Skip to main content
Erschienen in: Tumor Biology 5/2016

23.11.2015 | Original Article

Prognostic significance of β2-adrenergic receptor expression in malignant melanoma

verfasst von: Akira Shimizu, Kyoichi Kaira, Keita Mori, Madoka Kato, Kimihiro Shimizu, Masahito Yasuda, Ayumi Takahashi, Tetsunari Oyama, Takayuki Asao, Osamu Ishikawa

Erschienen in: Tumor Biology | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

Recent studies cite β2-adrenergic receptor (β2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The β2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the β2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of β2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for β2AR, Ki-67, the microvessel density (MVD) determined by CD34, and p53. β2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of β2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman’s rank test, the β2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P < 0.001), and the tumor size (r = 0.226; 95 % CI, 0.053 to 0.386; P = 0.008). Using a univariate analysis, the tumor thickness, ulceration, disease stage, β2AR, Ki-67, and CD34 had a significant relationship with the overall and progression-free survivals. A multivariable analysis confirmed that β2AR was an independent prognostic factor for predicting a poor overall survival (HR 1.730; 95 % CI 1.221–2.515) and progression-free survival (HR 1.576; 95 % CI 1.176–2.143) of malignant melanoma of the skin. β2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma.
Literatur
2.
Zurück zum Zitat Marsden JR, Newton-Bishop JA, Burrows L, Cook M, Corrie PG, Cox NH, et al. Revised UK guidelines for the management of cutaneous melanoma 2010. J Plast Reconstr Aesthet Surg JPRAS. 2010;63:1401–19.CrossRefPubMed Marsden JR, Newton-Bishop JA, Burrows L, Cook M, Corrie PG, Cox NH, et al. Revised UK guidelines for the management of cutaneous melanoma 2010. J Plast Reconstr Aesthet Surg JPRAS. 2010;63:1401–19.CrossRefPubMed
3.
Zurück zum Zitat Smalley KS. Understanding melanoma signaling networks as the basis for molecular targeted therapy. J Invest Dermatol. 2010;130:28–37.CrossRefPubMed Smalley KS. Understanding melanoma signaling networks as the basis for molecular targeted therapy. J Invest Dermatol. 2010;130:28–37.CrossRefPubMed
4.
Zurück zum Zitat Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRefPubMed Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–54.CrossRefPubMed
5.
Zurück zum Zitat Wnorowski A, Jozwiak K. Homo- and hetero-oligomerization of β2-adrenergic receptor in receptor trafficking, signaling pathways and receptor pharmacology. Cell Signal. 2014;26:2259–65.CrossRefPubMed Wnorowski A, Jozwiak K. Homo- and hetero-oligomerization of β2-adrenergic receptor in receptor trafficking, signaling pathways and receptor pharmacology. Cell Signal. 2014;26:2259–65.CrossRefPubMed
6.
Zurück zum Zitat Aronow WS. Current role of beta-blockers in the treatment of hypertension. Expert Opin Pharmacother. 2010;11:2599–607.CrossRefPubMed Aronow WS. Current role of beta-blockers in the treatment of hypertension. Expert Opin Pharmacother. 2010;11:2599–607.CrossRefPubMed
7.
Zurück zum Zitat Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163:269–74.CrossRefPubMed Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163:269–74.CrossRefPubMed
8.
Zurück zum Zitat Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 2001;61:2866–9.PubMed Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 2001;61:2866–9.PubMed
9.
Zurück zum Zitat Palm D, Lang K, Niggemann B, Drell 4th TL, Masur K, Zaenker KS, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer J Int Cancer. 2006;118:2744–9.CrossRef Palm D, Lang K, Niggemann B, Drell 4th TL, Masur K, Zaenker KS, et al. The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer J Int Cancer. 2006;118:2744–9.CrossRef
10.
Zurück zum Zitat Shang ZJ, Liu K, de Liang F. Expression of beta2-adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol Med: Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol. 2009;38:371–6.CrossRef Shang ZJ, Liu K, de Liang F. Expression of beta2-adrenergic receptor in oral squamous cell carcinoma. J Oral Pathol Med: Off Publ Int Assoc Oral Pathol Am Acad Oral Pathol. 2009;38:371–6.CrossRef
