Gut bacteria and cancer Susan E. Erdman, Theofilos Poutahidis PII: DOI: Reference:
S0304-419X(15)00043-8 doi: 10.1016/j.bbcan.2015.05.007 BBACAN 88047
To appear in:
BBA - Reviews on Cancer
Received date: Accepted date:
20 April 2015 24 May 2015
Please cite this article as: Susan E. Erdman, Theofilos Poutahidis, Gut bacteria and cancer, BBA - Reviews on Cancer (2015), doi: 10.1016/j.bbcan.2015.05.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Gut bacteria and cancer
PT
Susan E Erdman1* and Theofilos Poutahidis1,2
RI
Affiliations:
SC
1 Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 United States
NU
2 Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece 54124
D
MA
** Corresponding author: [email protected]
Abstract
AC CE P
TE
Key words: Enteric; microbes; breast cancer; mammary cancer; immune system; neutrophils; regulatory T cells
Microbiota on the mucosal surfaces of the gastrointestinal (GI) tract greatly outnumber the cells in the human body. Effects of antibiotics indicate that GI tract bacteria may be determining the fate of distal cancers. Recent data implicate dysregulated host responses to enteric bacteria leading to cancers in extra-intestinal sites. Together these findings point to novel anti-cancer strategies aimed at promoting GI tract homeostasis.
1
ACCEPTED MANUSCRIPT
1
Introduction
PT
Breast cancer is the most frequently diagnosed cancer in women [1-3]. It has been
RI
known for some time that antibiotics and anti-inflammatory drug therapy, such as
SC
aspirin, alter relative risks for breast cancer in women [4-6]. However, the etiopathogenic factors leading to breast malignancy are not well understood [5, 7, 8].
NU
During studies of gastrointestinal (GI) tract inflammation, it was discovered that certain
MA
gut commensal bacteria trigger not only colonic tumors but also mammary and prostate gland tumors in susceptible mouse models [9, 10]. More recently, human milk-borne
D
microbes were found to inhibit mammary neoplasms in predisposed mice [11], with
TE
effects transcending several generations [12]. This raises the intriguing possibility that
1.1
AC CE P
our microbial passengers may unveil novel targets for cancer prevention and therapy.
Cancer development is a multi-factorial process
Cancers of tissues including the colon and breast are attributable to complex interactions between cells surviving genetic damage and their micro- and macroenvironments [13-16]. This continuous interplay eventually leads to the formation of indestructible cancer cell clones through a natural selection process [14]. Immune and stromal cells, cytokines, proteases and hormones are now acknowledged as major environmental contributors in the natural history of cellular malignant transformations [13, 14]. Consequently, the immune system status [17], the metabolic profile [18] and the psychological condition of the host [19], which influence each other at the whole
2
ACCEPTED MANUSCRIPT organism level, could be viewed as external determinants of the perturbed ecosystem of
PT
abnormal cells with neoplastic potential.
RI
Studies in animal models of cancer increased the understanding of the multistep
SC
evolution of dysplasia and pre-neoplasia to cancer [11, 20-22]. Several of these studies have also highlighted the fact that early neoplastic lesions are less autonomous in their
NU
growth than previously thought [11, 22-26]. Instead, their thriving and evolution
MA
depends on their micro- and macro-environment[13-15, 17, 27, 28]. This finding raises interesting possibilities for cancer prevention. Indeed, accidental gene mutations
D
occurring during the lifetime of a human being are countless [15, 29]. Therefore, most
TE
people develop focal dysplastic and pre-neoplastic lesions during their lifetimes. These
AC CE P
lesions rarely develop into cancer. However, co-existing local or systemic smoldering inflammatory disturbances of homeostasis have a trophic effect on them, promote their development, and greatly increase the chances of carcinogenesis [15, 17, 23].
Taken together these recent conceptual advances in tumor biology suggest that immune system elements, hormones and psychosomatic factors may determine the fate of preneoplastic lesions towards progression to cancer through interrelated mechanisms. This raises an important question whether effective modalities that could contribute towards shaping an overall systemic homeostatic, non-tumor promoting status may exist.
3
ACCEPTED MANUSCRIPT Recent findings using mouse models suggest this may be possible. It appears that supplementation with certain gastrointestinal bacteria initiates multifaceted systemic
PT
events that overlap with basic pro-carcinogenic signaling [12, 27, 28, 30-34]. In this case,
RI
bacteria apparently suppress the evolution of early neoplastic lesions to cancer in
SC
epithelia locating distally from the gut, such as those of mammary gland, by downregulating the systemic inflammatory index in the form of pro-inflammatory cytokine
NU
levels and inflammatory cells [11]. Beneficial Firmicutes bacteria including Lactobacillus
MA
spp are likewise able in mice to interrupt metabolic disorders such as obesity and induce a reproductive fitness-matching hormonal milieu with youthful testosterone, free
D
thyroxin (T4), and oxytocin levels [35-37]. Interestingly, these same hormones have
TE
been connected with healthful mentality and anxiolytic effects [38-40]. As pivotal
AC CE P
elements of the gut microbiota-brain axis, certain gastrointestinal tract bacteria are being introduced as psychobiotics due to their potential to counteract depression and promote a sense of well-being [41].
2
Our gut reactions: a balancing act that shapes systemic immune tone
The GI tract encompasses the largest surface of the human body where microbial products interact with the immune system. It has become clear that balance of systemic health is routinely enforced by activities of CD4+ T regulatory (TREG) cells along mucosal surfaces. These lymphocytes have evolved to play a sophisticated balancing act of allowing host protective immune responses during acute inflammatory responses, while later regaining suppressive roles that limit deleterious pathological sequellae of chronic
4
ACCEPTED MANUSCRIPT smoldering inflammation
[42-44]. Recent evidence highlights
the important
developmental and functional associations of intestinal microbiota with TREG cells [45-
PT
48]. Both in vitro data and lymphocyte titration experiments in preclinical models have
RI
revealed that homeostatic potency of TREG [ie., ability of TREG to restore homeostasis
SC
after environmental insults] is modulated by prior intestinal bacterial challenges [9, 23, 49-55]. These studies on TREG cells complement other data showing an array of different
NU
effects of gut bacteria on systemic innate and adaptive immunity [56] thus solidifying a
MA
pivotal role for gut microbiota in shaping systemic immune tone and responses [Figure
D
1].
TE
Disruptive events in the GI tract also increase risk for microbial translocations [57]
AC CE P
together with systemic immune cell trafficking. Microbial translocation from gut to mammary tissue has been postulated in breast cancer etiopathogenesis [ 74]. The subsequent increase of the systemic inflammatory index would be expected to increase likelihood of cancer in distal tissues. However, the bacterial translocation due to the compromised intestinal integrity caused by cancer treatment therapies has been shown to augment anti-tumor immunity networks of activated myeloid cells and Tlymphocytes. This beneficial effect was lost in germ-free mice or animals treated with antibiotics. Therefore, in this setting, bacterial translocation worked synergistically to certain cancer therapeutic regimens [32, 33, 56, 58]. This discrepancy is not surprising. The divergent effects of translocating bacteria-induced systemic immune responses on
5
ACCEPTED MANUSCRIPT neoplastic disease outcomes reflect the multifaceted relationship of inflammation with
PT
cancer.
RI
Taken together, there is abundant evidence that bacteria modulate cancer development
SC
and growth. Finding that bowel bacteria or their products promote a competent, healthy immune system provides an explanation for perplexing increases in cancers
NU
arising from epithelia in colon, breast and other sites in countries with more stringent
MA
hygiene practices [23, 59]. Along similar lines, chronic antibiotic therapy may disrupt constructive bacterial processes, ultimately leading to higher rates of breast cancer in
D
women [4]. Systemic NSAID therapy has been linked with significant decreases in
TE
several types of cancer [60-63]. Thus, ways in which gut microbiota stimulate inherent
AC CE P
host homeostatic properties are an attractive target for systemic good health approaches using probiotic bacteria or microbial product vaccines.
3
Cancer and Inflammation: Interleukin-6 and neutrophils
In the context of cancer, inflammation is widely believed to represent the body’s fight against tumor cells [64, 65]. Other data, however, suggests just the opposite; chronic smoldering inflammation may be a cause of cancer and is a powerful stimulus for tumor growth and invasion [66-68]. These opposing observations are not easily reconciled, and are most easily comprehended in the context of immune balance, with cancer arising during dysregulated attempts by the host animal to restore homeostasis after an insult.
6
ACCEPTED MANUSCRIPT Several lines of evidence support that pathogenic GI tract microbiota stimulate certain innate immune cells to enhance tumor formation throughout the body [9, 22, 69-73] [9,
PT
74]. In order to identify the key immune cell players, prior studies have built upon
RI
reciprocal systemic relationships existing between neutrophils, mast cells and
SC
macrophages with cells of adaptive immunity [70, 75-81]. During homeostasis, these immune networks are persistently down-regulated by anti-inflammatory activities of
NU
CD4+ TREG that bestow intestinal homeostasis [9, 52, 69]. In this context, a weakened
MA
TREG-mediated inhibitory loop imparts carcinogenic consequences of elevated IL-6 and possibly IL-17, leading to more frequent inflammation-associated distal cancers [82]. In
D
this context, neutrophils have been identified in animal models as an important factor in
TE
cancer initiation and development [24-26, 70] [83] [84-88]. A distant neoplastic effect of
AC CE P
a commensal gut microbe was recently shown in FVB-Tg(C3-1-TAg)cJeg/JegJ mammary tissue by a neutrophil-mediated mechanism [75]. Importantly, systemic interplay between microbes, IL-6, and neutrophils was recently shown in human patients with breast cancer [77].
To the same extent that pathogenic gut bacteria can lead to carcinogenic events in distant tissues, it appears that beneficial bacteria may inhibit or even suppress carcinogenesis. A prototype beneficial microbe Lactobacillus reuteri was recently shown to rescue mice from age-associated obesity and the deleterious IL-6 and IL-17-rich smoldering systemic inflammatory obese status [10]. Obesity has been linked with postmenopausal mammary cancer [89-91]; thus, it was subsequently examined and
7
ACCEPTED MANUSCRIPT shown that beneficial Lactobacillus sp microbes inhibit obesity-associated mammary carcinogenesis in mice [75]. Interestingly, the same anti-neoplastic effect occurred in
PT
the Her-2/Neu mouse, a genetically engineered mouse model of mammary cancer, in
RI
which the association between immunity and mammary carcinogenesis is less obvious.
SC
This animal model is transgenic for ErbB2 Epidermal Growth Factor [EGF] receptor and
4
MA
patients and carries a poor prognosis [20].
