air and administered vehicle or mecamylamine (an inhibitor of nAChR); SHS signiﬁcantly Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a complex multistep process increased tumor size, weight, capillary density, VEGF, and involved in a number of physiological processes such as MCP-1 levels, and circulating endothelial progenitor cells wound healing, embryogenesis and reproduction. In addi- (EPC). Mecamylamine partially inhibited the eﬀects of SHS tion, angiogenesis is necessary for the sustained growth on these angiogenic processes and nearly abolished the eﬀects of the primary tumor as well as metastatic dissemination. of SHS on tumor capillary density suggesting that nicotine Nicotine has been shown to enhance angiogenesis in many mediated the eﬀects of SHS on tumor angiogenesis and experimental systems and animal models. The proangiogenic growth [77]. Several recent studies have implicated that nicotine- activity of nicotine is mediated by nicotinic acetylcholine receptors, particularly α7 subunit. The pioneering study by induced angiogenesis could be mediated by growth stabi- Villablanca (1998) demonstrated the ability of nicotine to lization and transmigration of endothelial progenitor cells (EPC) [75, 78, 79]. Nicotine accelerated the growth of induce endothelial cell proliferation [24]. This observation was followed by the elegant studies from the John Cooke’s syngenic colon cancer CMT93 cells when grown subcuta- laboratory suggesting a cholinergic pathway for nicotine- neously in mice by inducing angiogenesis via bone marrow induced angiogenesis where they demonstrated complete derived EPCs [78]. To determine if the angiogenic eﬀects inhibition of endothelial network formation using nons- of nicotine is mediated by EPC mobilization, Heeschen et al. used a model of mouse parabiosis and found that elective nAChR antagonist mecamylamine in an in vitro angiogenesis model [25]. Although several nAChR isoforms nicotine enhances EPC mobilization into the vasculature of are expressed on endothelial cells, a similar inhibition was the ischemic tissue. This eﬀect may be due to the direct actions of nicotine on EPC proliferation, migration and/or obtained only with the selective α7-nAChR antagonist α- bungarotoxin, conﬁrming the speciﬁc involvement of α7- mobilization as suggested by in vitro models [80]and plasma nAChR. Further, in vivo pharmacological inhibition of markers used in the investigation [79]. They also noticed that in the absence of acute ischemia, nicotine did not stimulate nAChR and a genetic disruption of α7-nAChR expres- sion signiﬁcantly inhibited inﬂammatory angiogenesis and EPC mobilization. The activation of nAChRs in response to reduced ischemia-induced angiogenesis and tumor growth. ischemia induced the release of proangiogenic factors like They also provided anatomic and functional evidence for VEGF and stem cell derived factor-1, both of which are regu- nicotine-induced angiogenesis and arteriogenesis when they lated by hypoxia, which in turn facilitates EPC mobilization [81]. Evidence from another study also demonstrated that observed that nicotine accelerated the growth of tumor and atheroma in association with increased neovascularization nicotine promotes angiogenesis via stimulation of nAChR- [23]. dependent endothelial cell migration. nAChR antagonism not only abolished nicotine-induced human microvascular Nicotine increased endothelial-cell growth and tube formation in vitro, and accelerated ﬁbrovascular growth endothelial cells (HMVEC) migration but also abolished 6 Journal of Oncology migration induced by bFGF and attenuated migration studies from our laboratory demonstrated that nicotine can induced by VEGF. Transcriptional proﬁling identiﬁed gene induce invasion and migration in cell lines derived from lung expression programs which were concordantly regulated by cancer, breast cancer, and pancreatic cancer via α7-nAChR- all 3 angiogens (nicotine, VEGF, and bFGF), a notable feature mediated signal transduction pathways [90]. The proinvasive of which includes corepression of thioredoxin-interacting eﬀects of nicotine were mediated by α7-nAChR in lung protein (TXNIP), endogenous inhibitor of the redox regu- cancer cells while α7-nAChR and DhβEsensitive nAChRs lator thioredoxin. Furthermore, TXNIP repression by all 3 mediated invasion of breast cancer cells. Nicotine was also angiogens induced thioredoxin activity. Interestingly, nAChR found to inhibit anoikis in lung airway epithelial cells. antagonism abrogates growth factor (VEGF- and bFGF-) Further, nicotine could induce changes in gene expression mediated induction of thioredoxin activity suggesting the consistent with EMT. Long-term treatment of lung cancer requirement of nAChR activation in endothelial cell migra- and breast cancer cells with nicotine was found to diminish tion, a key angiogenesis event [82]. levels of epithelial markers namely β-catenin and E-cadherin The proangiogenic eﬀects of nicotine have been found and upregulate mesenchymal proteins like ﬁbronectin and to be mediated by α7-nAChR on endothelial cells by acti- vimentin, indicative of disruption of cell-cell contacts and vating ERK/MAP kinase pathway, PI3 kinase/Akt pathway, increased motility [90]. and NF-κB[23, 25, 