From the time of their introduction, the popularity of e-cigarettes (electronic nicotine-delivery systems) has been rising. This trend may reflect the general belief that e-cigarettes are a less hazardous alternative to combustible cigarettes. However, the potential cancer-related effects of increased activation of the sympathoadrenal system induced by the inhalation of nicotine, the primary component of the e-cigarettes, are completely overlooked. Therefore, the aim of this review is to describe mechanisms that may connect the use of e-cigarettes and an increased risk for cancer development, as well as their stimulatory effect on cancer progression. Available preclinical data indicate that activation of the sympathetic nervous system by nicotine inhaled from e-cigarettes may stimulate cancer development and growth by several mechanisms. This issue might be especially important for oncological patients as they may have the misconception that compared with combustible cigarettes, e-cigarettes represent a risk-free alternative.

During the last 50 years, a robust body of evidence has accumulated documenting the negative health consequences of both active tobacco smoking and exposure to secondhand smoke. For example, evaluation of epidemiologic data has shown that at least 12 types of human cancers can be attributed to smoking (1). Therefore, it is not surprising that as information about the negative consequences of smoking is spreading within populations, more and more smokers are choosing e-cigarettes (electronic nicotine-delivery systems) as a “less harmful” source of nicotine.

The first commercially available e-cigarette, a device that is designed to deliver nicotine without tobacco smoke by heating a nicotine solution, was invented in 2003 by the Chinese pharmacist Lik Hon in Hong Kong. Since the introduction of e-cigarettes, they have been become increasingly popular among never-smokers and adolescents, as well as smokers who want to reduce the health risks of smoking or would like to quit smoking (2). This fact is documented by data from the 2011–2018 National Youth Tobacco Survey of U.S. middle and high school students. It was shown that the use of e-cigarettes increased in this group from 1.5% (220,000 students) in 2011 to 20.8% (3.05 million students) in 2018 (3). In the study investigating e-cigarettes use among adults in the United States, it was found that even if the weighted prevalence of current use of e-cigarettes decreased from 2014 to 2016 in some subgroups, the prevalence increased significantly among former smokers from 3.8% in 2014 to 4.8% in 2016 and never-smokers from 0.4% to 0.7% over the same time period (4). This increased popularity of e-cigarettes is also reflected in the variety of e-cigarette device models, numerous brands, and product designs that have been developed over the last few years. Today, the fourth generation of e-cigarettes is available with a heating temperature control mechanism (5, 6). However, even if the levels of carcinogens and toxins are substantially reduced in users of e-cigarettes in comparison with tobacco smokers (7), recent data have shown that the vapor from e-cigarettes also contains, in addition to nicotine, many toxic chemicals found in traditional cigarettes such as acetaldehyde, formaldehyde, acetone, acrolein, chromium, N-nitrosamines, and others (5, 6, 8). Moreover, the vapor derived from e-cigarettes accumulates in the airway epithelium in a similar fashion as smoke from combustible cigarettes (5). These facts indicate that the safety of e-cigarettes remains questionable, and it is still unknown as to whether their use can contribute to cancer development and progression (9). In addition, there are no data about the potential toxic effects of long-term exposure to the vapor produced by nicotine-containing cartridge fluid (10). Therefore, it is not surprising that increased attention is being paid to the effects of substances inhaled by e-cigarette users on their body. However, research into the potentially harmful effects of e-cigarettes in humans is faced with several issues. First, the relatively short period of time during which e-cigarettes have been on the market results in a lack of relevant data, especially those related to the chronic consequences of vapor inhalation (6). Moreover, many factors affecting the composition of inhaled vapor (e.g., device voltage, resistance, temperature, e-liquid flavors and ingredients, nicotine content, and puff topography of e-cigarettes users) and thus the degree of harm have been only recently identified, which makes comparison of previously published studies difficult (5, 6, 11). Nonetheless, there is an increasing number of both cell culture and animal model studies investigating the various biological, toxicological, and immunological effects of exposure to both the liquid used in e-cigarettes and the vapor generated by it on different organ systems, including respiratory, cardiovascular, immune, nervous, or uropoetic (10, 12–15). Importantly, prospective, randomized studies on e-cigarettes are starting to be performed (6).

Recently, the direct modulation of processes in cells or organs by the chemicals present in vapor of e-cigarettes has been studied. These investigations were focused on nicotine because a variety of its harmful effects, including stimulation of cancer growth, are well documented (15–19). In addition, the additives and substances generated by the heating process in e-cigarette cartridges have been widely studied due to their potentially toxic and mutagenic effects (5). However, the potential cancer-related effect of increased activation of the sympathoadrenal system induced by inhalation of nicotine, the primary component of e-cigarettes, has been overlooked in the available studies.

E-cigarettes are considered a less hazardous alternative to combustible cigarettes (20). In support of this, significantly lower levels of toxic substances have been observed in e-cigarette vapor compared with cigarette smoke (21). Consistent with these findings, significantly lower concentrations of biomarkers of exposure to tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons, most volatile organic compounds were observed in e-cigarette users when compared with concentrations found in tobacco smokers (22). However, it should be noted that levels of TSNAs, namely, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, are significantly lower in non-smokers than in e-cigarette smokers (8, 22).