NU
over-produces the protein HER-2; a condition that occurs in up to 30% of breast cancer
It starts earlier in life
D
Recently, much attention has been focused on the possibility that modulating intestinal
TE
flora early in life may provide life-long protection against cancer. Prior work [9, 51, 52,
AC CE P
74, 92] supports a model whereby prior enteric infections serve to suppress gut inflammation, consistent with the observations of Belkaid and Rouse (2005) involving immune competency and TREG cells
[50]. More recent evidence highlights the
importance of intestinal microbiota during maturation of the immune system [45-48]. Data from preclinical models has substantiated this notion that host ability to restore homeostasis after environmental insults is modulated by prior intestinal bacterial exposures [9, 23, 49-55]. This makes sense involving a paradigm proposed by Kuchroo and co-workers [93, 94] showing that ability of TREG to enforce homeostasis and inhibit immune-mediated diseases depending upon levels of inflammation, and IL-6 in particular. In this paradigm, elevated levels of IL-6 trigger a T helper type (Th)-17 host response that contributes to worsening systemic disease conditions. Taken together,
8
ACCEPTED MANUSCRIPT these observations link the immune system, gastrointestinal infections, and seemingly divergent downstream phenotypes: allergies, autoimmune disease, and cancer. These
PT
observations suggest that TREG may do more than block constructive anti-cancer
RI
responses [64, 65]. Following this reasoning, a model in which childhood infections
SC
protect from inflammatory diseases later in life, TREG cell biology may help explain
NU
unanswered questions of cancer risk and modern lifestyle.
MA
During early life in mammals, the immune system programming process is chaperoned by milk-borne lactic acid bacteria that apparently serve to protect nursing infants by
D
stimulating anti-inflammatory cytokine IL-10 and TREG cells along naïve mucosal surfaces.
TE
Modern lifestyle practices that remove natural exposures due to Caesarian births and
AC CE P
bottle-feeding may compromise host ability to navigate future mucosal challenges. It is promising that administration of similar beneficial bacteria later in life may serve to prevent enteric inflammation [95, 96] as well as a wide variety of inflammationassociated systemic disorders [97]. For example, as a consequence of eating L. reuteri, aged mice displayed superb integumentary health with increased wound healing capacity, and resisted age-associated thyroid and testicular involution [10, 98]. Dosing mice orally with L. reuteri isolated from human milk was proven sufficient to downregulate systemic inflammatory cytokines and neutrophil accumulations [37, 98], in addition to lowered risk for mammary cancer [78], in mouse models.
9
ACCEPTED MANUSCRIPT According to recent studies, diet and dietary microbes may have transgenerational cancer consequences involving integrated immune and hormonal factors [99]. De Assis
PT
et al have shown that descendant generations of female rats fed a high-fat diet or
RI
exposed to estrogen during pregnancy are more prone to carcinogen-induced mammary
SC
cancer. In those studies, the increased sensitivity to mammary chemical carcinogenesis was epigenetically inherited, since offspring rats had an altered mammary tissue DNA
NU
methylation pattern [99]. Interestingly, both treatments used to achieve this
MA
epigenetically-regulated effect connect with pivotal elements of one proposed gutcentric mechanism of remote cancer risk control involving gut microbiota and regulatory
D
T-cells. High fat diets have been shown to alter gut microbial communities in both
TE
rodents [98][99] and human beings [100]. In mice, high-fat diet and the related obesity-
AC CE P
type gut microbiota coincide with reduced numbers of T REG cells in both mesenteric and mammary lymph nodes [78, 98]. In the offspring with maternal estrogen changes, the prenatal exposure to estrogens disrupts T-cell differentiation in the thymus and has long-term effects in its immune system [103] including reduced TREG cells [104]. Disrupted thymic maturation of suppressive CD4+ T cells has been recently shown to be responsible for spontaneous cancer upon aging [55]. Estrogenic prenatal exposures have been associated with increased mammary cancer later in life, but the mechanism has not been fully elucidated [101] [102] [105]. It is intriguing to hypothesize that gut microbiota, hormones and dysfunctional thymus, during the perinatal period are implicated with TREG cells and unbalanced immune responses to explain increased cancer risk in subsequent generations. Indeed, a recent study showed that detrimental
10
ACCEPTED MANUSCRIPT effects of the obesity-type gut microbiota were neutralized by enriching the microbiota
Conclusion
RI
5
PT
of descendent mice with beneficial lactic acid bacteria [99].
SC
It would follow logically that microbial measures aimed at restoring immune balance and reducing systemic inflammatory index would be beneficial for counteracting cancer.
NU
Yet, the roles of gut microbes may be far more complex, depending on the stage of the
MA
neoplastic disease or the specific aspects examined. Although it remains unclear precisely how microbes achieve these beneficial effects, this work highlights the need to
D
exploit bacteria in novel cancer prevention and treatment strategies aimed at
AC CE P
TE
promoting intestinal homeostasis.
Acknowledgements: This work was supported by National Institutes of Health grants R01CA108854 (to S.E.E), and U01 CA164337 (S.E.E.).
11
ACCEPTED MANUSCRIPT Figure Legend: Figure 1. A proposed model of gut microbe-induced extra-intestinal carcinogenesis.
PT
Humans infected with pathogenic gut bacteria are at increased risk for inflammation
RI
and cancer. The compromised intestinal epithelial barrier during pathogenic infection
SC
leads to translocation of bacteria thereby triggering systemic activation of immune cells, culminating in an elevated septic and systemic inflammatory index and to cancer in
NU
distant sites such as breast tissue. Immunocompetent hosts have efficient T regulatory
MA
(Treg) cell responses in response to microbial challenges that help restore gut epithelial
AC CE P
TE
D
homeostasis.
12
ACCEPTED MANUSCRIPT
References
PT
[1] ACS cancer facts and figures, US Cancer Fact and Figures, (2004).
RI
[2] A. Jemal, R.C. Tiwari, T. Murray, A. Ghafoor, A. Samuels, E. Ward, E.J. Feuer, M.J.
SC
Thun, Cancer statistics, 2004, CA Cancer J Clin, 54 (2004) 8-29.
[3] J. Ferlay, GLOBOCAN 2000: Cancer incidence, mortality, and prevalence
NU
worldwide, IARC Press, 2001.
[4] R.B. Ness, J.A. Cauley, Antibiotics and breast cancer--what's the meaning of this?, Jama, 291 (2004) 880-881.
MA
[5] C.M. Ulrich, J. Bigler, J.D. Potter, Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics, Nat Rev Cancer, 6 (2006) 130-140.
D
[6] R.E. Harris, J. Beebe-Donk, H. Doss, D. Burr Doss, Aspirin, ibuprofen, and other
TE
non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of nonselective COX-2 blockade (review), Oncol Rep, 13 (2005) 559-583.
AC CE P
[7] L.R. Howe, S.H. Chang, K.C. Tolle, R. Dillon, L.J. Young, R.D. Cardiff, R.A. Newman, P. Yang, H.T. Thaler, W.J. Muller, C. Hudis, A.M. Brown, T. Hla, K. Subbaramaiah, A.J. Dannenberg, HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice, Cancer Res, 65 (2005) 10113-10119.
[8] D. Mazhar, R. Ang, J. Waxman, COX inhibitors and breast cancer, Br J Cancer, 94 (2006) 346-350. [9] V.P. Rao, T. Poutahidis, Z. Ge, P.R. Nambiar, C. Boussahmain, Y.Y. Wang, B.H. Horwitz, J.G. Fox, S.E. Erdman, Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice, Cancer Res, 66 (2006) 7395-7400. [10] T. Poutahidis, K. Cappelle, T. Levkovich, C.W. Lee, M. Doulberis, Z. Ge, J.G. Fox, B.H. Horwitz, S.E. Erdman, Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice, PLoS One, 8 (2013) e73933.
13
ACCEPTED MANUSCRIPT [11] J.R. Lakritz, T. Poutahidis, T. Levkovich, B.J. Varian, Y.M. Ibrahim, A. Chatzigiagkos, S. Mirabal, E.J. Alm, S.E. Erdman, Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in
PT
mice, Int J Cancer, In Press (2013).
[12] T. Poutahidis, B.J. Varian, T. Levkovich, J.R. Lakritz, S. Mirabal, C. Kwok, Y.M.
RI
Ibrahim, S.M. Kearney, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Dietary microbes
SC
modulate transgenerational cancer risk, Cancer Res, 75 (2015) 1197-1204. [13] D. Hanahan, L.M. Coussens, Accessories to the crime: functions of cells recruited to
NU
the tumor microenvironment, Cancer Cell, 21 (2012) 309-322. [14] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell, 144
MA
(2011) 646-674.
[15] M.J. Bissell, W.C. Hines, Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression, Nature medicine, 17 (2011) 320-
D
329.
TE
[16] M. Greaves, An evolutionary foundation for cancer control, WORLD CANCER REPORT 2014 from IACR, (2014).
AC CE P
[17] S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer, Cell, 140 (2010) 883-899.
[18] M.H. Faulds, K. Dahlman-Wright, Metabolic diseases and cancer risk, Curr Opin Oncol, 24 (2012) 58-61.
[19] K. Lillberg, P.K. Verkasalo, J. Kaprio, L. Teppo, H. Helenius, M. Koskenvuo, Stressful life events and risk of breast cancer in 10,808 women: a cohort study, Am J Epidemiol, 157 (2003) 415-423. [20] R.D. Cardiff, M.R. Anver, B.A. Gusterson, L. Hennighausen, R.A. Jensen, M.J. Merino, S. Rehm, J. Russo, F.A. Tavassoli, L.M. Wakefield, J.M. Ward, J.E. Green, The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting, Oncogene, 19 (2000) 968-988. [21] S.B. Shappell, G.V. Thomas, R.L. Roberts, R. Herbert, M.M. Ittmann, M.A. Rubin, P.A. Humphrey, J.P. Sundberg, N. Rozengurt, R. Barrios, J.M. Ward, R.D. Cardiff, Prostate pathology of genetically engineered mice: definitions and classification. The
14
ACCEPTED MANUSCRIPT consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee, Cancer Res, 64 (2004) 2270-2305. [22] S.E. Erdman, T. Poutahidis, M. Tomczak, A.B. Rogers, K. Cormier, B. Plank, B.H.
PT
Horwitz, J.G. Fox, CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice, Am J Pathol, 162 (2003) 691-702.
RI
[23] S.E. Erdman, T. Poutahidis, Cancer inflammation and regulatory T cells, Int J
SC
Cancer, 127 (2010) 768-779.
[24] S.E. Erdman, T. Poutahidis, Roles for inflammation and regulatory T cells in colon
NU
cancer, Toxicologic pathology, 38 (2010) 76-87.
[25] E. Karamanavi, K. Angelopoulou, S. Lavrentiadou, A. Tsingotjidou, Z. Abas, I.