83, 84]. Further, nicotine has been In addition to facilitating EMT, nicotine and NNK shown to induce the proangiogenic factors like VEGF have been shown to aﬀect various aspects of tumor cell and HIF-1α in NSCLC cell lines [85]. Pharmacologically invasion and migration. For example, both nicotine and blocking nAChR-mediated signaling cascades, including the NNK are shown to promote the invasion of NSCLC by Ca2+/calmodulin,Src,protein kinase C, PI3K/Akt, MAPK/ phosphorylation of μ and m-calpains [62]. Several lines of ERK1/2, mTOR pathways, signiﬁcantly attenuated nicotine- evidence show that calpain-mediated proteolysis mediates induced upregulation of HIF-1α. These proangiogenic and various aspects of cell physiology including cell migration invasive eﬀects of nicotine were partially abrogated by and invasion. Nicotine was found to induce phosphorylation depleting HIF-1α using siRNA techniques. Additionally, of both μ and m-calpains via α7-nAChR; the binding of nicotine could promote angiogenesis of gastric cancers nicotine to α7-nAChR in turn was found to activate Src by upregulating COX2 and VEGFR2 [86]. Nicotine also and PKC-iota, leading to enhanced invasion and migration enhanced the activity of matrix metalloproteinase 2 and 9 of NSCLC cell line H1299. Similarly, NNK also could and expression of plasminogen activators in a COX2 and promote invasion and migration through phosphorylation VEGFR2-dependent manner. The proangiogenic eﬀect of of μ and m-calpains in a α7-nAChR-dependent fashion nicotine has been shown to be dependent on Src activity by [62]. our laboratory [41]. The inhibition of Src, using chemical Several observations in patients suggest that those inhibitors or siRNA has been shown to inhibit endothelial exposed to tobacco carcinogens are more likely to develop cell proliferation, migration, and angiogenic tubule forma- larger, more vascularized tumors with a high propensity tion on matrigel. As mentioned earlier, studies from our for metastatic spread and resistance to chemotherapy [90]. laboratory suggest that the scaﬀolding protein β-arrestin-1 About 30% of lung cancer patients who are smokers continue causes the activation of Src. Oligomeric complex comprising to smoke after they have been diagnosed [91], which might of nAChR, β-arrestin-1, and Src is vital for nAChR signaling. result in increased adverse medical consequences such as In addition, depletion of β-arrestin-1 caused abrogation of increased tumor progression, development of a second endothelial cell proliferation and angiogenic tubule forma- cancer, greater recurrence, greater cancer-related mortality tion [29, 41]. These data suggest that nicotine behaves in a and reduced quality of life [92, 93]. While these studies manner analogous to growth factors and induces cell cycle demonstrate a role for tobacco carcinogens in the initiation, progression in endothelial cells. growth, and progression of cancers, the relative contribution of nicotine by itself to these processes is not well explored. A recent study from our laboratory demonstrated that 6. nAChRs in EMT and Tumor Metastasis nicotine by itself can induce the growth and metastasis Epithelial to mesenchymal transition (EMT) is a biolog- of tumors in immunocompetent mice, independent of other tobacco carcinogens [26]. Nicotine administered either ical process that allows a polarized epithelial cell, which normally interacts with the basement membrane through intraperitonially or by commercially available transdermal its basal surface, to undergo multiple biochemical changes patches could substantially promote tumor growth. Similar eﬀects were observed on implanted tumors as well as tumors with a signature of more advanced and less diﬀerentiated cancer that allow it to assume a mesenchymal phenotype. induced by tobacco carcinogen, NNK. Furthermore, mice This enhanced migratory capacity, invasiveness, resistance exposed to nicotine showed signiﬁcantly enhanced lung to apoptosis, and greatly increased production of ECM metastasis as well as tumor recurrence after surgical removal components [87–89]. This process results in degradation of of the primary tumor, indicating that nicotine can enhance the growth and metastasis of pre-established lung tumors basement membrane and the formation of a mesenchymal like cell, which can migrate away from the epithelial layer [26]. As mentioned earlier, repetitive exposure to nicotine on in which it originated [88]. Epithelial to mesenchymal SCLC-N417 cells resulted in neuronal-like appearance along with increased adhesion to the extracellular matrix. These transition (EMT) is involved in tumor progression from noninvasive tumor cells into metastatic carcinomas. Recent changes were accompanied by enhanced migration through Journal of Oncology 7 collagen matrices and adhesion to and transmigration across isoform, OPNc, is selectively inducible by nicotine and lymphatic endothelial cell monolayers [37]. is highly expressed in PDA tissues from smokers which Accumulating evidence from epidemiological studies induced the expression of monocyle chemoattractant protein suggest a strong association between smoking and pul- (MCP-1) indicating a proinﬂammatory role of nicotine monary metastatic disease in women with