Whereas concentrations of non-nicotine toxic substances in the blood of e-cigarette smokers are significantly lower than in users of combustible cigarettes, the concentration of nicotine is increasing as new generations of e-cigarettes emerge. Even if the first generation of e-cigarettes had inefficient nicotine delivery, users of newer, third-generation models achieve nicotine plasma levels comparable with levels found in smokers of combustible cigarettes (23).

In 2014, two studies demonstrated the possible carcinogenic effects of e-cigarettes in immortalized, human bronchial epithelial cells. They found that exposure of these cells in culture medium to the vapor of e-cigarettes induced a similar pattern of gene expression as found in cells exposed to tobacco smoke (24, 25). Later, the findings of Park and colleagues (26) showed that exposure to clinically relevant concentrations of e-cigarette vapor-conditioned media enhanced cancer-associated processes of “at-risk” airways, including a demonstrated capacity for malignant transformation. The authors observed enhanced colony growth in anchorage-independent assays and increased cell invasion–associated morphologic changes in three-dimensional air–liquid interface models. In addition, they found that exposure of mutant epithelial cells to e-cigarette vapor-conditioned media induced airway gene-expression changes similar to those seen with combustible cigarette smoke exposure (26). It was also demonstrated that e-cigarette aerosol increased the proinflammatory cytokines IL6 and IL8 and diminished lung glutathione levels in human and mice lung epithelial cells (27). Importantly, data have shown that increased IL6 levels might, through the STAT3 signaling cascade, promote lung cancer cell growth (28).

In 2017, Canistro and colleagues demonstrated that e-cigarette vapor has powerful comutagenic and cancer-initiating effects in a rat lung cancer model. They showed that e-cigarettes have a booster effect on phase-I carcinogen-bioactivating enzymes, including activators of polycyclic aromatic hydrocarbons (PAH), increased oxygen-free radical production, and DNA oxidation to 8-hydroxy2′-deoxyguanosine (9). Later, Lee and colleagues published data showing an enhanced susceptibility of lung epithelium to oncogenic transformation and tumorigenesis via the action of nicotine metabolites, as well as the subsequent generation of mutagenic nucleotide products in the lung and urinary bladder of mice exposed to e-cigarette vapor, with similar results found in human bronchial epithelial and urothelial cell cultures. In addition, both the DNA-repair activity and expression of the repair proteins XPC and OGG1/2 were significantly reduced in the lungs of mice as well as in human bronchial epithelial cell cultures after exposure to e-cigarette vapor (29, 30). Interestingly, e-cigarettes induce DNA-strand breaks in the human epithelial cell line HaCaT independent of nicotine, while there is evidence that e-cigarette vapor exaggerates the extent of nicotine induced DNA damage (31).

In 2018, Staudt and colleagues demonstrated that even short-term use of e-cigarettes induces tumor- and metastasis-promoting factors related to lung cancer in small airway epithelium (32). It has also been shown that e-cigarettes enhance both the migration and stemness of non–small cell lung cancer cells through expression of the embryonic stem cell factor Sox2 (33, 34). Recently, Tommasi and colleagues reported significant epigenetic changes in the oral cells of users of e-cigarettes. Further analysis revealed that these deregulated genes are associated with signaling pathways implicated in cancer (35).

E-cigarette–related activation of nicotinic receptors in the cancer microenvironment

Nicotinic receptors are expressed on the surface of tumor and immune cells (36, 37), enabling nicotine to directly affect the tumor microenvironment. As a result, this alkaloid has a pronounced tumor-promoting effect on several types of cancers (36, 38).

Through binding to nicotinic receptors, nicotine may potentiate cancer cell survival (39, 40), tumor cell proliferation (41, 42), metastasis, invasion, epithelial–mesenchymal transition (43, 44), and angiogenesis (45, 46). It can also reduce cancer cell apoptosis induced by chemotherapy, radiotherapy, or receptor tyrosine kinase inhibitors (47–49). In addition, nicotine may stimulate proliferation and angiogenesis through the induction of norepinephrine and epinephrine synthesis in colorectal and pancreatic tumor cells, and this effect was blocked by the β-adrenergic receptor antagonists propranolol and ICI-118,551 (46, 50–52).

As mentioned above, many studies have been focused on determining the direct effects of e-cigarettes on normal and cancerous cells. However, nicotine inhaled from e-cigarettes may also indirectly exert tumor-promoting effects via stimulation of the sympathoadrenal system (Fig. 1).

The sympathoadrenal system stimulates cancer initiation and progression

Over the past two decades, a combination of neuroscientific and oncological research has gradually uncovered the role of the nervous system in cancer. It has been found that the sympathoadrenal system stimulates both carcinogenesis and processes related to tumor progression and metastasis (53–55). Such important effects are induced by norepinephrine released from nerve terminals in tissues innervated by the sympathetic nervous system, as well as by epinephrine and norepinephrine released from the adrenal medulla into the systemic circulation (56). Preclinical and clinical studies have shown that norepinephrine and epinephrine, via binding to β-adrenergic receptors, potentiate the induction of DNA mutations via induction of oxidative stress that reduces the efficiency of DNA-repair mechanisms (57, 58), activate oncogenes (59, 60), induce tumor-promoting inflammation (61), inhibit antitumor immunity by suppression of NK cell activity (62, 63), directly stimulate the proliferation of tumor cells by binding to β-adrenergic receptors expressed by these cells (64–66), protect cancer cells from apoptosis (67, 68), potentiate both neoangiogenesis (69, 70) and lymphatic vessel rearrangement (71) in tumor tissue, enhance matrix metalloproteinase activity (72, 73), and stimulate the mobility (55) and deformability (74) of tumor cells, leading to the development of metastases (75). In addition, published data indicate that catecholamine-induced increase of systemic vascular resistance might redirect blood flow to cancer tissue (76). Moreover, metabolic changes induced by an activated sympathoadrenal nervous system (77) might also affect cancer nourishment. Therefore, it is not surprising that approaches attenuating the effect of norepinephrine and epinephrine (e.g., sympathectomy or administration of β-blockers) can also help to impede the course of cancer progression, as documented by many preclinical and clinical studies (51, 78–86).