MA
Taitzoglou, I. Vlemmas, S.E. Erdman, T. Poutahidis, Urokinase-Type Plasminogen Activator Deficiency Promotes Neoplasmatogenesis in the Colon of Mice, Translational Oncology, 7 (2014) 174-187.
D
[26] M. Doulberis, K. Angelopoulou, E. Kaldrymidou, A. Tsingotjidou, Z. Abas, S.E.
TE
Erdman, T. Poutahidis, Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer, Carcinogenesis, 36 (2015) 280-290.
AC CE P
[27] S.E. Erdman, T. Poutahidis, The microbiome modulates the tumor macroenvironment, Oncoimmunology, 3 (2014). [28] T. Poutahidis, M. Kleinewietfeld, S.E. Erdman, Gut microbiota and the paradox of cancer immunotherapy, Front Immunol, 5 (2014) 157. [29] C. Tomasetti, B. Vogelstein, Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions, Science, 347 (2015) 78-81. [30] A. de Moreno de LeBlanc, C. Matar, G. Perdigon, The application of probiotics in cancer, Br J Nutr, 98 Suppl 1 (2007) S105-110. [31] S.E. Erdman, T. Poutahidis, Probiotic 'glow of health': it's more than skin deep, Benef Microbes, 5 (2014) 109-119. [32] N. Iida, A. Dzutsev, C.A. Stewart, L. Smith, N. Bouladoux, R.A. Weingarten, D.A. Molina, R. Salcedo, T. Back, S. Cramer, R.M. Dai, H. Kiu, M. Cardone, S. Naik, A.K. Patri, E. Wang, F.M. Marincola, K.M. Frank, Y. Belkaid, G. Trinchieri, R.S. Goldszmid, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science, 342 (2013) 967-970.
15
ACCEPTED MANUSCRIPT [33] S. Viaud, F. Saccheri, G. Mignot, T. Yamazaki, R. Daillere, D. Hannani, D.P. Enot, C. Pfirschke, C. Engblom, M.J. Pittet, A. Schlitzer, F. Ginhoux, L. Apetoh, E. Chachaty, P.L. Woerther, G. Eberl, M. Berard, C. Ecobichon, D. Clermont, C. Bizet, V. Gaboriau-
PT
Routhiau, N. Cerf-Bensussan, P. Opolon, N. Yessaad, E. Vivier, B. Ryffel, C.O. Elson, J. Dore, G. Kroemer, P. Lepage, I.G. Boneca, F. Ghiringhelli, L. Zitvogel, The intestinal
RI
microbiota modulates the anticancer immune effects of cyclophosphamide, Science, 342
SC
(2013) 971-976.
[34] A. de Moreno de Leblanc, C. Matar, E. Farnworth, G. Perdigon, Study of immune
NU
cells involved in the antitumor effect of kefir in a murine breast cancer model, J Dairy Sci, 90 (2007) 1920-1928.
MA
[35] T. Poutahidis, A. Springer, T. Levkovich, P. Qi, B.J. Varian, J.R. Lakritz, Y.M. Ibrahim, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice, PLoS One, 9 (2014) e84877.
D
[36] B.J. Varian, T. Poutahidis, T. Levkovich, Y.M. Ibrahim, J.R. Lakritz, A.
TE
Chatzigiagkos, A. Scherer-Hoock, E.J. Alm, S.E. Erdman, Beneficial Bacteria Stimulate Youthful Thyroid Gland Activity, J Obes Weight Loss Ther, 4 (2014).
AC CE P
[37] T. Poutahidis, S.M. Kearney, T. Levkovich, P. Qi, B.J. Varian, J.R. Lakritz, Y.M. Ibrahim, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Microbial Symbionts Accelerate Wound Healing via the Neuropeptide Hormone Oxytocin, PLoS One, 8 (2013) e78898. [38] S.C. Mueller, E.M. Grissom, G.P. Dohanich, Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models, Psychoneuroendocrinology, 46 (2014) 114-128. [39] M. Olff, J.L. Frijling, L.D. Kubzansky, B. Bradley, M.A. Ellenbogen, C. Cardoso, J.A. Bartz, J.R. Yee, M. van Zuiden, The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences, Psychoneuroendocrinology, 38 (2013) 1883-1894. [40] F. Roelfsema, J.D. Veldhuis, Thyrotropin secretion patterns in health and disease, Endocr Rev, 34 (2013) 619-657. [41] T.G. Dinan, C. Stanton, J.F. Cryan, Psychobiotics: a novel class of psychotropic, Biol Psychiatry, 74 (2013) 720-726.
16
ACCEPTED MANUSCRIPT [42] J. Chow, S.K. Mazmanian, Getting the bugs out of the immune system: do bacterial microbiota "fix" intestinal T cell responses?, Cell Host Microbe, 5 (2009) 8-12.
tolerance and autoimmunity, Nat Immunol, 11 (2010) 7-13.
PT
[43] K. Wing, S. Sakaguchi, Regulatory T cells exert checks and balances on self
homeostasis, Semin Immunol, 25 (2013) 352-357.
RI
[44] J. Bollrath, F.M. Powrie, Controlling the frontier: regulatory T-cells and intestinal
SC
[45] J.L. Round, S.K. Mazmanian, Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota, Proc Natl Acad Sci U S A, 107 (2010)
NU
12204-12209.
[46] M.B. Geuking, J. Cahenzli, M.A. Lawson, D.C. Ng, E. Slack, S. Hapfelmeier, K.D.
MA
McCoy, A.J. Macpherson, Intestinal bacterial colonization induces mutualistic regulatory T cell responses, Immunity, 34 (2011) 794-806.
[47] Y. Furusawa, Y. Obata, S. Fukuda, T.A. Endo, G. Nakato, D. Takahashi, Y.
D
Nakanishi, C. Uetake, K. Kato, T. Kato, M. Takahashi, N.N. Fukuda, S. Murakami, E.
TE
Miyauchi, S. Hino, K. Atarashi, S. Onawa, Y. Fujimura, T. Lockett, J.M. Clarke, D.L. Topping, M. Tomita, S. Hori, O. Ohara, T. Morita, H. Koseki, J. Kikuchi, K. Honda, K.
AC CE P
Hase, H. Ohno, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature, 504 (2013) 446-450. [48] M. Kinoshita, K. Takeda, Microbial and dietary factors modulating intestinal regulatory T cell homeostasis, FEBS Lett, 588 (2014) 4182-4187. [49] S. Ostman, C. Rask, A.E. Wold, S. Hultkrantz, E. Telemo, Impaired regulatory T cell function in germ-free mice, Eur J Immunol, 36 (2006) 2336-2346. [50] Y. Belkaid, B.T. Rouse, Natural regulatory T cells in infectious disease, Nat Immunol, 6 (2005) 353-360. [51] M.C. Kullberg, D. Jankovic, P.L. Gorelick, P. Caspar, J.J. Letterio, A.W. Cheever, A. Sher, Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticusinduced colitis, J Exp Med, 196 (2002) 505-515. [52] T. Poutahidis, K.M. Haigis, V.P. Rao, P.R. Nambiar, C.L. Taylor, Z. Ge, K. Watanabe, A. Davidson, B.H. Horwitz, J.G. Fox, S.E. Erdman, Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma, Carcinogenesis, 28 (2007) 2614-2623.
17
ACCEPTED MANUSCRIPT [53] T. Levkovich, T. Poutahidis, K. Cappelle, M.B. Smith, A. Perrotta, E.J. Alm, S.E. Erdman, ‘Hygienic’ Lymphocytes Convey Increased Cancer Risk, Journal of Analytical Oncology, 3 (2014).
PT
[54] P.M. Smith, M.R. Howitt, N. Panikov, M. Michaud, C.A. Gallini, Y.M. Bohlooly, J.N. Glickman, W.S. Garrett, The microbial metabolites, short-chain fatty acids, regulate
RI
colonic Treg cell homeostasis, Science, 341 (2013) 569-573.
SC
[55] L. Brisson, L. Pouyet, P. N'Guessan, S. Garcia, N. Lopes, G. Warcollier, J.L. Iovanna, A. Carrier, The thymus-specific serine protease TSSP/PRSS16 is crucial for the
NU
antitumoral role of CD4(+) T cells, Cell Rep, 10 (2015) 39-46. [56] A. Dzutsev, R.S. Goldszmid, S. Viaud, L. Zitvogel, G. Trinchieri, The role of the
MA
microbiota in inflammation, carcinogenesis, and cancer therapy, Eur J Immunol, 45 (2015) 17-31.
[57] M. Guma, D. Stepniak, H. Shaked, M.E. Spehlmann, S. Shenouda, H. Cheroutre, I.
D
Vicente-Suarez, L. Eckmann, M.F. Kagnoff, M. Karin, Constitutive intestinal NF-kappaB
TE
does not trigger destructive inflammation unless accompanied by MAPK activation, J Exp Med, 208 (2011) 1889-1900.
AC CE P
[58] S. Viaud, R. Daillere, I.G. Boneca, P. Lepage, P. Langella, M. Chamaillard, M.J. Pittet, F. Ghiringhelli, G. Trinchieri, R. Goldszmid, L. Zitvogel, Gut microbiome and anticancer immune response: really hot Sh*t!, Cell Death Differ, 22 (2015) 199-214. [59] G.A. Rook, A. Dalgleish, Infection, immunoregulation, and cancer, Immunol Rev, 240 (2011) 141-159.
[60] D. Labayle, D. Fischer, P. Vielh, F. Drouhin, A. Pariente, C. Bories, O. Duhamel, M. Trousset, P. Attali, Sulindac causes regression of rectal polyps in familial adenomatous polyposis, Gastroenterology, 101 (1991) 635-639. [61] L.J. Marnett, R.N. DuBois, COX-2: a target for colon cancer prevention, Annu Rev Pharmacol Toxicol, 42 (2002) 55-80. [62] W.R. Waddell, R.E. Gerner, M.P. Reich, Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach, J Surg Oncol, 22 (1983) 197-211. [63] R.E. Harris, R.T. Chlebowski, R.D. Jackson, D.J. Frid, J.L. Ascenseo, G. Anderson, A. Loar, R.J. Rodabough, E. White, A. McTiernan, Breast cancer and nonsteroidal anti-
18
ACCEPTED MANUSCRIPT inflammatory drugs: prospective results from the Women's Health Initiative, Cancer Res, 63 (2003) 6096-6101. [64] T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-
PT
Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, W. Zou, Specific
RI
recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and
SC
predicts reduced survival, Nature medicine, 10 (2004) 942-949.
