Sympathetic nervous system regulation of the tumour microenvironment

Nature Reviews Cancer

Volumn 15, Issue 9, 2015, Pages 563-572

  Cole, Steven W ^a   Nagaraja, Archana S ^b   Lutgendorf, Susan K ^c,d   Green, Paige A ^e   Sood, Anil K ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c M D Anderson Comprehensive Cancer Center ^*  (United States)

^d UNIVERSITY OF IOWA HOSPITALS AND CLINICS   (United States)

^e NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADRENERGIC SYSTEM; ANGIOGENESIS; APOPTOSIS; CANCER GROWTH; CELL SURVIVAL; CELLULAR IMMUNITY; CIRCADIAN RHYTHM; DNA REPAIR; EPITHELIAL MESENCHYMAL TRANSITION; GENE ACTIVATION; GENE EXPRESSION; HEMATOPOIESIS; HUMAN; IMMUNE RESPONSE; IN VIVO STUDY; INFLAMMATION; INNERVATION; ONCOGENE; PHYSIOLOGICAL STRESS; PRIORITY JOURNAL; REVIEW; SOLID TUMOR; TUMOR INVASION; TUMOR MICROENVIRONMENT; CELL DIFFERENTIATION; GENE EXPRESSION REGULATION; GENETICS; NEOPLASMS; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY;

CELL DIFFERENTIATION; EPITHELIAL-MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; SYMPATHETIC NERVOUS SYSTEM; TUMOR MICROENVIRONMENT;

EID: 84940028564     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3978     Document Type: Review

References (125)