Nicotine activates the sympathoadrenal system

Importantly, it is well known that nicotine increases the release of norepinephrine and epinephrine due to its stimulatory effect at several levels of the sympathoadrenal system (87). This effect is mediated by mechanisms including (i) direct stimulation of nerve endings of sympathetic nerves, (ii) activation of nicotinic receptors on cell bodies of sympathetic postganglionic neurons, and (iii) activation of structures of the central nervous system that regulate sympathetic outflow (88). The net stimulatory effect of nicotine on the sympathoadrenal system is documented by the significantly increased plasma norepinephrine and epinephrine levels found in smokers (89). Importantly, the acute sympathomimetic effect of e-cigarettes is attributable to the inhaled nicotine but not the non-nicotine compounds found in the vapor of e-cigarettes (90).

Especially important is the issue of e-cigarettes usage by oncological patients. As noted by Sanford and colleagues, the popularity of e-cigarettes is rising not only in the general population but also among patients with cancer (91). This rise in the use of e-cigarettes in patients with cancer may result from the fact that e-cigarettes are being perceived as a less hazardous alternative to combustible cigarettes (20) due to reports that e-cigarettes produce a smaller quantity of pollutants compared with combustible cigarettes (8). Therefore, patients with cancer may assume that e-cigarettes are almost harmless from the point of view of their disease. However, as mentioned above, the stimulatory effect of nicotine inhaled from e-cigarettes on the sympathoadrenal system may represent an important factor that stimulates progression of their disease. In addition, their use might also be hazardous in individuals with a predisposition for oncological disease. Moreover, as data have shown that epinephrine and norepinephrine act as an angiogenic switch (92) that activates dormant tumors, e-cigarettes might participate in the clinical manifestation of previously dormant cancer. Importantly, the stimulatory effect of nicotine on cancer induction and progression might also be related to other nicotine-delivery systems (e.g., patch, nasal or mouth spray, inhalator, mouth strip, gum, lozenge, and microtabs).

As there are an increasing number of new smokers that start with e-cigarettes instead of combustible cigarettes, these individuals should be informed of the potential interconnection between e-cigarettes and cancer (for recommendations on how to inform patients about the potential harmful effects of e-cigarettes see ref. 93). This information about the stimulatory effects of nicotine and other chemicals inhaled from e-cigarettes on cancer initiation, progression, and development of metastases must be especially provided to oncological patients and individuals with a predisposition to cancer. However, in patients with cancer that are not able to quit smoking and would like to switch from combustible to e-cigarettes, it is necessary to take into consideration the fact that available data indicate that the harmful effects of e-cigarettes are significantly lower than those of combustible cigarettes (7). Therefore, based on available data, e-cigarettes might be recommended to smokers with cancer as a less hazardous alternative (94). In addition, e-cigarettes might also be used in patients with cancer as an effective tool for smoking cessation (95). However, if patients with cancer are informed that even if e-cigarettes are a less hazardous alternative to combustible cigarettes, the risk of potentiating the progression of their disease by e-cigarettes still exists, this might motivate some patients with cancer to quit smoking.

Because e-cigarettes have only been on the market for 16 years (2), it is obvious that our understanding of their effects, especially long term, is still fragmentary. Even if data from recent studies indicate that compounds inhaled from e-cigarettes might participate in carcinogenesis, the indirect effects of nicotine on cancer initiation and progression in smokers of e-cigarettes, mediated by the sympathoadrenal system, have not yet been investigated. Therefore, there is an urgent need for preclinical studies using cancer models in which we can test the effect of long-term inhalation of nicotine from e-cigarettes on the activity of the sympathoadrenal system as determined by plasma epinephrine and norepinephrine levels, as well as their effect on cancer incidence and progression. In these preclinical studies, the fact that e-cigarettes differ in nicotine content (23) needs to be taken in consideration and therefore the effect of different concentrations of this compound on sympathoadrenal system activity and cancer needs to be determined. Similarly, it is necessary to elucidate the effect of e-cigarettes on the incidence and progression of cancer, development of metastases, recurrence of disease, and efficiency of oncological therapy in both retrospective and prospective clinical trials. In studies investigating the effect of e-cigarettes on the progression of disease in patients with cancer, it is necessary to take several factors into consideration:

  • (i) Whether patients with cancer started smoking before or after cancer diagnosis and the duration and frequency of smoking, as the stimulatory effect of nicotine on cancer initiation and progression might be dose and time dependent;

  • (ii) Type of cancer, as some cancers seem to be more sensitive to the stimulatory effect of the sympathoadrenal system (96);

  • (iii) Eventual therapy by β-blockers (e.g., as treatment of hypertension) as these compounds attenuate the effects of epinephrine and norepinephrine released by the sympathoadrenal system on cancer initiation and progression;

  • (iv) The typology of the individual, their age, and extent of social interactions, as these factors affect the activity of the sympathoadrenal system and are known to affect the clinical course of cancer (97).