[65] M.P. Colombo, S. Piconese, Regulatory-T-cell inhibition versus depletion: the right
NU
choice in cancer immunotherapy, Nat Rev Cancer, 7 (2007) 880-887. [66] F. Balkwill, K.A. Charles, A. Mantovani, Smoldering and polarized inflammation in
MA
the initiation and promotion of malignant disease, Cancer Cell, 7 (2005) 211-217. [67] F. Balkwill, L.M. Coussens, Cancer: an inflammatory link, Nature, 431 (2004) 405406.
D
[68] L.M. Coussens, Z. Werb, Inflammation and cancer, Nature, 420 (2002) 860-867.
TE
[69] S.E. Erdman, V.P. Rao, T. Poutahidis, M.M. Ihrig, Z. Ge, Y. Feng, M. Tomczak, A.B. Rogers, B.H. Horwitz, J.G. Fox, CD4(+)CD25(+) regulatory lymphocytes require
6050.
AC CE P
interleukin 10 to interrupt colon carcinogenesis in mice, Cancer Res, 63 (2003) 6042-
[70] S.E. Erdman, V.P. Rao, T. Poutahidis, A.B. Rogers, C.L. Taylor, E.A. Jackson, Z. Ge, C.W. Lee, D.B. Schauer, G.N. Wogan, S.R. Tannenbaum, J.G. Fox, Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticusinfected, Rag2-deficient mice, Proc Natl Acad Sci U S A, 106 (2009) 1027-1032. [71] Y. Li, P. Kundu, S.W. Seow, C.T. de Matos, L. Aronsson, K.C. Chin, K. Karre, S. Pettersson, G. Greicius, Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice, Carcinogenesis, 33 (2012) 1231-1238. [72] C.M. Nagamine, A.B. Rogers, J.G. Fox, D.B. Schauer, Helicobacter hepaticus promotes azoxymethane-initiated colon tumorigenesis in BALB/c-IL10-deficient mice, Int J Cancer, 122 (2008) 832-838. [73] J.C. Arthur, E. Perez-Chanona, M. Muhlbauer, S. Tomkovich, J.M. Uronis, T.J. Fan, B.J. Campbell, T. Abujamel, B. Dogan, A.B. Rogers, J.M. Rhodes, A. Stintzi, K.W.
19
ACCEPTED MANUSCRIPT Simpson, J.J. Hansen, T.O. Keku, A.A. Fodor, C. Jobin, Intestinal inflammation targets cancer-inducing activity of the microbiota, Science, 338 (2012) 120-123. [74] V.P. Rao, T. Poutahidis, J.G. Fox, S.E. Erdman, Breast cancer: should
PT
gastrointestinal bacteria be on our radar screen?, Cancer Res, 67 (2007) 847-850. [75] J. Lakritz, T. Poutahidis, S. Mirabal, B. Varian, T. Levkovich, Y. Ibrahim, J. Ward,
RI
E. Teng, B. Fisher, N. Parry, S. Lesage, N. Alberg, S. Gourishetti, J. Fox, Z. Ge, S.
SC
Erdman, Gut bacteria infection stimulates neutrophils required for mammary tumorigenesis, Oncotarget, (2015).
NU
[76] S. Buonocore, P.P. Ahern, H.H. Uhlig, Ivanov, II, D.R. Littman, K.J. Maloy, F. Powrie, Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology,
MA
Nature, 464 (2010) 1371-1375.
[77] M.R. Rutkowski, T.L. Stephen, N. Svoronos, M.J. Allegrezza, A.J. Tesone, A. Perales-Puchalt, E. Brencicova, X. Escovar-Fadul, J.M. Nguyen, M.G. Cadungog, R.
D
Zhang, M. Salatino, J. Tchou, G.A. Rabinovich, J.R. Conejo-Garcia, Microbially Driven
TE
TLR5-Dependent Signaling Governs Distal Malignant Progression through TumorPromoting Inflammation, Cancer Cell, 27 (2015) 27-40.
AC CE P
[78] J.R. Lakritz, T. Poutahidis, T. Levkovich, B.J. Varian, Y.M. Ibrahim, A. Chatzigiagkos, S. Mirabal, E.J. Alm, S.E. Erdman, Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice, Int J Cancer, 135 (2014) 529-540. [79] D.G. DeNardo, L.M. Coussens, Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression, Breast Cancer Res, 9 (2007) 212. [80] L.M. Coussens, J.W. Pollard, Leukocytes in mammary development and cancer, Cold Spring Harb Perspect Biol, 3 (2011). [81] X. Jiang, D.J. Shapiro, The immune system and inflammation in breast cancer, Mol Cell Endocrinol, 382 (2014) 673-682. [82] S.E. Erdman, V.P. Rao, W. Olipitz, C.L. Taylor, E.A. Jackson, T. Levkovich, C.W. Lee, B.H. Horwitz, J.G. Fox, Z. Ge, T. Poutahidis, Unifying roles for regulatory T cells and inflammation in cancer, Int J Cancer, 126 (2010) 1651-1665.
20
ACCEPTED MANUSCRIPT [83] A.D. Gregory, A.M. Houghton, Tumor-associated neutrophils: new targets for cancer therapy, Cancer Res, 71 (2011) 2411-2416. [84] P. Lonkar, P.C. Dedon, Reactive species and DNA damage in chronic inflammation:
PT
reconciling chemical mechanisms and biological fates, Int J Cancer, 128 (2011) 19992009.
RI
[85] V. Bouvard, R. Baan, K. Straif, Y. Grosse, B. Secretan, F. El Ghissassi, L.
SC
Benbrahim-Tallaa, N. Guha, C. Freeman, L. Galichet, V. Cogliano, W.H.O.I.A.f.R.o.C.M.W. Group, A review of human carcinogens--Part B: biological
NU
agents, Lancet Oncol, 10 (2009) 321-322.
[86] E. Shacter, S.A. Weitzman, Chronic inflammation and cancer, Oncology (Williston
MA
Park), 16 (2002) 217-226, 229; discussion 230-212.
[87] C.T. Pham, Neutrophil serine proteases: specific regulators of inflammation, Nature reviews. Immunology, 6 (2006) 541-550.
D
[88] M.R. Galdiero, E. Bonavita, I. Barajon, C. Garlanda, A. Mantovani, S. Jaillon,
1402-1410.
TE
Tumor associated macrophages and neutrophils in cancer, Immunobiology, 218 (2013)
AC CE P
[89] E.E. Calle, R. Kaaks, Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms, Nat Rev Cancer, 4 (2004) 579-591. [90] P. Bhardwaj, B. Du, X.K. Zhou, E. Sue, M.D. Harbus, D.J. Falcone, D. Giri, C.A. Hudis, L. Kopelovich, K. Subbaramaiah, A.J. Dannenberg, Caloric restriction reverses obesity-induced mammary gland inflammation in mice, Cancer Prev Res (Phila), 6 (2013) 282-289.
[91] V.W. Ho, K. Leung, A. Hsu, B. Luk, J. Lai, S.Y. Shen, A.I. Minchinton, D. Waterhouse, M.B. Bally, W. Lin, B.H. Nelson, L.M. Sly, G. Krystal, A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation, Cancer Res, 71 (2011) 4484-4493. [92] S.K. Mazmanian, J.L. Round, D.L. Kasper, A microbial symbiosis factor prevents intestinal inflammatory disease, Nature, 453 (2008) 620-625. [93] E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, V.K. Kuchroo, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature, 441 (2006) 235-238.
21
ACCEPTED MANUSCRIPT [94] E. Bettelli, T. Korn, V.K. Kuchroo, Th17: the third member of the effector T cell trilogy, Curr Opin Immunol, 19 (2007) 652-657. [95] C. Di Giacinto, M. Marinaro, M. Sanchez, W. Strober, M. Boirivant, Probiotics
PT
ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells, J Immunol, 174 (2005) 3237-3246.
RI
[96] J.A. Pena, A.B. Rogers, Z. Ge, V. Ng, S.Y. Li, J.G. Fox, J. Versalovic, Probiotic
SC
Lactobacillus spp. diminish Helicobacter hepaticus-induced inflammatory bowel disease in interleukin-10-deficient mice, Infection and immunity, 73 (2005) 912-920.
NU
[97] L.E. Niers, H.M. Timmerman, G.T. Rijkers, G.M. van Bleek, N.O. van Uden, E.F. Knol, M.L. Kapsenberg, J.L. Kimpen, M.O. Hoekstra, Identification of strong
MA
interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines, Clin Exp Allergy, 35 (2005) 1481-1489. [98] T. Poutahidis, M. Kleinewietfeld, C. Smillie, T. Levkovich, A. Perrotta, S. Bhela,
D
B.J. Varian, Y.M. Ibrahim, J.R. Lakritz, S.M. Kearney, A. Chatzigiagkos, D.A. Hafler,
TE
E.J. Alm, S.E. Erdman, Microbial reprogramming inhibits Western diet-associated obesity, PLoS One, 8 (2013) e68596.
AC CE P
[99] T. Poutahidis, B.J. Varian, T. Levkovich, J.R. Lakritz, S. Mirabal, C. Kwok, Y.M. Ibrahim, S.M. Kearney, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Dietary microbes modulate transgenerational cancer risk, Cancer Res, 75 (2015) 1197-1204. [100] S.J. Kallus, L.J. Brandt, The intestinal microbiota and obesity, J Clin Gastroenterol, 46 (2012) 16-24.
[101] D.P. Robinson, S.L. Klein, Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis, Horm Behav, 62 (2012) 263-271. [102] J. Mjosberg, J. Svensson, E. Johansson, L. Hellstrom, R. Casas, M.C. Jenmalm, R. Boij, L. Matthiesen, J.I. Jonsson, G. Berg, J. Ernerudh, Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol, J Immunol, 183 (2009) 759769. [103] N.P. Singh, U.P. Singh, P.S. Nagarkatti, M. Nagarkatti, Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression
22
ACCEPTED MANUSCRIPT through estrogen receptor element and nuclear factor-kappaB motifs, J Pharmacol Exp Ther, 343 (2012) 351-361. [104] H. Yan, M. Takamoto, K. Sugane, Exposure to Bisphenol A prenatally or in
PT
adulthood promotes T(H)2 cytokine production associated with reduction of CD4CD25 regulatory T cells, Environ Health Perspect, 116 (2008) 514-519.
RI
[105] A.M. Soto, C. Brisken, C. Schaeberle, C. Sonnenschein, Does cancer start in the
SC
womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors, Journal of mammary gland biology and neoplasia,
AC CE P
TE
D
MA
NU
18 (2013) 199-208.