1. Weiner H. Perturbing the Organism: The Biology of Stressful Experience (Univ. of Chicago Press, 1992
2. Sapolsky R. M. Why Zebras Dont Get Ulcers: A Guide To Stress, Stress-Related Diseases, And Coping (Freeman, 1994
3. Sherwood L. Human Physiology: From Cells to Systems (Cengage Learning, 2015
4. Katayama Y., et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407-421 (2006
5. Sloan E. K., et al. Social stress enhances sympathetic innervation of primate lymph nodes: mechanisms and implications for viral pathogenesis. J. Neurosci. 27, 8857-8865 (2007
6. Lutgendorf S. K., et al. Depression, social support, and β-adrenergic transcription control in human ovarian cancer. Brain Behav. Immun. 23, 176-183 (2009
7. Powell N. D., et al. Social stress up regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc. Natl Acad. Sci. USA 110, 16574-16579 (2013
8. Scheiermann C., Kunisaki Y., & Frenette P. S. Circadian control of the immune system. Nat. Rev. Immunol. 13, 190-198 (2013
9. Cole S. W. Social regulation of human gene expression: mechanisms and implications for public health. Am. J. Publ. Health 103 (Suppl. 1), S84-S92 (2013
10. Cole S. W. Human social genomics. PLoS Genet. 10, e1004601 (2014
11. Hanoun M., Maryanovich M., Arnal-Estape A., & Frenette P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360-373 (2015
12. Irwin M. R., & Cole S. W. Reciprocal regulation of the neural and innate immune systems. Nat. Rev. Immunol. 11, 625-632 (2011
13. Antoni M. H., et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat. Rev. Cancer. 6, 240-248 (2006
14. Cole S. W., & Sood A. K. Molecular pathways: β-adrenergic signaling in cancer. Clin. Cancer Res. 18, 1201-1206 (2012
15. Armaiz-Pena G. N., Cole S. W., Lutgendorf S. K., & Sood A. K. Neuroendocrine influences on cancer progression. Brain Behav. Immun. 30, S19-S25 (2013
16. Cole S. W. Nervous system regulation of the cancer genome. Brain Behav. Immun. 30 (Suppl.), S10-S18 (2013
17. Powe D. G., & Entschladen F. Targeted therapies: using β-blockers to inhibit breast cancer progression. Nat. Rev. Clin. Oncol. 8, 511-512 (2011
18. Richter S. D., et al. Time kinetics of the endocrine response to acute psychological stress. J. Clin. Endocrinol. Metab. 81, 1956-1960 (1996
19. Schommer N. C., Hellhammer D. H., & Kirschbaum C. Dissociation between reactivity of the hypothalamus-pituitary-adrenal axis and the sympathetic-adrenal-medullary system to repeated psychosocial stress. Psychosom. Med. 65, 450-460 (2003
20. Wingenfeld K., Whooley M. A., Neylan T. C., Otte C., & Cohen B. E. Effect of current and lifetime posttraumatic stress disorder on 24 h urinary catecholamines and cortisol: results from the Mind Your Heart Study. Psychoneuroendocrinology 52, 83-91 (2015
21. Sloan E. K., Capitanio J. P., Tarara R. P., & Cole S. W. Social temperament and lymph node innervation. Brain Behav. Immun. 22, 717-726 (2008
22. Schofl C., Becker C., Prank K., von zur Muhlen A., & Brabant G. Twenty-four-hour rhythms of plasma catecholamines and their relation to cardiovascular parameters in healthy young men. Eur. J. Endocrinol. 137, 675-683 (1997
23. Dimitrov S., et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 113, 5134-5143 (2009
24. Eng J. W., et al. Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2 adrenergic receptor activation. Nat. Commun. 6, 6426 (2015
25. Mendez-Ferrer S., Lucas D., Battista M., & Frenette P. S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452, 442-447 (2008
26. Dutta P., et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325-329 (2012
27. Heidt T., et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754-758 (2014
28. Nakai A., Hayano Y., Furuta F., Noda M., & Suzuki K. Control of lymphocyte egress from lymph nodes through β2 adrenergic receptors. J. Exp. Med. 211, 2583-2598 (2014
29. Sloan E. K., Capitanio J. P., & Cole S. W. Stress-induced remodeling of lymphoid innervation. Brain Behav. Immun. 22, 15-21 (2008
30. Elenkov I. J., Wilder R. L., Chrousos G. P., & Vizi E. S. The sympathetic nerve - an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595-638 (2000
31. Kohm A. P., & Sanders V. M. Norepinephrine and β 2 adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol. Rev. 53, 487-525 (2001
32. Cole S., et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc. Natl Acad. Sci. USA 107, 5681-5686 (2010
33. Hori Y., et al. Naftopidil, a selective α1 adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma. Cancer Prev. Res. 4, 87-96 (2011
34. Calvani M., et al. Norepinephrine promotes tumor microenvironment reactivity through β3 adrenoreceptors during melanoma progression. Oncotarget 6, 4615-4632 (2015
35. Thaker P. H., et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939-944 (2006
36. Dal Monte M., et al. Functional involvement of β3 adrenergic receptors in melanoma growth and vascularization. J. Mol. Med. 91, 1407-1419 (2013
37. Sterling P. in Allostasis, Homeostasis, and the Costs of Physiological Adaptation (ed. Schulkin J.) 17-64 (Cambridge Univ. Press, 2004
38. Chida Y., Hamer M., Wardle J., & Steptoe A. Do stress-related psychosocial factors contribute to cancer incidence and survival?. Nat. Clin. Pract. Oncol. 5, 466-475 (2008
39. Powe D. G., et al. β-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628-638 (2010
40. Barron T. I., Connolly R. M., Sharp L., Bennett K., & Visvanathan K. β blockers and breast cancer mortality: a population-based study. J. Clin. Oncol. 29, 2635-2644 (2011
41. Melhem-Bertrandt A., et al. β-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 2645-2652 (2011