Although e-cigarettes seem to be less harmful to users and therefore may appear to be a less hazardous alternative to combustible cigarettes, the above-mentioned facts indicating an interconnection between e-cigarettes containing nicotine and cancer support that much effort should be made to strictly regulate the e-cigarette market. This assumption is also supported by the fact that clinical trials investigating the long-term effects of e-cigarettes on cancer incidence and progression are still absent. Therefore, further preclinical and clinical studies focusing on elucidating the potential mechanisms and pathways interconnecting e-cigarettes and cancer are necessary.

No potential conflicts of interest were disclosed.

This work was supported by the Slovak Research and Development Agency (APVV-17-0090).

1.
National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health
.
The health consequences of smoking–50 years of progress: a report of the Surgeon General
.
Atlanta, GA
:
Centers for Disease Control and Prevention (US)
; 
2014
.
2.
Hajek
P
,
Etter
JF
,
Benowitz
N
,
Eissenberg
T
,
McRobbie
H
. 
Electronic cigarettes: review of use, content, safety, effects on smokers and potential for harm and benefit
.
Addiction
2014
;
109
:
1801
10
.
3.
Cullen
KA
,
Ambrose
BK
,
Gentzke
AS
,
Apelberg
BJ
,
Jamal
A
,
King
BA
. 
Notes from the field: use of electronic cigarettes and any tobacco product among middle and high school students – United States, 2011–2018
.
MMWR Morb Mortal Wkly Rep
2018
;
67
:
1276
7
.
4.
Bao
W
,
Xu
G
,
Lu
J
,
Snetselaar
LG
,
Wallace
RB
. 
Changes in electronic cigarette use among adults in the United States, 2014–2016
.
JAMA
2018
;
319
:
2039
41
.
5.
Kaur
G
,
Pinkston
R
,
McLemore
B
,
Dorsey
WC
,
Batra
S
. 
Immunological and toxicological risk assessment of e-cigarettes
.
Eur Respir Rev
2018
;
27
.
pii: 170119
.
6.
Lohler
J
,
Wollenberg
B
. 
Are electronic cigarettes a healthier alternative to conventional tobacco smoking?
Eur Arch Otorhinolaryngol
2019
;
276
:
17
25
.
7.
Stephens
WE
. 
Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke
.
Tob Control
2017 Aug 4
[Epub ahead of print]
.
8.
Shahab
L
,
Goniewicz
ML
,
Blount
BC
,
Brown
J
,
McNeill
A
,
Alwis
KU
, et al
Nicotine, carcinogen, and toxin exposure in long-term e-cigarette and nicotine replacement therapy users: a cross-sectional study
.
Ann Intern Med
2017
;
166
:
390
400
.
9.
Canistro
D
,
Vivarelli
F
,
Cirillo
S
,
Babot Marquillas
C
,
Buschini
A
,
Lazzaretti
M
, et al
E-cigarettes induce toxicological effects that can raise the cancer risk
.
Sci Rep
2017
;
7
:
2028
.
10.
Hiemstra
PS
,
Bals
R
. 
Basic science of electronic cigarettes: assessment in cell culture and in vivo models
.
Respir Res
2016
;
17
:
127
.
11.
Breland
A
,
Soule
E
,
Lopez
A
,
Ramoa
C
,
El-Hellani
A
,
Eissenberg
T
. 
Electronic cigarettes: what are they and what do they do?
Ann N Y Acad Sci
2017
;
1394
:
5
30
.
12.
Bourke
L
,
Bauld
L
,
Bullen
C
,
Cumberbatch
M
,
Giovannucci
E
,
Islami
F
, et al
E-cigarettes and urologic health: a collaborative review of toxicology, epidemiology, and potential risks
.
Eur Urol
2017
;
71
:
915
23
.
13.
Benowitz
NL
,
Burbank
AD
. 
Cardiovascular toxicity of nicotine: implications for electronic cigarette use
.
Trends Cardiovasc Med
2016
;
26
:
515
23
.
14.
Rowell
TR
,
Reeber
SL
,
Lee
SL
,
Harris
RA
,
Nethery
RC
,
Herring
AH
, et al
Flavored e-cigarette liquids reduce proliferation and viability in the CALU3 airway epithelial cell line
.
Am J Physiol Lung Cell Mol Physiol
2017
;
313
:
L52
L66
.
15.
Eltorai
AE
,
Choi
AR
,
Eltorai
AS
. 
Impact of electronic cigarettes on various organ systems
.
Respir Care
2019
;
64
:
328
36
.
16.
Lien
YC
,
Wang
W
,
Kuo
LJ
,
Liu
JJ
,
Wei
PL
,
Ho
YS
, et al
Nicotine promotes cell migration through alpha7 nicotinic acetylcholine receptor in gastric cancer cells