23
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
Graphical abstract
24
Fig. 1
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
25
S0304-419X(15)00043-8 doi: 10.1016/j.bbcan.2015.05.007 BBACAN 88047
To appear in:
BBA - Reviews on Cancer
Received date: Accepted date:
20 April 2015 24 May 2015
Please cite this article as: Susan E. Erdman, Theofilos Poutahidis, Gut bacteria and cancer, BBA - Reviews on Cancer (2015), doi: 10.1016/j.bbcan.2015.05.007
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Gut bacteria and cancer
PT
Susan E Erdman1* and Theofilos Poutahidis1,2
RI
Affiliations:
SC
1 Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 United States
NU
2 Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece 54124
D
MA
** Corresponding author: [email protected]
Abstract
AC CE P
TE
Key words: Enteric; microbes; breast cancer; mammary cancer; immune system; neutrophils; regulatory T cells
Microbiota on the mucosal surfaces of the gastrointestinal (GI) tract greatly outnumber the cells in the human body. Effects of antibiotics indicate that GI tract bacteria may be determining the fate of distal cancers. Recent data implicate dysregulated host responses to enteric bacteria leading to cancers in extra-intestinal sites. Together these findings point to novel anti-cancer strategies aimed at promoting GI tract homeostasis.
1
ACCEPTED MANUSCRIPT
1
Introduction
PT
Breast cancer is the most frequently diagnosed cancer in women [1-3]. It has been
RI
known for some time that antibiotics and anti-inflammatory drug therapy, such as
SC
aspirin, alter relative risks for breast cancer in women [4-6]. However, the etiopathogenic factors leading to breast malignancy are not well understood [5, 7, 8].
NU
During studies of gastrointestinal (GI) tract inflammation, it was discovered that certain
MA
gut commensal bacteria trigger not only colonic tumors but also mammary and prostate gland tumors in susceptible mouse models [9, 10]. More recently, human milk-borne
D
microbes were found to inhibit mammary neoplasms in predisposed mice [11], with
TE
effects transcending several generations [12]. This raises the intriguing possibility that
1.1
AC CE P
our microbial passengers may unveil novel targets for cancer prevention and therapy.
Cancer development is a multi-factorial process
Cancers of tissues including the colon and breast are attributable to complex interactions between cells surviving genetic damage and their micro- and macroenvironments [13-16]. This continuous interplay eventually leads to the formation of indestructible cancer cell clones through a natural selection process [14]. Immune and stromal cells, cytokines, proteases and hormones are now acknowledged as major environmental contributors in the natural history of cellular malignant transformations [13, 14]. Consequently, the immune system status [17], the metabolic profile [18] and the psychological condition of the host [19], which influence each other at the whole
2
ACCEPTED MANUSCRIPT organism level, could be viewed as external determinants of the perturbed ecosystem of
PT
abnormal cells with neoplastic potential.
RI
Studies in animal models of cancer increased the understanding of the multistep
SC
evolution of dysplasia and pre-neoplasia to cancer [11, 20-22]. Several of these studies have also highlighted the fact that early neoplastic lesions are less autonomous in their
NU
growth than previously thought [11, 22-26]. Instead, their thriving and evolution
MA
depends on their micro- and macro-environment[13-15, 17, 27, 28]. This finding raises interesting possibilities for cancer prevention. Indeed, accidental gene mutations
D
occurring during the lifetime of a human being are countless [15, 29]. Therefore, most
TE
people develop focal dysplastic and pre-neoplastic lesions during their lifetimes. These
AC CE P
lesions rarely develop into cancer. However, co-existing local or systemic smoldering inflammatory disturbances of homeostasis have a trophic effect on them, promote their development, and greatly increase the chances of carcinogenesis [15, 17, 23].
Taken together these recent conceptual advances in tumor biology suggest that immune system elements, hormones and psychosomatic factors may determine the fate of preneoplastic lesions towards progression to cancer through interrelated mechanisms. This raises an important question whether effective modalities that could contribute towards shaping an overall systemic homeostatic, non-tumor promoting status may exist.
3
ACCEPTED MANUSCRIPT Recent findings using mouse models suggest this may be possible. It appears that supplementation with certain gastrointestinal bacteria initiates multifaceted systemic
PT
events that overlap with basic pro-carcinogenic signaling [12, 27, 28, 30-34]. In this case,
RI
bacteria apparently suppress the evolution of early neoplastic lesions to cancer in
SC
epithelia locating distally from the gut, such as those of mammary gland, by downregulating the systemic inflammatory index in the form of pro-inflammatory cytokine
NU
levels and inflammatory cells [11]. Beneficial Firmicutes bacteria including Lactobacillus
MA
spp are likewise able in mice to interrupt metabolic disorders such as obesity and induce a reproductive fitness-matching hormonal milieu with youthful testosterone, free
D
thyroxin (T4), and oxytocin levels [35-37]. Interestingly, these same hormones have
TE
been connected with healthful mentality and anxiolytic effects [38-40]. As pivotal
AC CE P
elements of the gut microbiota-brain axis, certain gastrointestinal tract bacteria are being introduced as psychobiotics due to their potential to counteract depression and promote a sense of well-being [41].
2
Our gut reactions: a balancing act that shapes systemic immune tone
The GI tract encompasses the largest surface of the human body where microbial products interact with the immune system. It has become clear that balance of systemic health is routinely enforced by activities of CD4+ T regulatory (TREG) cells along mucosal surfaces. These lymphocytes have evolved to play a sophisticated balancing act of allowing host protective immune responses during acute inflammatory responses, while later regaining suppressive roles that limit deleterious pathological sequellae of chronic
4
ACCEPTED MANUSCRIPT smoldering inflammation
[42-44]. Recent evidence highlights
the important
developmental and functional associations of intestinal microbiota with TREG cells [45-
PT
48]. Both in vitro data and lymphocyte titration experiments in preclinical models have
RI
revealed that homeostatic potency of TREG [ie., ability of TREG to restore homeostasis
SC
after environmental insults] is modulated by prior intestinal bacterial challenges [9, 23, 49-55]. These studies on TREG cells complement other data showing an array of different
NU
effects of gut bacteria on systemic innate and adaptive immunity [56] thus solidifying a
MA
pivotal role for gut microbiota in shaping systemic immune tone and responses [Figure
D
1].
TE
Disruptive events in the GI tract also increase risk for microbial translocations [57]
AC CE P
together with systemic immune cell trafficking. Microbial translocation from gut to mammary tissue has been postulated in breast cancer etiopathogenesis [ 74]. The subsequent increase of the systemic inflammatory index would be expected to increase likelihood of cancer in distal tissues. However, the bacterial translocation due to the compromised intestinal integrity caused by cancer treatment therapies has been shown to augment anti-tumor immunity networks of activated myeloid cells and Tlymphocytes. This beneficial effect was lost in germ-free mice or animals treated with antibiotics. Therefore, in this setting, bacterial translocation worked synergistically to certain cancer therapeutic regimens [32, 33, 56, 58]. This discrepancy is not surprising. The divergent effects of translocating bacteria-induced systemic immune responses on
5
ACCEPTED MANUSCRIPT neoplastic disease outcomes reflect the multifaceted relationship of inflammation with
PT
cancer.
RI
Taken together, there is abundant evidence that bacteria modulate cancer development
SC
and growth. Finding that bowel bacteria or their products promote a competent, healthy immune system provides an explanation for perplexing increases in cancers
NU
arising from epithelia in colon, breast and other sites in countries with more stringent
MA
hygiene practices [23, 59]. Along similar lines, chronic antibiotic therapy may disrupt constructive bacterial processes, ultimately leading to higher rates of breast cancer in
D
women [4]. Systemic NSAID therapy has been linked with significant decreases in
TE
several types of cancer [60-63]. Thus, ways in which gut microbiota stimulate inherent
AC CE P
host homeostatic properties are an attractive target for systemic good health approaches using probiotic bacteria or microbial product vaccines.
3
Cancer and Inflammation: Interleukin-6 and neutrophils
In the context of cancer, inflammation is widely believed to represent the body’s fight against tumor cells [64, 65]. Other data, however, suggests just the opposite; chronic smoldering inflammation may be a cause of cancer and is a powerful stimulus for tumor growth and invasion [66-68]. These opposing observations are not easily reconciled, and are most easily comprehended in the context of immune balance, with cancer arising during dysregulated attempts by the host animal to restore homeostasis after an insult.
6
ACCEPTED MANUSCRIPT Several lines of evidence support that pathogenic GI tract microbiota stimulate certain innate immune cells to enhance tumor formation throughout the body [9, 22, 69-73] [9,
PT
74]. In order to identify the key immune cell players, prior studies have built upon
RI
reciprocal systemic relationships existing between neutrophils, mast cells and
SC
macrophages with cells of adaptive immunity [70, 75-81]. During homeostasis, these immune networks are persistently down-regulated by anti-inflammatory activities of
NU
CD4+ TREG that bestow intestinal homeostasis [9, 52, 69]. In this context, a weakened
MA
TREG-mediated inhibitory loop imparts carcinogenic consequences of elevated IL-6 and possibly IL-17, leading to more frequent inflammation-associated distal cancers [82]. In
D
this context, neutrophils have been identified in animal models as an important factor in
TE
cancer initiation and development [24-26, 70] [83] [84-88]. A distant neoplastic effect of
AC CE P
a commensal gut microbe was recently shown in FVB-Tg(C3-1-TAg)cJeg/JegJ mammary tissue by a neutrophil-mediated mechanism [75]. Importantly, systemic interplay between microbes, IL-6, and neutrophils was recently shown in human patients with breast cancer [77].
To the same extent that pathogenic gut bacteria can lead to carcinogenic events in distant tissues, it appears that beneficial bacteria may inhibit or even suppress carcinogenesis. A prototype beneficial microbe Lactobacillus reuteri was recently shown to rescue mice from age-associated obesity and the deleterious IL-6 and IL-17-rich smoldering systemic inflammatory obese status [10]. Obesity has been linked with postmenopausal mammary cancer [89-91]; thus, it was subsequently examined and
7
ACCEPTED MANUSCRIPT shown that beneficial Lactobacillus sp microbes inhibit obesity-associated mammary carcinogenesis in mice [75]. Interestingly, the same anti-neoplastic effect occurred in
PT
the Her-2/Neu mouse, a genetically engineered mouse model of mammary cancer, in
RI
which the association between immunity and mammary carcinogenesis is less obvious.
SC
This animal model is transgenic for ErbB2 Epidermal Growth Factor [EGF] receptor and
4
MA
patients and carries a poor prognosis [20].