breast cancer [108]. Altogether, these results suggest that nicotine plays a [94]. In a murine model of metastatic mammary cell key role in the regulation of the complex cellular cascades cancer, cigarette smoke exposure was associated with an that modulate cell adhesion, invasion, and migration leading increase in the total pulmonary metastatic burden providing to metastasis. experimental support for an adverse eﬀect of smoking on the metastatic process and suggesting a possible mechanism for 7. Discussion and Conclusions smokers’ increased breast cancer mortality [95]. In addition, it was observed that cigarette smoking was correlated with Tobacco smoking is a well-documented risk factor for increased lymph node metastases at mastectomy in women many cancers. As summarized in Figure 1, nicotine, the older than 50 years of age suggesting that tobacco usage principal addictive component of tobacco smoke, as well may potentiate the early spread of malignant disease [96]. as other nitrosamines have been found to act through Although numerous studies have indicated the role of nico- nAChRs on nonneuronal cells to facilitate tumor growth, tine exposure in tumor promotion, little is known about the angiogenesis, metastasis, survival, and chemoresistance by molecular mechanisms by which nicotine promoted breast regulating diverse signaling pathways. Binding of agonist tumor development, especially on the metastatic process of to nAChR facilitates the complex formation between the breast cancer. At least four diﬀerent subunits of nAChRs receptor, scaﬀolding protein β-arrestin and tyrosine kinase including α5, α7, α9, and β4 are shown to be expressed in Src. Activation of Src was found to be important for cancer breast cancer cells [46]. It has been demonstrated that in as well as endothelial cell proliferation and angiogenic tube addition to proliferative eﬀect, nicotine promoted migration formation in vitro.Proliferative eﬀect of nAChR-activation of breast cell lines (mammary epithelial cell line MCF10A was also supported by indirect stimulation of β-adrenergic and breast cancer cell line MCF7) through a signaling cascade receptor (β-AR) signaling. Further, chemotherapy-induced involving PKC activation and its downstream eﬀector cdc42 apoptosis was found to be blocked by nicotine-induced [46]. Exposure to nicotine has shown to increase the survivin expression as well as NF-κB activation. Activation expression of α9-nAChR in breast cancer cells [47, 97]. of nAChR is also correlated with EMT-like changes and Studies using a soft agar transforming assay and a mouse metastatic dissemination of primary tumor cells. Given the xenograft model demonstrated that noncancerous human ability of nicotine to aﬀect various aspects of tumor growth breast epithelial cell line, MCF10A, could be neoplastically and metastasis, antagonists of nAChR signaling might be transformed by exposure to either a cigarette smoke con- beneﬁcial in controlling the growth and progression of densate or the tobacco speciﬁc carcinogen, NNK [98, 99]. tumors. Recently, alpha cobratoxin (α-CbT) has been shown In a recent study, α9-nAChR expression was silenced in to block the growth of a variety of NSCLC and mesothelioma MDA-MB-231 breast cancer cells which resulted in reduced cell lines both in vitro and in vivo [109, 110]. The most proliferation and tumorigenic potential in both in vitro and striking eﬀect of α-CbT was its ability to eﬀectively inhibit in vivo assays, indicating the role of α9-nAChR in breast the metastatic potential of lung cancer cells transplanted carcinogenesis [100]. into nude mice, indicating the possibility of using nAChR Cigarette smoking has recently been recognized as a risk antagonists as adjuvant therapy in preventing metastatic factor for gastric cancer [101] and long-term exposure of spread. At the same time, the potential side eﬀects of nicotine-induced EMT like changes in gastric cancer cell nAChR antagonists on the brain and central nervous system lines by activating Erk/5-Lox signaling pathway [102]. A need to be investigated before using them as a viable drug study on the association between cigarette smoking and for combating lung cancer. Moreover, the direct role of pancreatic cancer showed that smokers had a signiﬁcantly nicotine alone on several aspects of tumorigenesis raises higher risk (70%) of developing pancreatic cancer compared the need to revisit the potential tumor promoting eﬀects of to nonsmokers [103–105]. Accumulating evidence suggests nicotine-replacement therapy. Also, the modulation eﬀects of that nicotine induces expression of osteopontin, a secreted secondhand smoke on nAChRs require detailed investigation phosphoprotein that confers on cancer cells a migratory phe- in the future. notype and activates signaling pathways that induce cell sur- vival, proliferation, invasion, and metastasis. Rats exposed to cigarette smoke showed a dose-dependent increase in Acknowledgments pancreatic osteopontin expression. 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Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

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Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis

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