.
Ann Surg Oncol
2011
;
18
:
2671
9
.
17.
Zhang
Q
,
Tang
X
,
Zhang
ZF
,
Velikina
R
,
Shi
S
,
Le
AD
. 
Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways
.
Clin Cancer Res
2007
;
13
:
4686
94
.
18.
Shin
VY
,
Jin
HC
,
Ng
EK
,
Yu
J
,
Leung
WK
,
Cho
CH
, et al
Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: involvement of nicotinic acetylcholine receptor (nAChR) and beta-adrenergic receptor signaling pathways
.
Toxicol Appl Pharmacol
2008
;
233
:
254
61
.
19.
Calleja-Macias
IE
,
Kalantari
M
,
Bernard
HU
. 
Cholinergic signaling through nicotinic acetylcholine receptors stimulates the proliferation of cervical cancer cells: an explanation for the molecular role of tobacco smoking in cervical carcinogenesis?
Int J Cancer
2009
;
124
:
1090
6
.
20.
National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems
;
Eaton
DL
,
Kwan
LY
, et al
Public health consequences of e-cigarettes
.
Washington, DC
:
National Academies Press
; 
2018
.
21.
Goniewicz
ML
,
Knysak
J
,
Gawron
M
,
Kosmider
L
,
Sobczak
A
,
Kurek
J
, et al
Levels of selected carcinogens and toxicants in vapour from electronic cigarettes
.
Tob Control
2014
;
23
:
133
9
.
22.
Goniewicz
ML
,
Smith
DM
,
Edwards
KC
,
Blount
BC
,
Caldwell
KL
,
Feng
J
, et al
Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes
.
JAMA Netw Open
2018
;
1
:
e185937
.
23.
Wagener
TL
,
Floyd
EL
,
Stepanov
I
,
Driskill
LM
,
Frank
SG
,
Meier
E
, et al
Have combustible cigarettes met their match? The nicotine delivery profiles and harmful constituent exposures of second-generation and third-generation electronic cigarette users
.
Tob Control
2017
;
26
:
e23
e8
.
24.
Park
SJ
,
Walser
TC
,
Perdomo
C
,
Wang
T
,
Pagano
PC
,
Liclican
EL
, et al
The effect of e-cigarette exposure on airway epithelial cell gene expression and transformation. [abstract]
.
In
:
Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6–9; San Diego, CA
.
Philadelphia (PA)
:
AACR
; 
2014
.
Abstract nr B16
.
25.
Cressey
D
. 
E-cigarettes affect cells
.
Nature
2014
;
508
:
159
.
26.
Park
SJ
,
Walser
TC
,
Tran
LM
,
Perdomo
C
,
Wang
T
,
Hong
L-S
, et al
The biological impact of e-cigarettes on airway epithelial cell transformation and gene expression
.
J Thorac Oncol
2016
;
11
:
35
.
27.
Lerner
CA
,
Sundar
IK
,
Yao
H
,
Gerloff
J
,
Ossip
DJ
,
McIntosh
S
, et al
Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung
.
PLoS One
2015
;
10
:
e0116732
.
28.
Qu
Z
,
Sun
F
,
Zhou
J
,
Li
L
,
Shapiro
SD
,
Xiao
G
. 
Interleukin-6 prevents the initiation but enhances the progression of lung cancer
.
Cancer Res
2015
;
75
:
3209
15
.
29.
Lee
HW
,
Park
SH
,
Weng
MW
,
Wang
HT
,
Huang
WC
,
Lepor
H
, et al
E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells
.
Proc Natl Acad Sci U S A
2018
;
115
:
E1560
e9
.
30.
Ganapathy
V
,
Manyanga
J
,
Brame
L
,
McGuire
D
,
Sadhasivam
B
,
Floyd
E
, et al
Electronic cigarette aerosols suppress cellular antioxidant defenses and induce significant oxidative DNA damage
.
PLoS One
2017
;
12
:
e0177780
.
31.
Yu
V
,
Rahimy
M
,
Korrapati
A
,
Xuan
Y
,
Zou
AE
,
Krishnan
AR
, et al
Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines
.
Oral Oncol
2016
;
52
:
58
65
.
32.
Staudt
MR
,
Salit
J
,
Kaner
RJ
,
Hollmann
C
,
Crystal
RG
. 
Altered lung biology of healthy never smokers following acute inhalation of E-cigarettes
.
Respir Res
2018
;
19
:
78
.
33.
Schaal
CM
,
Bora-Singhal
N
,
Kumar
DM
,
Chellappan
SP
. 
Regulation of Sox2 and stemness by nicotine and electronic-cigarettes in non-small cell lung cancer
.
Mol Cancer
2018
;
17
:
149
.
34.
Zahedi
A
,
Phandthong
R
,
Chaili
A
,
Remark
G
,
Talbot
P
. 
Epithelial-to-mesenchymal transition of A549 lung cancer cells exposed to electronic cigarettes
.
Lung Cancer
2018
;
122
:
224
33
.
35.
Tommasi
S
,
Caliri
AW
,
Caceres
A
,
Moreno
DE
,
Li
M
,
Chen
Y
, et al