NU
over-produces the protein HER-2; a condition that occurs in up to 30% of breast cancer
It starts earlier in life
D
Recently, much attention has been focused on the possibility that modulating intestinal
TE
flora early in life may provide life-long protection against cancer. Prior work [9, 51, 52,
AC CE P
74, 92] supports a model whereby prior enteric infections serve to suppress gut inflammation, consistent with the observations of Belkaid and Rouse (2005) involving immune competency and TREG cells
[50]. More recent evidence highlights the
importance of intestinal microbiota during maturation of the immune system [45-48]. Data from preclinical models has substantiated this notion that host ability to restore homeostasis after environmental insults is modulated by prior intestinal bacterial exposures [9, 23, 49-55]. This makes sense involving a paradigm proposed by Kuchroo and co-workers [93, 94] showing that ability of TREG to enforce homeostasis and inhibit immune-mediated diseases depending upon levels of inflammation, and IL-6 in particular. In this paradigm, elevated levels of IL-6 trigger a T helper type (Th)-17 host response that contributes to worsening systemic disease conditions. Taken together,
8
ACCEPTED MANUSCRIPT these observations link the immune system, gastrointestinal infections, and seemingly divergent downstream phenotypes: allergies, autoimmune disease, and cancer. These
PT
observations suggest that TREG may do more than block constructive anti-cancer
RI
responses [64, 65]. Following this reasoning, a model in which childhood infections
SC
protect from inflammatory diseases later in life, TREG cell biology may help explain
NU
unanswered questions of cancer risk and modern lifestyle.
MA
During early life in mammals, the immune system programming process is chaperoned by milk-borne lactic acid bacteria that apparently serve to protect nursing infants by
D
stimulating anti-inflammatory cytokine IL-10 and TREG cells along naïve mucosal surfaces.
TE
Modern lifestyle practices that remove natural exposures due to Caesarian births and
AC CE P
bottle-feeding may compromise host ability to navigate future mucosal challenges. It is promising that administration of similar beneficial bacteria later in life may serve to prevent enteric inflammation [95, 96] as well as a wide variety of inflammationassociated systemic disorders [97]. For example, as a consequence of eating L. reuteri, aged mice displayed superb integumentary health with increased wound healing capacity, and resisted age-associated thyroid and testicular involution [10, 98]. Dosing mice orally with L. reuteri isolated from human milk was proven sufficient to downregulate systemic inflammatory cytokines and neutrophil accumulations [37, 98], in addition to lowered risk for mammary cancer [78], in mouse models.
9
ACCEPTED MANUSCRIPT According to recent studies, diet and dietary microbes may have transgenerational cancer consequences involving integrated immune and hormonal factors [99]. De Assis
PT
et al have shown that descendant generations of female rats fed a high-fat diet or
RI
exposed to estrogen during pregnancy are more prone to carcinogen-induced mammary
SC
cancer. In those studies, the increased sensitivity to mammary chemical carcinogenesis was epigenetically inherited, since offspring rats had an altered mammary tissue DNA
NU
methylation pattern [99]. Interestingly, both treatments used to achieve this
MA
epigenetically-regulated effect connect with pivotal elements of one proposed gutcentric mechanism of remote cancer risk control involving gut microbiota and regulatory
D
T-cells. High fat diets have been shown to alter gut microbial communities in both
TE
rodents [98][99] and human beings [100]. In mice, high-fat diet and the related obesity-
AC CE P
type gut microbiota coincide with reduced numbers of T REG cells in both mesenteric and mammary lymph nodes [78, 98]. In the offspring with maternal estrogen changes, the prenatal exposure to estrogens disrupts T-cell differentiation in the thymus and has long-term effects in its immune system [103] including reduced TREG cells [104]. Disrupted thymic maturation of suppressive CD4+ T cells has been recently shown to be responsible for spontaneous cancer upon aging [55]. Estrogenic prenatal exposures have been associated with increased mammary cancer later in life, but the mechanism has not been fully elucidated [101] [102] [105]. It is intriguing to hypothesize that gut microbiota, hormones and dysfunctional thymus, during the perinatal period are implicated with TREG cells and unbalanced immune responses to explain increased cancer risk in subsequent generations. Indeed, a recent study showed that detrimental
10
ACCEPTED MANUSCRIPT effects of the obesity-type gut microbiota were neutralized by enriching the microbiota
Conclusion
RI
5
PT
of descendent mice with beneficial lactic acid bacteria [99].
SC
It would follow logically that microbial measures aimed at restoring immune balance and reducing systemic inflammatory index would be beneficial for counteracting cancer.
NU
Yet, the roles of gut microbes may be far more complex, depending on the stage of the
MA
neoplastic disease or the specific aspects examined. Although it remains unclear precisely how microbes achieve these beneficial effects, this work highlights the need to
D
exploit bacteria in novel cancer prevention and treatment strategies aimed at
AC CE P
TE
promoting intestinal homeostasis.
Acknowledgements: This work was supported by National Institutes of Health grants R01CA108854 (to S.E.E), and U01 CA164337 (S.E.E.).
11
ACCEPTED MANUSCRIPT Figure Legend: Figure 1. A proposed model of gut microbe-induced extra-intestinal carcinogenesis.
PT
Humans infected with pathogenic gut bacteria are at increased risk for inflammation
RI
and cancer. The compromised intestinal epithelial barrier during pathogenic infection
SC
leads to translocation of bacteria thereby triggering systemic activation of immune cells, culminating in an elevated septic and systemic inflammatory index and to cancer in
NU
distant sites such as breast tissue. Immunocompetent hosts have efficient T regulatory
MA
(Treg) cell responses in response to microbial challenges that help restore gut epithelial
AC CE P
TE
D
homeostasis.
12
ACCEPTED MANUSCRIPT
References
PT
[1] ACS cancer facts and figures, US Cancer Fact and Figures, (2004).
RI
[2] A. Jemal, R.C. Tiwari, T. Murray, A. Ghafoor, A. Samuels, E. Ward, E.J. Feuer, M.J.
SC
Thun, Cancer statistics, 2004, CA Cancer J Clin, 54 (2004) 8-29.
[3] J. Ferlay, GLOBOCAN 2000: Cancer incidence, mortality, and prevalence
NU
worldwide, IARC Press, 2001.
[4] R.B. Ness, J.A. Cauley, Antibiotics and breast cancer--what's the meaning of this?, Jama, 291 (2004) 880-881.
MA
[5] C.M. Ulrich, J. Bigler, J.D. Potter, Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics, Nat Rev Cancer, 6 (2006) 130-140.
D
[6] R.E. Harris, J. Beebe-Donk, H. Doss, D. Burr Doss, Aspirin, ibuprofen, and other
TE
non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of nonselective COX-2 blockade (review), Oncol Rep, 13 (2005) 559-583.
AC CE P
[7] L.R. Howe, S.H. Chang, K.C. Tolle, R. Dillon, L.J. Young, R.D. Cardiff, R.A. Newman, P. Yang, H.T. Thaler, W.J. Muller, C. Hudis, A.M. Brown, T. Hla, K. Subbaramaiah, A.J. Dannenberg, HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice, Cancer Res, 65 (2005) 10113-10119.
[8] D. Mazhar, R. Ang, J. Waxman, COX inhibitors and breast cancer, Br J Cancer, 94 (2006) 346-350. [9] V.P. Rao, T. Poutahidis, Z. Ge, P.R. Nambiar, C. Boussahmain, Y.Y. Wang, B.H. Horwitz, J.G. Fox, S.E. Erdman, Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice, Cancer Res, 66 (2006) 7395-7400. [10] T. Poutahidis, K. Cappelle, T. Levkovich, C.W. Lee, M. Doulberis, Z. Ge, J.G. Fox, B.H. Horwitz, S.E. Erdman, Pathogenic intestinal bacteria enhance prostate cancer development via systemic activation of immune cells in mice, PLoS One, 8 (2013) e73933.
13
ACCEPTED MANUSCRIPT [11] J.R. Lakritz, T. Poutahidis, T. Levkovich, B.J. Varian, Y.M. Ibrahim, A. Chatzigiagkos, S. Mirabal, E.J. Alm, S.E. Erdman, Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in
PT
mice, Int J Cancer, In Press (2013).
[12] T. Poutahidis, B.J. Varian, T. Levkovich, J.R. Lakritz, S. Mirabal, C. Kwok, Y.M.
RI
Ibrahim, S.M. Kearney, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Dietary microbes
SC
modulate transgenerational cancer risk, Cancer Res, 75 (2015) 1197-1204. [13] D. Hanahan, L.M. Coussens, Accessories to the crime: functions of cells recruited to
NU
the tumor microenvironment, Cancer Cell, 21 (2012) 309-322. [14] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell, 144
MA
(2011) 646-674.
[15] M.J. Bissell, W.C. Hines, Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression, Nature medicine, 17 (2011) 320-
D
329.
TE
[16] M. Greaves, An evolutionary foundation for cancer control, WORLD CANCER REPORT 2014 from IACR, (2014).
AC CE P
[17] S.I. Grivennikov, F.R. Greten, M. Karin, Immunity, inflammation, and cancer, Cell, 140 (2010) 883-899.
[18] M.H. Faulds, K. Dahlman-Wright, Metabolic diseases and cancer risk, Curr Opin Oncol, 24 (2012) 58-61.
[19] K. Lillberg, P.K. Verkasalo, J. Kaprio, L. Teppo, H. Helenius, M. Koskenvuo, Stressful life events and risk of breast cancer in 10,808 women: a cohort study, Am J Epidemiol, 157 (2003) 415-423. [20] R.D. Cardiff, M.R. Anver, B.A. Gusterson, L. Hennighausen, R.A. Jensen, M.J. Merino, S. Rehm, J. Russo, F.A. Tavassoli, L.M. Wakefield, J.M. Ward, J.E. Green, The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting, Oncogene, 19 (2000) 968-988. [21] S.B. Shappell, G.V. Thomas, R.L. Roberts, R. Herbert, M.M. Ittmann, M.A. Rubin, P.A. Humphrey, J.P. Sundberg, N. Rozengurt, R. Barrios, J.M. Ward, R.D. Cardiff, Prostate pathology of genetically engineered mice: definitions and classification. The
14
ACCEPTED MANUSCRIPT consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee, Cancer Res, 64 (2004) 2270-2305. [22] S.E. Erdman, T. Poutahidis, M. Tomczak, A.B. Rogers, K. Cormier, B. Plank, B.H.
PT
Horwitz, J.G. Fox, CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice, Am J Pathol, 162 (2003) 691-702.
RI
[23] S.E. Erdman, T. Poutahidis, Cancer inflammation and regulatory T cells, Int J
SC
Cancer, 127 (2010) 768-779.
[24] S.E. Erdman, T. Poutahidis, Roles for inflammation and regulatory T cells in colon
NU
cancer, Toxicologic pathology, 38 (2010) 76-87.
[25] E. Karamanavi, K. Angelopoulou, S. Lavrentiadou, A. Tsingotjidou, Z. Abas, I.
MA
Taitzoglou, I. Vlemmas, S.E. Erdman, T. Poutahidis, Urokinase-Type Plasminogen Activator Deficiency Promotes Neoplasmatogenesis in the Colon of Mice, Translational Oncology, 7 (2014) 174-187.