42. De Giorgi V., et al. Treatment with β-blockers and reduced disease progression in patients with thick melanoma. Arch. Intern. Med. 171, 779-781 (2011
43. Lemeshow S., et al. β-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol. Biomarkers Prev. 20, 2273-2279 (2011
44. Aydiner A., Ciftci R., Karabulut S., & Kilic L. Does β-blocker therapy improve the survival of patients with metastatic non-small cell lung cancer?. Asian Pac. J. Cancer Prev. 14, 6109-6114 (2013
45. Botteri E., et al. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res. Treat. 140, 567-575 (2013
46. De Giorgi V., et al. Effect of β-blockers and other antihypertensive drugs on the risk of melanoma recurrence and death. Mayo Clin. Proc. 88, 1196-1203 (2013
47. Grytli H. H., Fagerland M. W., Fossa S. D., Tasken K. A., & Haheim L. L. Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy. Prostate 73, 250-260 (2013
48. Grytli H. H., Fagerland M. W., Fossa S. D., & Tasken K. A. Association between use of β-blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur. Urol. 65, 635-641 (2014
49. Sloan E. K., et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042-7052 (2010
50. Madden K. S., Szpunar M. J., & Brown E. B. β-adrenergic receptors (β AR) regulate VEGF and IL 6 production by divergent pathways in high β AR expressing breast cancer cell lines. Breast Cancer Res. Treat. 130, 747-758 (2011
51. Palm D., et al. The norepinephrine-driven metastasis development of PC 3 human prostate cancer cells in BALB/c nude mice is inhibited by β-blockers. Int. J. Cancer. 118, 2744-2749 (2006
52. Hassan S., et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Invest. 123, 874-886 (2013
53. Pasquier E., et al. β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma. Br. J. Cancer 108, 2485-2494 (2013
54. Wolter J. K., et al. Anti-tumor activity of the β-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 5, 161-172 (2014
55. Hasegawa H., & Saiki I. Psychosocial stress augments tumor development through β-adrenergic activation in mice. Jpn J. Cancer Res. 93, 729-735 (2002
56. Goldfarb Y., et al. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann. Surg. 253, 798-810 (2011
57. Kim-Fuchs C., et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for β-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40-47 (2014
58. Lamkin D. M., et al. Chronic stress enhances progression of acute lymphoblastic leukemia via β-adrenergic signaling. Brain Behav. Immun. 26, 635-641 (2012
59. Inbar S., et al. Do stress responses promote leukemia progression?. An animal study suggesting a role for epinephrine and prostaglandin E2 through reduced NK activity. PLoS ONE 6, e19246 (2011
60. Hara M. R., et al. A stress response pathway regulates DNA damage through β2 adrenoreceptors and β-arrestin 1. Nature 477, 349-353 (2011
61. Hara M. R., Sachs B. D., Caron M. G., & Lefkowitz R. J. Pharmacological blockade of a β2AR β-arrestin 1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model. Cell Cycle 12, 219-224 (2013
62. Reeder A., et al. Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage. Br. J. Cancer 112, 1461-1470 (2015
63. Armaiz-Pena G. N., et al. Src activation by β-adrenoreceptors is a key switch for tumour metastasis. Nat. Commun. 4, 1403 (2013
64. Shi M., et al. The β2 adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res. Treat. 125, 351-362 (2011
65. Gu L., Lau S. K., Loera S., Somlo G., & Kane S. E. Protein kinase A activation confers resistance to trastuzumab in human breast cancer cell lines. Clin. Cancer Res. 15, 7196-7206 (2009
66. Chang M., et al. β-adrenoreceptors reactivate Kaposis sarcoma-associated herpesvirus lytic replication via PKA-dependent control of viral RTA. J. Virol. 79, 13538-13547 (2005
67. zur Hausen H. Infections Causing Human Cancer, (Wiley-VCH, 2008
68. Nilsson M. B., et al. Stress hormones regulate interleukin 6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J. Biol. Chem. 282, 29919-29926 (2007
69. Shahzad M. M., et al. Stress effects on FosB-and interleukin 8 (IL8)-driven ovarian cancer growth and metastasis. J. Biol. Chem. 285, 35462-35470 (2010
70. Yang R., Lin Q., Gao H. B., & Zhang P. Stress-related hormone norepinephrine induces interleukin 6 expression in GES 1 cells. Braz. J. Med. Biol. Res. 47, 101-109 (2014
71. Cakir Y., Plummer H. K., 3rd, Tithof P. K., & Schuller H. M. β-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int. J. Oncol. 21, 153-157 (2002
72. Armaiz-Pena G. N., et al. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. Oncotarget 6, 4266-4273 (2015
73. Collado-Hidalgo A., Sung C., & Cole S. Adrenergic inhibition of innate anti-viral response: PKA blockade of type I interferon gene transcription mediates catecholamine support for HIV 1 replication. Brain Behav. Immun. 20, 552-563 (2006
74. Cole S. W., Korin Y. D., Fahey J. L., & Zack J. A. Norepinephrine accelerates HIV replication via protein kinase A dependent effects on cytokine production. J. Immunol. 161, 610-616 (1998
75. Glasner A., et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase 2 inhibitor. J. Immunol. 184, 2449-2457 (2010
76. Lee J. W., et al. Surgical stress promotes tumor growth in ovarian carcinoma. Clin. Cancer Res. 15, 2695-2702 (2009
77. Magnon C., et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013
78. Bruzzone A., et al. α2 adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells. Curr. Cancer Drug Targets 11, 763-774 (2011
79. Flint M. S., et al. Chronic exposure to stress hormones promotes transformation and tumorigenicity of 3T3 mouse fibroblasts. Stress 16, 114-121 (2013
80. Cao L., et al. Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142, 52-64 (2010