Deregulation of biologically significant genes and associated molecular pathways in the oral epithelium of electronic cigarette users
.
Int J Mol Sci
2019
;
20
.
pii: E738
.
36.
Schuller
HM
. 
Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?
Nat Rev Cancer
2009
;
9
:
195
205
.
37.
Fujii
T
,
Mashimo
M
,
Moriwaki
Y
,
Misawa
H
,
Ono
S
,
Horiguchi
K
, et al
Physiological functions of the cholinergic system in immune cells
.
J Pharmacol Sci
2017
;
134
:
1
21
.
38.
Grando
SA
. 
Connections of nicotine to cancer
.
Nat Rev Cancer
2014
;
14
:
419
29
.
39.
Cucina
A
,
Dinicola
S
,
Coluccia
P
,
Proietti
S
,
D'Anselmi
F
,
Pasqualato
A
, et al
Nicotine stimulates proliferation and inhibits apoptosis in colon cancer cell lines through activation of survival pathways
.
J Surg Res
2012
;
178
:
233
41
.
40.
Nishioka
T
,
Guo
J
,
Yamamoto
D
,
Chen
L
,
Huppi
P
,
Chen
CY
. 
Nicotine, through upregulating pro-survival signaling, cooperates with NNK to promote transformation
.
J Cell Biochem
2010
;
109
:
152
61
.
41.
Shi
D
,
Guo
W
,
Chen
W
,
Fu
L
,
Wang
J
,
Tian
Y
, et al
Nicotine promotes proliferation of human nasopharyngeal carcinoma cells by regulating alpha7AChR, ERK, HIF-1α and VEGF/PEDF signaling
.
PLoS One
2012
;
7
:
e43898
.
42.
Dasgupta
P
,
Rastogi
S
,
Pillai
S
,
Ordonez-Ercan
D
,
Morris
M
,
Haura
E
, et al
Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways
.
J Clin Invest
2006
;
116
:
2208
17
.
43.
Momi
N
,
Ponnusamy
MP
,
Kaur
S
,
Rachagani
S
,
Kunigal
SS
,
Chellappan
S
, et al
Nicotine/cigarette smoke promotes metastasis of pancreatic cancer through alpha7nAChR-mediated MUC4 upregulation
.
Oncogene
2013
;
32
:
1384
95
.
44.
Dasgupta
P
,
Rizwani
W
,
Pillai
S
,
Kinkade
R
,
Kovacs
M
,
Rastogi
S
, et al
Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines
.
Int J Cancer
2009
;
124
:
36
45
.
45.
Natori
T
,
Sata
M
,
Washida
M
,
Hirata
Y
,
Nagai
R
,
Makuuchi
M
. 
Nicotine enhances neovascularization and promotes tumor growth
.
Mol Cells
2003
;
16
:
143
6
.
46.
Wong
HP
,
Yu
L
,
Lam
EK
,
Tai
EK
,
Wu
WK
,
Cho
CH
. 
Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation
.
Toxicol Sci
2007
;
97
:
279
87
.
47.
Warren
GW
,
Romano
MA
,
Kudrimoti
MR
,
Randall
ME
,
McGarry
RC
,
Singh
AK
, et al
Nicotinic modulation of therapeutic response in vitro and in vivo
.
Int J Cancer
2012
;
131
:
2519
27
.
48.
Dinicola
S
,
Morini
V
,
Coluccia
P
,
Proietti
S
,
D'Anselmi
F
,
Pasqualato
A
, et al
Nicotine increases survival in human colon cancer cells treated with chemotherapeutic drugs
.
Toxicol In Vitro
2013
;
27
:
2256
63
.
49.
Imabayashi
T
,
Uchino
J
,
Osoreda
H
,
Tanimura
K
,
Chihara
Y
,
Tamiya
N
, et al
Nicotine induces resistance to erlotinib therapy in non-small-cell lung cancer cells treated with serum from human patients
.
Cancers
2019
;
11
.
pii: E282
.
50.
Al-Wadei
MH
,
Al-Wadei
HA
,
Schuller
HM
. 
Pancreatic cancer cells and normal pancreatic duct epithelial cells express an autocrine catecholamine loop that is activated by nicotinic acetylcholine receptors α3, α5, and α7
.
Mol Cancer Res
2012
;
10
:
239
49
.
51.
Tang
J
,
Li
Z
,
Lu
L
,
Cho
CH
. 
β-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy
.
Semin Cancer Biol
2013
;
23
:
533
42
.
52.
Wong
HP
,
Yu
L
,
Lam
EK
,
Tai
EK
,
Wu
WK
,
Cho
CH
. 
Nicotine promotes cell proliferation via alpha7-nicotinic acetylcholine receptor and catecholamine-synthesizing enzymes-mediated pathway in human colon adenocarcinoma HT-29 cells
.
Toxicol Appl Pharmacol
2007
;
221
:
261
7
.
53.
Mravec
B
,
Gidron
Y
,
Hulin
I
. 
Neurobiology of cancer: Interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain
.
Semin Cancer Biol
2008
;
18
:
150
63
.
54.
Kuol
N
,
Stojanovska
L
,
Apostolopoulos
V
,
Nurgali
K
. 
Crosstalk between cancer and the neuro-immune system
.
J Neuroimmunol
2018
;
315
:
15
23
.
55.
Cole
SW
,
Nagaraja
AS
,
Lutgendorf
SK
,
Green
PA
,
Sood
AK
. 