D
[26] M. Doulberis, K. Angelopoulou, E. Kaldrymidou, A. Tsingotjidou, Z. Abas, S.E.
TE
Erdman, T. Poutahidis, Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer, Carcinogenesis, 36 (2015) 280-290.
AC CE P
[27] S.E. Erdman, T. Poutahidis, The microbiome modulates the tumor macroenvironment, Oncoimmunology, 3 (2014). [28] T. Poutahidis, M. Kleinewietfeld, S.E. Erdman, Gut microbiota and the paradox of cancer immunotherapy, Front Immunol, 5 (2014) 157. [29] C. Tomasetti, B. Vogelstein, Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions, Science, 347 (2015) 78-81. [30] A. de Moreno de LeBlanc, C. Matar, G. Perdigon, The application of probiotics in cancer, Br J Nutr, 98 Suppl 1 (2007) S105-110. [31] S.E. Erdman, T. Poutahidis, Probiotic 'glow of health': it's more than skin deep, Benef Microbes, 5 (2014) 109-119. [32] N. Iida, A. Dzutsev, C.A. Stewart, L. Smith, N. Bouladoux, R.A. Weingarten, D.A. Molina, R. Salcedo, T. Back, S. Cramer, R.M. Dai, H. Kiu, M. Cardone, S. Naik, A.K. Patri, E. Wang, F.M. Marincola, K.M. Frank, Y. Belkaid, G. Trinchieri, R.S. Goldszmid, Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment, Science, 342 (2013) 967-970.
15
ACCEPTED MANUSCRIPT [33] S. Viaud, F. Saccheri, G. Mignot, T. Yamazaki, R. Daillere, D. Hannani, D.P. Enot, C. Pfirschke, C. Engblom, M.J. Pittet, A. Schlitzer, F. Ginhoux, L. Apetoh, E. Chachaty, P.L. Woerther, G. Eberl, M. Berard, C. Ecobichon, D. Clermont, C. Bizet, V. Gaboriau-
PT
Routhiau, N. Cerf-Bensussan, P. Opolon, N. Yessaad, E. Vivier, B. Ryffel, C.O. Elson, J. Dore, G. Kroemer, P. Lepage, I.G. Boneca, F. Ghiringhelli, L. Zitvogel, The intestinal
RI
microbiota modulates the anticancer immune effects of cyclophosphamide, Science, 342
SC
(2013) 971-976.
[34] A. de Moreno de Leblanc, C. Matar, E. Farnworth, G. Perdigon, Study of immune
NU
cells involved in the antitumor effect of kefir in a murine breast cancer model, J Dairy Sci, 90 (2007) 1920-1928.
MA
[35] T. Poutahidis, A. Springer, T. Levkovich, P. Qi, B.J. Varian, J.R. Lakritz, Y.M. Ibrahim, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice, PLoS One, 9 (2014) e84877.
D
[36] B.J. Varian, T. Poutahidis, T. Levkovich, Y.M. Ibrahim, J.R. Lakritz, A.
TE
Chatzigiagkos, A. Scherer-Hoock, E.J. Alm, S.E. Erdman, Beneficial Bacteria Stimulate Youthful Thyroid Gland Activity, J Obes Weight Loss Ther, 4 (2014).
AC CE P
[37] T. Poutahidis, S.M. Kearney, T. Levkovich, P. Qi, B.J. Varian, J.R. Lakritz, Y.M. Ibrahim, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Microbial Symbionts Accelerate Wound Healing via the Neuropeptide Hormone Oxytocin, PLoS One, 8 (2013) e78898. [38] S.C. Mueller, E.M. Grissom, G.P. Dohanich, Assessing gonadal hormone contributions to affective psychopathologies across humans and animal models, Psychoneuroendocrinology, 46 (2014) 114-128. [39] M. Olff, J.L. Frijling, L.D. Kubzansky, B. Bradley, M.A. Ellenbogen, C. Cardoso, J.A. Bartz, J.R. Yee, M. van Zuiden, The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences, Psychoneuroendocrinology, 38 (2013) 1883-1894. [40] F. Roelfsema, J.D. Veldhuis, Thyrotropin secretion patterns in health and disease, Endocr Rev, 34 (2013) 619-657. [41] T.G. Dinan, C. Stanton, J.F. Cryan, Psychobiotics: a novel class of psychotropic, Biol Psychiatry, 74 (2013) 720-726.
16
ACCEPTED MANUSCRIPT [42] J. Chow, S.K. Mazmanian, Getting the bugs out of the immune system: do bacterial microbiota "fix" intestinal T cell responses?, Cell Host Microbe, 5 (2009) 8-12.
tolerance and autoimmunity, Nat Immunol, 11 (2010) 7-13.
PT
[43] K. Wing, S. Sakaguchi, Regulatory T cells exert checks and balances on self
homeostasis, Semin Immunol, 25 (2013) 352-357.
RI
[44] J. Bollrath, F.M. Powrie, Controlling the frontier: regulatory T-cells and intestinal
SC
[45] J.L. Round, S.K. Mazmanian, Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota, Proc Natl Acad Sci U S A, 107 (2010)
NU
12204-12209.
[46] M.B. Geuking, J. Cahenzli, M.A. Lawson, D.C. Ng, E. Slack, S. Hapfelmeier, K.D.
MA
McCoy, A.J. Macpherson, Intestinal bacterial colonization induces mutualistic regulatory T cell responses, Immunity, 34 (2011) 794-806.
[47] Y. Furusawa, Y. Obata, S. Fukuda, T.A. Endo, G. Nakato, D. Takahashi, Y.
D
Nakanishi, C. Uetake, K. Kato, T. Kato, M. Takahashi, N.N. Fukuda, S. Murakami, E.
TE
Miyauchi, S. Hino, K. Atarashi, S. Onawa, Y. Fujimura, T. Lockett, J.M. Clarke, D.L. Topping, M. Tomita, S. Hori, O. Ohara, T. Morita, H. Koseki, J. Kikuchi, K. Honda, K.
AC CE P
Hase, H. Ohno, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature, 504 (2013) 446-450. [48] M. Kinoshita, K. Takeda, Microbial and dietary factors modulating intestinal regulatory T cell homeostasis, FEBS Lett, 588 (2014) 4182-4187. [49] S. Ostman, C. Rask, A.E. Wold, S. Hultkrantz, E. Telemo, Impaired regulatory T cell function in germ-free mice, Eur J Immunol, 36 (2006) 2336-2346. [50] Y. Belkaid, B.T. Rouse, Natural regulatory T cells in infectious disease, Nat Immunol, 6 (2005) 353-360. [51] M.C. Kullberg, D. Jankovic, P.L. Gorelick, P. Caspar, J.J. Letterio, A.W. Cheever, A. Sher, Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticusinduced colitis, J Exp Med, 196 (2002) 505-515. [52] T. Poutahidis, K.M. Haigis, V.P. Rao, P.R. Nambiar, C.L. Taylor, Z. Ge, K. Watanabe, A. Davidson, B.H. Horwitz, J.G. Fox, S.E. Erdman, Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma, Carcinogenesis, 28 (2007) 2614-2623.
17
ACCEPTED MANUSCRIPT [53] T. Levkovich, T. Poutahidis, K. Cappelle, M.B. Smith, A. Perrotta, E.J. Alm, S.E. Erdman, ‘Hygienic’ Lymphocytes Convey Increased Cancer Risk, Journal of Analytical Oncology, 3 (2014).
PT
[54] P.M. Smith, M.R. Howitt, N. Panikov, M. Michaud, C.A. Gallini, Y.M. Bohlooly, J.N. Glickman, W.S. Garrett, The microbial metabolites, short-chain fatty acids, regulate
RI
colonic Treg cell homeostasis, Science, 341 (2013) 569-573.
SC
[55] L. Brisson, L. Pouyet, P. N'Guessan, S. Garcia, N. Lopes, G. Warcollier, J.L. Iovanna, A. Carrier, The thymus-specific serine protease TSSP/PRSS16 is crucial for the
NU
antitumoral role of CD4(+) T cells, Cell Rep, 10 (2015) 39-46. [56] A. Dzutsev, R.S. Goldszmid, S. Viaud, L. Zitvogel, G. Trinchieri, The role of the
MA
microbiota in inflammation, carcinogenesis, and cancer therapy, Eur J Immunol, 45 (2015) 17-31.
[57] M. Guma, D. Stepniak, H. Shaked, M.E. Spehlmann, S. Shenouda, H. Cheroutre, I.
D
Vicente-Suarez, L. Eckmann, M.F. Kagnoff, M. Karin, Constitutive intestinal NF-kappaB
TE
does not trigger destructive inflammation unless accompanied by MAPK activation, J Exp Med, 208 (2011) 1889-1900.
AC CE P
[58] S. Viaud, R. Daillere, I.G. Boneca, P. Lepage, P. Langella, M. Chamaillard, M.J. Pittet, F. Ghiringhelli, G. Trinchieri, R. Goldszmid, L. Zitvogel, Gut microbiome and anticancer immune response: really hot Sh*t!, Cell Death Differ, 22 (2015) 199-214. [59] G.A. Rook, A. Dalgleish, Infection, immunoregulation, and cancer, Immunol Rev, 240 (2011) 141-159.
[60] D. Labayle, D. Fischer, P. Vielh, F. Drouhin, A. Pariente, C. Bories, O. Duhamel, M. Trousset, P. Attali, Sulindac causes regression of rectal polyps in familial adenomatous polyposis, Gastroenterology, 101 (1991) 635-639. [61] L.J. Marnett, R.N. DuBois, COX-2: a target for colon cancer prevention, Annu Rev Pharmacol Toxicol, 42 (2002) 55-80. [62] W.R. Waddell, R.E. Gerner, M.P. Reich, Nonsteroid antiinflammatory drugs and tamoxifen for desmoid tumors and carcinoma of the stomach, J Surg Oncol, 22 (1983) 197-211. [63] R.E. Harris, R.T. Chlebowski, R.D. Jackson, D.J. Frid, J.L. Ascenseo, G. Anderson, A. Loar, R.J. Rodabough, E. White, A. McTiernan, Breast cancer and nonsteroidal anti-
18
ACCEPTED MANUSCRIPT inflammatory drugs: prospective results from the Women's Health Initiative, Cancer Res, 63 (2003) 6096-6101. [64] T.J. Curiel, G. Coukos, L. Zou, X. Alvarez, P. Cheng, P. Mottram, M. Evdemon-
PT
Hogan, J.R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M.L. Disis, K.L. Knutson, L. Chen, W. Zou, Specific
RI
recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and
SC
predicts reduced survival, Nature medicine, 10 (2004) 942-949.