11.
Zurück zum Zitat Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:369–75.CrossRef Sood AK, Bhatty R, Kamat AA, Landen CN, Han L, Thaker PH, et al. Stress hormone-mediated invasion of ovarian cancer cells. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:369–75.CrossRef
12.
Zurück zum Zitat Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23:267–75.CrossRefPubMed Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23:267–75.CrossRefPubMed
13.
Zurück zum Zitat Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2645–52.CrossRef Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2645–52.CrossRef
14.
Zurück zum Zitat Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2635–44.CrossRef Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol: Off J Am Soc Clin Oncol. 2011;29:2635–44.CrossRef
15.
Zurück zum Zitat De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, et al. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011;171:779–81.PubMed De Giorgi V, Grazzini M, Gandini S, Benemei S, Lotti T, Marchionni N, et al. Treatment with beta-blockers and reduced disease progression in patients with thick melanoma. Arch Intern Med. 2011;171:779–81.PubMed
16.
Zurück zum Zitat Lemeshow S, Sørensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, et al. Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomark Prev: Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2011;20:2273–9.CrossRef Lemeshow S, Sørensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, et al. Beta-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomark Prev: Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2011;20:2273–9.CrossRef
17.
Zurück zum Zitat Moretti S, Massi D, Farini V, Baroni G, Parri M, Innocenti S, et al. Beta-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Investig: J Tech Methods Pathol. 2013;93:279–90.CrossRef Moretti S, Massi D, Farini V, Baroni G, Parri M, Innocenti S, et al. Beta-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab Investig: J Tech Methods Pathol. 2013;93:279–90.CrossRef
18.
Zurück zum Zitat Shimizu A, Kaira K, Kato M, Yasuda M, Takahashi A, Tominaga H, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma. Melanoma Res 2015; in press. Shimizu A, Kaira K, Kato M, Yasuda M, Takahashi A, Tominaga H, et al. Prognostic significance of L-type amino acid transporter 1 (LAT1) expression in cutaneous melanoma. Melanoma Res 2015; in press.
19.
Zurück zum Zitat Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, et al. Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28:3746–53.CrossRef Kaira K, Endo M, Abe M, Nakagawa K, Ohde Y, Okumura T, et al. Biologic correlation of 2-[18F]-fluoro-2-deoxy-D-glucose uptake on positron emission tomography in thymic epithelial tumors. J Clin Oncol: Off J Am Soc Clin Oncol. 2010;28:3746–53.CrossRef
20.
Zurück zum Zitat Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. CD98 expression is associated with poor prognosis in resected non-small-cell lung cancer with lymph node metastases. Ann Surg Oncol. 2009;16:3473–81.CrossRefPubMed Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, et al. CD98 expression is associated with poor prognosis in resected non-small-cell lung cancer with lymph node metastases. Ann Surg Oncol. 2009;16:3473–81.CrossRefPubMed
21.
Zurück zum Zitat Livingstone E, Hollestein LM, van Herk-Sukel MP, van de Poll-Franse L, Nijsten T, Schadendorf D, et al. beta-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study. Eur J Cancer. 2013;49:3863–71.CrossRefPubMed Livingstone E, Hollestein LM, van Herk-Sukel MP, van de Poll-Franse L, Nijsten T, Schadendorf D, et al. beta-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study. Eur J Cancer. 2013;49:3863–71.CrossRefPubMed
22.