Sympathetic nervous system regulation of the tumour microenvironment
.
Nat Rev Cancer
2015
;
15
:
563
72
.
56.
Cole
SW
,
Sood
AK
. 
Molecular pathways: beta-adrenergic signaling in cancer
.
Clin Cancer Res
2012
;
18
:
1201
6
.
57.
Flint
MS
,
Baum
A
,
Chambers
WH
,
Jenkins
FJ
. 
Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones
.
Psychoneuroendocrinology
2007
;
32
:
470
9
.
58.
Hara
MR
,
Kovacs
JJ
,
Whalen
EJ
,
Rajagopal
S
,
Strachan
RT
,
Grant
W
, et al
A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1
.
Nature
2011
;
477
:
349
53
.
59.
Armaiz-Pena
GN
,
Allen
JK
,
Cruz
A
,
Stone
RL
,
Nick
AM
,
Lin
YG
, et al
Src activation by β-adrenoreceptors is a key switch for tumour metastasis
.
Nat Commun
2013
;
4
:
1403
.
60.
Shi
M
,
Liu
D
,
Duan
H
,
Qian
L
,
Wang
L
,
Niu
L
, et al
The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells
.
Breast Cancer Res Treat
2011
;
125
:
351
62
.
61.
Huan
HB
,
Wen
XD
,
Chen
XJ
,
Wu
L
,
Wu
LL
,
Zhang
L
, et al
Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells
.
Brain Behav Immun
2017
;
59
:
118
34
.
62.
Ben-Eliyahu
S
,
Shakhar
G
,
Page
GG
,
Stefanski
V
,
Shakhar
K
. 
Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors
.
Neuroimmunomodulation
2000
;
8
:
154
64
.
63.
Inbar
S
,
Neeman
E
,
Avraham
R
,
Benish
M
,
Rosenne
E
,
Ben-Eliyahu
S
. 
Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity
.
PLoS One
2011
;
6
:
e19246
.
64.
Schuller
HM
,
Cole
B
. 
Regulation of cell proliferation by beta-adrenergic receptors in a human lung adenocarcinoma cell line
.
Carcinogenesis
1989
;
10
:
1753
5
.
65.
Huang
XY
,
Wang
HC
,
Yuan
Z
,
Huang
J
,
Zheng
Q
. 
Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via beta-adrenergic receptor-dependent activation of P38/MAPK pathway
.
Hepatogastroenterology
2012
;
59
:
889
93
.
66.
Lackovicova
L
,
Banovska
L
,
Bundzikova
J
,
Janega
P
,
Bizik
J
,
Kiss
A
, et al
Chemical sympathectomy suppresses fibrosarcoma development and improves survival of tumor-bearing rats
.
Neoplasma
2011
;
58
:
424
9
.
67.
Sastry
KS
,
Karpova
Y
,
Prokopovich
S
,
Smith
AJ
,
Essau
B
,
Gersappe
A
, et al
Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation
.
J Biol Chem
2007
;
282
:
14094
100
.
68.
Horvathova
L
,
Padova
A
,
Tillinger
A
,
Osacka
J
,
Bizik
J
,
Mravec
B
. 
Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse
.
Stress
2016
;
19
:
528
34
.
69.
Yang
EV
,
Kim
SJ
,
Donovan
EL
,
Chen
M
,
Gross
AC
,
Webster Marketon
JI
, et al
Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression
.
Brain Behav Immun
2009
;
23
:
267
75
.
70.
Park
SY
,
Kang
JH
,
Jeong
KJ
,
Lee
J
,
Han
JW
,
Choi
WS
, et al
Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1alpha protein-dependent mechanism
.
Int J Cancer
2011
;
128
:
2306
16
.
71.
Le
CP
,
Nowell
CJ
,
Kim-Fuchs
C
,
Botteri
E
,
Hiller
JG
,
Ismail
H
, et al
Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination
.
Nat Commun
2016
;
7
:
10634
.
72.
Yang
EV
,
Sood
AK
,
Chen
M
,
Li
Y
,
Eubank
TD
,
Marsh
CB
, et al
Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells
.
Cancer Res
2006
;
66
:
10357
64
.
73.
Sood
AK
,
Bhatty
R
,
Kamat
AA
,
Landen
CN
,
Han
L
,
Thaker
PH
, et al
Stress hormone-mediated invasion of ovarian cancer cells
.
Clin Cancer Res
2006
;
12
:
369
75
.
74.
Kim
TH
,
Gill
NK
,
Nyberg
KD
,
Nguyen
AV
,
Hohlbauch
SV
,
Geisse
NA
, et al
Cancer cells become less deformable and more invasive with activation of beta-adrenergic signaling
.
J Cell Sci
2016
;
129
:
4563
75
.
75.
Sloan
EK
,
Priceman
SJ
,
Cox
BF
,
Yu
S
,
Pimentel
MA
,
Tangkanangnukul
V
, et al
The sympathetic nervous system induces a metastatic switch in primary breast cancer
.
Cancer Res
2010
;
70
:
7042
52
.
76.
Maccari
S
,
Buoncervello
M
,
Rampin
A
,
Spada
M
,
Macchia
D
,
Giordani
L
, et al
Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice
.
Br J Pharmacol
2017
;
174
