Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas

Open access


Objectives. Previously we have shown that 20 days after the tumor cells injection smaller melanomas have been developed in chemically sympathectomized mice in comparison with animals having intact sympathetic nervous system. However, it is known that chemical sympathectomy reduces the sympathetic neurotransmission only temporarily. In the present study, we monitored the survival of the sympathectomized mice with melanoma with an attempt to find out how long the suppressing effect of sympathectomy on the melanoma growth may endure.

Methods. The chemical sympathectomy was performed by intraperitoneal injection of neurotoxin 6-hydroxydopamine in male C57BL/6J mice. Seven days later, the animals were injected subcutaneously with B16-F10 melanoma cells. Then, melanoma development, survival of the tumor-bearing mice and weight of the developed tumor mass were analyzed.

Results. Sympathectomy delayed the development of the palpable tumors (18th day vs.14th day) and significantly prolonged the survival of the tumor-bearing mice (median 34 days vs. 29 days). However, the weight of the developed melanoma was significantly increased in the sympathectomized mice in comparison with the animals having intact sympathetic nervous system.

Conclusions. The data of the present study showed that effect of the chemical sympathectomy, performed before the tumor growth induction, persisted even at the time when sympathetic nerves started to regenerate that resulted in a prolonged survival of the mice with melanoma. However, comparing to our previous study, in which we have shown a reduced tumor mass in earlier stages of the tumor growth, specifically 20 days after melanoma cells injection, now we indicate that in later stages of the melanoma progression, the tumor mass was significantly increased in sympathectomized animals. These contra-intuitive findings may indicate that interventions affecting the sympathetic nervous system may exert complex effect on the tumor progression. Based on these data we may suggest that the potential therapeutic interventions affecting the sympathetic signaling in the tumor tissue and its microenvironment should attenuate the sympathetic neurotransmission not only temporarily but till the complete regression of the tumor tissue.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Andersen BL Farrar WB Golden-Kreutz D Emery CF Glaser R Crespin T Carson WE 3rd. Distress reduction from a psychological intervention contributes to improved health for cancer patients. Brain Behav Immun 21 953–961 2007.

  • Barron TI Connolly RM Sharp L Bennett K Visvanathan K. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 29 2635–2644 2011.

  • Basu S Sarkar C Chakroborty D Nagy J Mitra RB Dasgupta PS Mukhopadhyay D. Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis. Cancer Res 64 5551–5555 2004.

  • Brenner GJ Felten SY Felten DL Moynihan JA. Sympathetic nervous system modulation of tumor metastases and host defense mechanisms. J Neuroimmunol 37 191–201 1992.

  • Cole SW Sood AK. Molecular pathways: beta-adrenergic signaling in cancer. Clin Cancer Res 18 1201–1206 2012.

  • Giese-Davis J Collie K Rancourt KM Neri E Kraemer HC Spiegel D. Decrease in depression symptoms is associated with longer survival in patients with metastatic breast cancer: a secondary analysis. J Clin Oncol 29 413–420 2011.

  • Glasner A Avraham R Rosenne E Benish M Zmora O Shemer S Meiboom H Ben-Eliyahu S. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184 2449–2457 2010.

  • Godbout JP Glaser R. Stress-induced immune dysregulation: implications for wound healing infectious disease and cancer. J Neuroimmune Pharmacol 1 421–427 2006.

  • Grzanna R Frondoza CG Otten U. Sympathectomy inhibits growth of a murine plasmacytoma tumor. J Auton Nerv Syst 13 149–160 1985.

  • Hassan S Karpova Y Baiz D Yancey D Pullikuth A Flores A Register T Cline JM D’Agostino R Jr. Danial N Datta SR Kulik G. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest 123 874–886 2013.

  • Holohan C Van Schaeybroeck S Longley DB Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 13 714–726 2013.

  • Horvathova L Padova A Tillinger A Osacka J Bizik J Mravec B. Sympathectomy reduces tumor weight and affects expression of tumor-related genes in melanoma tissue in the mouse. Stress 19 528–534 2016.