Zurück zum Zitat McCourt C, Coleman HG, Murray LJ, Cantwell MM, Dolan O, Powe DG, et al. Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study. Br J Dermatol. 2014;170:930–8.CrossRefPubMed McCourt C, Coleman HG, Murray LJ, Cantwell MM, Dolan O, Powe DG, et al. Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study. Br J Dermatol. 2014;170:930–8.CrossRefPubMed
23.
Zurück zum Zitat Bravo-Calderon DM, Oliveira DT, Marana AN, Nonogaki S, Carvalho AL, Kowalski LP. Prognostic significance of beta-2 adrenergic receptor in oral squamous cell carcinoma. Cancer Biomark: Sect A Dis Mark. 2011;10:51–9.CrossRef Bravo-Calderon DM, Oliveira DT, Marana AN, Nonogaki S, Carvalho AL, Kowalski LP. Prognostic significance of beta-2 adrenergic receptor in oral squamous cell carcinoma. Cancer Biomark: Sect A Dis Mark. 2011;10:51–9.CrossRef
24.
Zurück zum Zitat Chen D, Xing W, Hong J, Wang M, Huang Y, Zhu C, et al. The beta2-adrenergic receptor is a potential prognostic biomarker for human hepatocellular carcinoma after curative resection. Ann Surg Oncol. 2012;19:3556–65.CrossRefPubMed Chen D, Xing W, Hong J, Wang M, Huang Y, Zhu C, et al. The beta2-adrenergic receptor is a potential prognostic biomarker for human hepatocellular carcinoma after curative resection. Ann Surg Oncol. 2012;19:3556–65.CrossRefPubMed
25.
Zurück zum Zitat Wenjuan Y, Yujun L, Ceng Y. Association of single nucleotide polymorphisms of beta2-adrenergic receptor gene with clinicopathological features of pancreatic carcinoma. Acta Histochem. 2013;115:198–203.CrossRefPubMed Wenjuan Y, Yujun L, Ceng Y. Association of single nucleotide polymorphisms of beta2-adrenergic receptor gene with clinicopathological features of pancreatic carcinoma. Acta Histochem. 2013;115:198–203.CrossRefPubMed
26.
Zurück zum Zitat Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010;70:7042–52.CrossRefPubMedPubMedCentral Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010;70:7042–52.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Lang K, Drell 4th TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer J Int Cancer. 2004;112:231–8.CrossRef Lang K, Drell 4th TL, Lindecke A, Niggemann B, Kaltschmidt C, Zaenker KS, et al. Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer J Int Cancer. 2004;112:231–8.CrossRef
28.
Zurück zum Zitat Liu X, Wu WK, Yu L, Li ZJ, Sung JJ, Zhang ST, et al. Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of beta-adrenoceptors. J Pharmacol Exp Ther. 2008;326:69–75.CrossRefPubMed Liu X, Wu WK, Yu L, Li ZJ, Sung JJ, Zhang ST, et al. Epidermal growth factor-induced esophageal cancer cell proliferation requires transactivation of beta-adrenoceptors. J Pharmacol Exp Ther. 2008;326:69–75.CrossRefPubMed
29.
Zurück zum Zitat Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci. 2006;119:592–602.CrossRefPubMed Pullar CE, Isseroff RR. The beta 2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms. J Cell Sci. 2006;119:592–602.CrossRefPubMed
30.
Zurück zum Zitat Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y, et al. The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 2010;23:151–7.PubMed Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y, et al. The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 2010;23:151–7.PubMed
31.
Zurück zum Zitat Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.CrossRefPubMed Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol. 2002;12:258–66.CrossRefPubMed
32.
Zurück zum Zitat Wrobel LJ, Le Gal FA. Inhibition of human melanoma growth by a non-cardioselective beta-blocker. J Investig Dermatol. 2015;135:525–31.CrossRefPubMed Wrobel LJ, Le Gal FA. Inhibition of human melanoma growth by a non-cardioselective beta-blocker. J Investig Dermatol. 2015;135:525–31.CrossRefPubMed
Metadaten
Titel
Prognostic significance of β2-adrenergic receptor expression in malignant melanoma
verfasst von
Akira Shimizu
Kyoichi Kaira
Keita Mori
Madoka Kato
Kimihiro Shimizu
Masahito Yasuda
Ayumi Takahashi
Tetsunari Oyama
Takayuki Asao
Osamu Ishikawa
Publikationsdatum
23.11.2015
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 5/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4420-0

Weitere Artikel der Ausgabe 5/2016

Tumor Biology 5/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.