:
139
49
.
77.
Deibert
DC
,
DeFronzo
RA
. 
Epinephrine-induced insulin resistance in man
.
J Clin Invest
1980
;
65
:
717
21
.
78.
De Giorgi
V
,
Grazzini
M
,
Benemei
S
,
Marchionni
N
,
Botteri
E
,
Pennacchioli
E
, et al
Propranolol for off-label treatment of patients with melanoma: results from a cohort study
.
JAMA Oncol
2018
;
4
:
e172908
.
79.
Diaz
ES
,
Karlan
BY
,
Li
AJ
. 
Impact of beta blockers on epithelial ovarian cancer survival
.
Gynecol Oncol
2012
;
127
:
375
8
.
80.
Wang
HM
,
Liao
ZX
,
Komaki
R
,
Welsh
JW
,
O'Reilly
MS
,
Chang
JY
, et al
Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy
.
Ann Oncol
2013
;
24
:
1312
9
.
81.
Grytli
HH
,
Fagerland
MW
,
Fossa
SD
,
Tasken
KA
. 
Association between use of beta-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease
.
Eur Urol
2014
;
65
:
635
41
.
82.
Powe
DG
,
Voss
MJ
,
Zanker
KS
,
Habashy
HO
,
Green
AR
,
Ellis
IO
, et al
Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival
.
Oncotarget
2010
;
1
:
628
38
.
83.
Lemeshow
S
,
Sorensen
HT
,
Phillips
G
,
Yang
EV
,
Antonsen
S
,
Riis
AH
, et al
Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study
.
Cancer Epidemiol Biomarkers Prev
2011
;
20
:
2273
9
.
84.
Baek
MH
,
Kim
DY
,
Kim
SO
,
Kim
YJ
,
Park
YH
. 
Impact of beta blockers on survival outcomes in ovarian cancer: a nationwide population-based cohort study
.
J Gynecol Oncol
2018
;
29
:
e82
.
85.
Spera
G
,
Fresco
R
,
Fung
H
,
Dyck
JRB
,
Pituskin
E
,
Paterson
I
, et al
Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study
.
Ann Oncol
2017
;
28
:
1836
41
.
86.
Udumyan
R
,
Montgomery
S
,
Fang
F
,
Almroth
H
,
Valdimarsdottir
U
,
Ekbom
A
, et al
Beta-blocker drug use and survival among patients with pancreatic adenocarcinoma
.
Cancer Res
2017
;
77
:
3700
7
.
87.
Grassi
G
,
Seravalle
G
,
Calhoun
DA
,
Bolla
GB
,
Giannattasio
C
,
Marabini
M
, et al
Mechanisms responsible for sympathetic activation by cigarette smoking in humans
.
Circulation
1994
;
90
:
248
53
.
88.
Middlekauff
HR
,
Park
J
,
Moheimani
RS
. 
Adverse effects of cigarette and noncigarette smoke exposure on the autonomic nervous system: mechanisms and implications for cardiovascular risk
.
J Am Coll Cardiol
2014
;
64
:
1740
50
.
89.
Cryer
PE
,
Haymond
MW
,
Santiago
JV
,
Shah
SD
. 
Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events
.
N Engl J Med
1976
;
295
:
573
7
.
90.
Moheimani
RS
,
Bhetraratana
M
,
Peters
KM
,
Yang
BK
,
Yin
F
,
Gornbein
J
, et al
Sympathomimetic effects of acute e-cigarette use: role of nicotine and non-nicotine constituents
.
J Am Heart Assoc
2017
;
6
: pii:
e006579
.
91.
Sanford
NN
,
Sher
DJ
,
Xu
X
,
Aizer
AA
,
Mahal
BA
. 
Trends in smoking and e-cigarette use among US patients with cancer, 2014-2017
.
JAMA Oncol
2019
;
5
:
426
8
.
92.
Zahalka
AH
,
Arnal-Estape
A
,
Maryanovich
M
,
Nakahara
F
,
Cruz
CD
,
Finley
LWS
, et al
Adrenergic nerves activate an angio-metabolic switch in prostate cancer
.
Science
2017
;
358
:
321
6
.
93.
Cummings
KM
,
Morris
PB
,
Benowitz
NL
. 
Another article about e-cigarettes: why should I care?
J Am Heart Assoc
2018
;
7.
pii: e009944
.
94.
Dautzenberg
B
,
Garelik
D
. 
Patients with lung cancer: are electronic cigarettes harmful or useful?
Lung Cancer
2017
;
105
:
42
8
.
95.
Correa
JB
,
Brandon
KO
,
Meltzer
LR
,
Hoehn
HJ
,
Pineiro
B
,
Brandon
TH
, et al
Electronic cigarette use among patients with cancer: reasons for use, beliefs, and patient-provider communication
.
Psychooncology
2018
;
27
:
1757
64
.
96.
Rutledge
A
,
Jobling
P
,
Walker
MM
,
Denham
JW
,
Hondermarck
H
. 
Spinal cord injuries and nerve dependence in prostate cancer
.
Trends Cancer
2017
;
3
:
812
5
.
97.
Mirosevic
S
,
Jo
B
,
Kraemer
HC
,
Ershadi
M
,
Neri
E
,
Spiegel
D
. 
"Not just another meta-analysis": sources of heterogeneity in psychosocial treatment effect on cancer survival
.
Cancer Med
2019
;
8
:
363
73
.