81. Cao L., & During M. J. What is the brain-cancer connection?. Annu. Rev. Neurosci. 35, 331-345 (2012
82. Hanoun M., et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15, 365-375 (2014
83. Lang K., et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int. J. Cancer 112, 231-238 (2004
84. Drell T. L. t., et al. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA MB 468 human breast carcinoma cells. Breast Cancer Res. Treat. 80, 63-70 (2003
85. Landen C. N. Jr, et al. Neuroendocrine modulation of signal transducer and activator of transcription 3 in ovarian cancer. Cancer Res. 67, 10389-10396 (2007
86. Sood A. K., et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin. Cancer Res. 12, 369-375 (2006
87. Yang E. V., 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. 66, 10357-10364 (2006
88. Chakroborty D., Sarkar C., Basu B., Dasgupta P. S., & Basu S. Catecholamines regulate tumor angiogenesis. Cancer Res. 69, 3727-3730 (2009
89. Yang E. V., 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. 23, 267-275 (2009
90. Moretti S., et al. β-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Invest. 93, 279-290 (2013
91. Liu J., et al. The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models. Psychoneuroendocrinology 52, 130-142 (2015
92. Sood A. K., et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 120, 1515-1523 (2010
93. Sastry K. S., et al. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J. Biol. Chem. 282, 14094-14100 (2007
94. Deng G. H., et al. Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model. J. Exp. Clin. Cancer Res. 33, 21 (2014
95. Dar A., et al. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4 dependent SDF 1 release from bone marrow stromal cells. Leukemia 25, 1286-1296 (2011
96. Lucas D., et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19, 695-703 (2013
97. Lutgendorf S. K., et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav. Immun. 25, 250-255 (2011
98. Ayala G. E., et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593-7603 (2008
99. Voss M. J., & Entschladen F. Tumor interactions with soluble factors and the nervous system. Cell Commun. Signal 8, 21 (2010
100. Guo K., et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol. Cancer Ther. 12, 264-273 (2013
101. Xu Q., et al. Stromal-derived factor 1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. Oncotarget 6, 4717-4732 (2015
102. Flierl M. A., et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature. 449, 721-725 (2007
103. Campbell J. P., et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 10, e1001363 (2012
104. Lu H., et al. Impact of β-blockers on prostate cancer mortality: a meta-analysis of 16,825 patients. Onco Targets Ther. 8, 985-990 (2015
105. Wang H. M., et al. Improved survival outcomes with the incidental use of β-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann. Oncol. 24, 1312-1319 (2013
106. Diaz E. S., Karlan B. Y., & Li A. J. Impact of β blockers on epithelial ovarian cancer survival. Gynecol. Oncol. 127, 375-378 (2012
107. Watkins J. L., et al. Clinical impact of selective and non-selective β-blockers on survival in ovarian cancer patients. Cancer (in the press
108. Schuller H. M., Porter B., & Riechert A. β-adrenergic modulation of NNK-induced lung carcinogenesis in hamsters. J. Cancer Res. Clin. Oncol. 126, 624-630 (2000
109. Pasquier E., et al. Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment. Oncotarget 2, 797-809 (2011
110. Lin Q., et al. Effect of chronic restraint stress on human colorectal carcinoma growth in mice. PLoS ONE 8, e61435 (2013
111. Ganz P. A., & Cole S. W. Expanding our therapeutic options: β blockers for breast cancer?. J. Clin. Oncol. 29, 2612-2616 (2011
112. Neeman E., Zmora O., & Ben-Eliyahu S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin. Cancer Res. 18, 4895-4902 (2012
113. Horowitz M., Neeman E., Sharon E., & Ben-Eliyahu S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213-226 (2015
114. Boucek R. J. Jr., Kirsh A. L., Majesky M. W., & Perkins J. A. Propranolol responsiveness in vascular tumors is not determined by qualitative differences in adrenergic receptors. Otolaryngol. Head Neck Surg. 149, 772-776 (2013
115. Mendez-Ferrer S., Battista M., & Frenette P. S. Cooperation of β2-and β3 adrenergic receptors in hematopoietic progenitor cell mobilization. Ann. NY Acad. Sci. 1192, 139-144 (2010
116. Magnon C., Lucas D., & Frenette P. S. Trafficking of stem cells. Methods Mol. Biol. 750, 3-24 (2011
117. Szpunar M. J., Burke K. A., Dawes R. P., Brown E. B., & Madden K. S. The antidepressant desipramine and α2 adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev. Res. 6, 1262-1272 (2013
118. Lamkin D. M., et al. α2 adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology 51, 262-270 (2015
119. Friedman G. D., Udaltsova N., & Habel L. A. Norepinephrine antagonists and cancer risk. Int. J. Cancer 128, 737-738; author reply 739 (2011
120. Quail D. F., & Joyce J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423-1437 (2013
121. Shan T., et al. β2 adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction. Eur. J. Pharmacol. 665, 1-7 (2011
122. Obeid E. I., & Conzen S. D. The role of adrenergic signaling in breast cancer biology. Cancer Biomark. 13, 161-169 (2013
123. Zhao C. M., et al. Denervation suppresses gastric tumorigenesis. Sci. Transl Med. 6, 250ra115 (2014
124. Rosas-Ballina M., et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl Acad. Sci. USA 105, 11008-11013 (2008
125. Villanueva M. T. Therapeutics: gastric cancer gets a red carpet treatment. Nat. Rev. Cancer 14, 648-649 (2014