[65] M.P. Colombo, S. Piconese, Regulatory-T-cell inhibition versus depletion: the right
NU
choice in cancer immunotherapy, Nat Rev Cancer, 7 (2007) 880-887. [66] F. Balkwill, K.A. Charles, A. Mantovani, Smoldering and polarized inflammation in
MA
the initiation and promotion of malignant disease, Cancer Cell, 7 (2005) 211-217. [67] F. Balkwill, L.M. Coussens, Cancer: an inflammatory link, Nature, 431 (2004) 405406.
D
[68] L.M. Coussens, Z. Werb, Inflammation and cancer, Nature, 420 (2002) 860-867.
TE
[69] S.E. Erdman, V.P. Rao, T. Poutahidis, M.M. Ihrig, Z. Ge, Y. Feng, M. Tomczak, A.B. Rogers, B.H. Horwitz, J.G. Fox, CD4(+)CD25(+) regulatory lymphocytes require
6050.
AC CE P
interleukin 10 to interrupt colon carcinogenesis in mice, Cancer Res, 63 (2003) 6042-
[70] S.E. Erdman, V.P. Rao, T. Poutahidis, A.B. Rogers, C.L. Taylor, E.A. Jackson, Z. Ge, C.W. Lee, D.B. Schauer, G.N. Wogan, S.R. Tannenbaum, J.G. Fox, Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticusinfected, Rag2-deficient mice, Proc Natl Acad Sci U S A, 106 (2009) 1027-1032. [71] Y. Li, P. Kundu, S.W. Seow, C.T. de Matos, L. Aronsson, K.C. Chin, K. Karre, S. Pettersson, G. Greicius, Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice, Carcinogenesis, 33 (2012) 1231-1238. [72] C.M. Nagamine, A.B. Rogers, J.G. Fox, D.B. Schauer, Helicobacter hepaticus promotes azoxymethane-initiated colon tumorigenesis in BALB/c-IL10-deficient mice, Int J Cancer, 122 (2008) 832-838. [73] J.C. Arthur, E. Perez-Chanona, M. Muhlbauer, S. Tomkovich, J.M. Uronis, T.J. Fan, B.J. Campbell, T. Abujamel, B. Dogan, A.B. Rogers, J.M. Rhodes, A. Stintzi, K.W.
19
ACCEPTED MANUSCRIPT Simpson, J.J. Hansen, T.O. Keku, A.A. Fodor, C. Jobin, Intestinal inflammation targets cancer-inducing activity of the microbiota, Science, 338 (2012) 120-123. [74] V.P. Rao, T. Poutahidis, J.G. Fox, S.E. Erdman, Breast cancer: should
PT
gastrointestinal bacteria be on our radar screen?, Cancer Res, 67 (2007) 847-850. [75] J. Lakritz, T. Poutahidis, S. Mirabal, B. Varian, T. Levkovich, Y. Ibrahim, J. Ward,
RI
E. Teng, B. Fisher, N. Parry, S. Lesage, N. Alberg, S. Gourishetti, J. Fox, Z. Ge, S.
SC
Erdman, Gut bacteria infection stimulates neutrophils required for mammary tumorigenesis, Oncotarget, (2015).
NU
[76] S. Buonocore, P.P. Ahern, H.H. Uhlig, Ivanov, II, D.R. Littman, K.J. Maloy, F. Powrie, Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology,
MA
Nature, 464 (2010) 1371-1375.
[77] M.R. Rutkowski, T.L. Stephen, N. Svoronos, M.J. Allegrezza, A.J. Tesone, A. Perales-Puchalt, E. Brencicova, X. Escovar-Fadul, J.M. Nguyen, M.G. Cadungog, R.
D
Zhang, M. Salatino, J. Tchou, G.A. Rabinovich, J.R. Conejo-Garcia, Microbially Driven
TE
TLR5-Dependent Signaling Governs Distal Malignant Progression through TumorPromoting Inflammation, Cancer Cell, 27 (2015) 27-40.
AC CE P
[78] J.R. Lakritz, T. Poutahidis, T. Levkovich, B.J. Varian, Y.M. Ibrahim, A. Chatzigiagkos, S. Mirabal, E.J. Alm, S.E. Erdman, Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice, Int J Cancer, 135 (2014) 529-540. [79] D.G. DeNardo, L.M. Coussens, Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression, Breast Cancer Res, 9 (2007) 212. [80] L.M. Coussens, J.W. Pollard, Leukocytes in mammary development and cancer, Cold Spring Harb Perspect Biol, 3 (2011). [81] X. Jiang, D.J. Shapiro, The immune system and inflammation in breast cancer, Mol Cell Endocrinol, 382 (2014) 673-682. [82] S.E. Erdman, V.P. Rao, W. Olipitz, C.L. Taylor, E.A. Jackson, T. Levkovich, C.W. Lee, B.H. Horwitz, J.G. Fox, Z. Ge, T. Poutahidis, Unifying roles for regulatory T cells and inflammation in cancer, Int J Cancer, 126 (2010) 1651-1665.
20
ACCEPTED MANUSCRIPT [83] A.D. Gregory, A.M. Houghton, Tumor-associated neutrophils: new targets for cancer therapy, Cancer Res, 71 (2011) 2411-2416. [84] P. Lonkar, P.C. Dedon, Reactive species and DNA damage in chronic inflammation:
PT
reconciling chemical mechanisms and biological fates, Int J Cancer, 128 (2011) 19992009.
RI
[85] V. Bouvard, R. Baan, K. Straif, Y. Grosse, B. Secretan, F. El Ghissassi, L.
SC
Benbrahim-Tallaa, N. Guha, C. Freeman, L. Galichet, V. Cogliano, W.H.O.I.A.f.R.o.C.M.W. Group, A review of human carcinogens--Part B: biological
NU
agents, Lancet Oncol, 10 (2009) 321-322.
[86] E. Shacter, S.A. Weitzman, Chronic inflammation and cancer, Oncology (Williston
MA
Park), 16 (2002) 217-226, 229; discussion 230-212.
[87] C.T. Pham, Neutrophil serine proteases: specific regulators of inflammation, Nature reviews. Immunology, 6 (2006) 541-550.
D
[88] M.R. Galdiero, E. Bonavita, I. Barajon, C. Garlanda, A. Mantovani, S. Jaillon,
1402-1410.
TE
Tumor associated macrophages and neutrophils in cancer, Immunobiology, 218 (2013)
AC CE P
[89] E.E. Calle, R. Kaaks, Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms, Nat Rev Cancer, 4 (2004) 579-591. [90] P. Bhardwaj, B. Du, X.K. Zhou, E. Sue, M.D. Harbus, D.J. Falcone, D. Giri, C.A. Hudis, L. Kopelovich, K. Subbaramaiah, A.J. Dannenberg, Caloric restriction reverses obesity-induced mammary gland inflammation in mice, Cancer Prev Res (Phila), 6 (2013) 282-289.
[91] V.W. Ho, K. Leung, A. Hsu, B. Luk, J. Lai, S.Y. Shen, A.I. Minchinton, D. Waterhouse, M.B. Bally, W. Lin, B.H. Nelson, L.M. Sly, G. Krystal, A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation, Cancer Res, 71 (2011) 4484-4493. [92] S.K. Mazmanian, J.L. Round, D.L. Kasper, A microbial symbiosis factor prevents intestinal inflammatory disease, Nature, 453 (2008) 620-625. [93] E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, V.K. Kuchroo, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature, 441 (2006) 235-238.
21
ACCEPTED MANUSCRIPT [94] E. Bettelli, T. Korn, V.K. Kuchroo, Th17: the third member of the effector T cell trilogy, Curr Opin Immunol, 19 (2007) 652-657. [95] C. Di Giacinto, M. Marinaro, M. Sanchez, W. Strober, M. Boirivant, Probiotics
PT
ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells, J Immunol, 174 (2005) 3237-3246.
RI
[96] J.A. Pena, A.B. Rogers, Z. Ge, V. Ng, S.Y. Li, J.G. Fox, J. Versalovic, Probiotic
SC
Lactobacillus spp. diminish Helicobacter hepaticus-induced inflammatory bowel disease in interleukin-10-deficient mice, Infection and immunity, 73 (2005) 912-920.
NU
[97] L.E. Niers, H.M. Timmerman, G.T. Rijkers, G.M. van Bleek, N.O. van Uden, E.F. Knol, M.L. Kapsenberg, J.L. Kimpen, M.O. Hoekstra, Identification of strong
MA
interleukin-10 inducing lactic acid bacteria which down-regulate T helper type 2 cytokines, Clin Exp Allergy, 35 (2005) 1481-1489. [98] T. Poutahidis, M. Kleinewietfeld, C. Smillie, T. Levkovich, A. Perrotta, S. Bhela,
D
B.J. Varian, Y.M. Ibrahim, J.R. Lakritz, S.M. Kearney, A. Chatzigiagkos, D.A. Hafler,
TE
E.J. Alm, S.E. Erdman, Microbial reprogramming inhibits Western diet-associated obesity, PLoS One, 8 (2013) e68596.
AC CE P
[99] T. Poutahidis, B.J. Varian, T. Levkovich, J.R. Lakritz, S. Mirabal, C. Kwok, Y.M. Ibrahim, S.M. Kearney, A. Chatzigiagkos, E.J. Alm, S.E. Erdman, Dietary microbes modulate transgenerational cancer risk, Cancer Res, 75 (2015) 1197-1204. [100] S.J. Kallus, L.J. Brandt, The intestinal microbiota and obesity, J Clin Gastroenterol, 46 (2012) 16-24.
[101] D.P. Robinson, S.L. Klein, Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis, Horm Behav, 62 (2012) 263-271. [102] J. Mjosberg, J. Svensson, E. Johansson, L. Hellstrom, R. Casas, M.C. Jenmalm, R. Boij, L. Matthiesen, J.I. Jonsson, G. Berg, J. Ernerudh, Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol, J Immunol, 183 (2009) 759769. [103] N.P. Singh, U.P. Singh, P.S. Nagarkatti, M. Nagarkatti, Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression
22
ACCEPTED MANUSCRIPT through estrogen receptor element and nuclear factor-kappaB motifs, J Pharmacol Exp Ther, 343 (2012) 351-361. [104] H. Yan, M. Takamoto, K. Sugane, Exposure to Bisphenol A prenatally or in
PT
adulthood promotes T(H)2 cytokine production associated with reduction of CD4CD25 regulatory T cells, Environ Health Perspect, 116 (2008) 514-519.
RI
[105] A.M. Soto, C. Brisken, C. Schaeberle, C. Sonnenschein, Does cancer start in the
SC
womb? altered mammary gland development and predisposition to breast cancer due to in utero exposure to endocrine disruptors, Journal of mammary gland biology and neoplasia,
AC CE P
TE
D
MA
NU
18 (2013) 199-208.
23
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
Graphical abstract
24
Fig. 1
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
25