  • Kruszewska B Felten SY Moynihan JA. Alterations in cytokine and antibody production following chemical sympathectomy in two strains of mice. J Immunol 155 4613–4620 1995.

  • Lackovicova L Banovska L Bundzikova J Janega P Bizik J Kiss A Mravec B. Chemical sympathectomy suppresses fibrosarcoma development and improves survival of tumor-bearing rats. Neoplasma 58 424–429 2011.

  • Magnon C Hall SJ Lin J Xue X Gerber L Freedland SJ Frenette PS. Autonomic nerve development contributes to prostate cancer progression. Science 341 1236361 2013.

  • Nagaraja AS Armaiz-Pena GN Lutgendorf SK Sood AK. Why stress is BAD for cancer patients. J Clin Invest 123 558–560 2013.

  • 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.

  • Powe DG Entschladen F. Targeted therapies: Using beta-blockers to inhibit breast cancer progression. Nat Rev Clin Oncol 8 511–512 2011.

  • Raju B Haug SR Ibrahim SO Heyeraas KJ. Sympathectomy decreases size and invasiveness of tongue cancer in rats. Neuroscience 149 715–725 2007.

  • Raju B Hultstrom M Haug SR Ibrahim SO Heyeraas KJ. Sympathectomy suppresses tumor growth and alters geneexpression profiles in rat tongue cancer. Eur J Oral Sci 117 351–361 2009.

  • Romeo HE Colombo LL Esquifino AI Rosenstein RE Chuluyan HE Cardinali DP. Slower growth of tumours in sympathetically denervated murine skin. J Auton Nerv Syst 32 159–164 1991.

  • Sephton SE Dhabhar FS Keuroghlian AS Giese-Davis J McEwen BS Ionan AC Spiegel D. Depression cortisol and suppressed cell-mediated immunity in metastatic breast cancer. Brain Behav Immun 23 1148–1155 2009.

  • Schuller HM. Beta-adrenergic signaling a novel target for cancer therapy? Oncotarget 1 466–469 201

  • Sloan EK Priceman SJ Cox BF Yu S Pimentel MA Tangkanangnukul V Arevalo JM Morizono K Karanikolas BD Wu L Sood AK Cole SW. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70 7042–7052 2010.

  • Sood AK Bhatty R Kamat AA Landen CN Han L Thaker PH Li Y Gershenson DM Lutgendorf S Cole SW. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res 12 369–375 2006.

  • Tang J Li Z Lu L Cho CH: beta-Adrenergic system a backstage manipulator regulating tumour progression and drug target in cancer therapy. Semin Cancer Biol 23 533–542 2013.

  • Tatsuta M Iishi H Baba M Taniguchi H. Inhibitions by 6-hydroxydopamine and neostigmine singly or together of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats. Int J Cancer 51 767–771 1992.

  • Thaker PH Han LY Kamat AA Arevalo JM Takahashi R Lu C Jennings NB Armaiz-Pena G Bankson JA Ravoori M Merritt WM Lin YG Mangala LS Kim TJ Coleman RL Landen CN Li Y Felix E Sanguino AM Newman RA Lloyd M Gershenson DM Kundra V Lopez-Berestein G Lutgendorf SK Cole SW Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12 939–944 2006.

  • Tilan J Kitlinska J. Sympathetic Neurotransmitters and Tumor Angiogenesis-Link between Stress and Cancer Progression. J Oncol 2010 539706 2010.

  • Yang EV. Role for catecholamines in tumor progression: possible use for beta-blockers in the treatment of cancer. Cancer Biol Ther 10 30–32 2010.

Journal information
Impact Factor

CiteScore 2018: 1.27

SCImago Journal Rank (SJR) 2018: 0.411
Source Normalized Impact per Paper (SNIP) 2018: 0.441

Cited By
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 350 137 12
PDF Downloads 185 88 12