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Surgery Today
Published in: Surgery Today 11/2017

01-11-2017 | Original Article

Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma

Authors: Yuta Kawakita, Satoru Motoyama, Yusuke Sato, Souichi Koyota, Akiyuki Wakita, Jiajia Liu, Hajime Saito, Yoshihiro Minamiya

Published in: Surgery Today | Issue 11/2017

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Abstract

Purpose

To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma.

Methods

Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model.

Results

Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group.

Conclusions

S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.
Literature
1.
2.
3.
Motoyama S, Ishiyama K, Maruyama K, Okuyama M, Sato Y, Hayashi K, et al. Preoperative mapping of lymphatic drainage from the tumor using ferumoxide-enhanced magnetic resonance imaging in clinical submucosal thoracic squamous cell esophageal cancer. Surgery. 2007;141:736–47.CrossRefPubMed
4.
Murakami G, Abe M, Abe T. Last-intercalated node and direct lymphatic drainage into the thoracic duct from the thoracoabdominal viscera. Jpn J Thorac Cardiovasc Surg. 2002;50:93–103.CrossRefPubMed
5.
Matsubara T, Ueda M, Kaisaki S, Kuroda J, Uchida C, Kokudo N, et al. Location of initial lymph node metastasis from carcinoma of the thoracic esophagus. Cancer. 2000;89:1869–73.CrossRefPubMed
6.
Matsubara T, Ueda M, Abe T, Akimori T, Kokudo N, Takahashi T. Unique distribution patterns of metastatic lymph nodes in patients with superficial carcinoma of the thoracic oesophagus. Br J Surg. 1999;86:669–73.CrossRefPubMed
7.
Katayama H, Kurokawa Y, Nakamura K, Ito H, Kanemitsu Y, Masuda N, et al. Extended Clavien-Dindo classification of surgical complications: Japan Clinical Oncology Group postoperative complications criteria. Surg Today. 2016;46:668–85.CrossRefPubMed
8.
Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Nakamura Y, et al. Expression of BRCA1, a factor closely associated with relapse-free survival, in patients who underwent neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil for squamous cell carcinoma of the esophagus. Surg Today. 2017;47:65–73.CrossRefPubMed
9.
10.
Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010;140:460–76.CrossRefPubMed
11.
Takabe K, Paugh SW, Milstien S, Spiegel S. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60:181–95.CrossRefPubMedPubMedCentral
12.
13.
14.
Gault CR, Obeid LM. Still benched on its way to the bedside: sphingosine kinase 1 as an emerging target in cancer chemotherapy. Crit Rev Biochem Mol Biol. 2011;46:342–51.CrossRefPubMedPubMedCentral
15.
Nagahashi M, Matsuda Y, Moro K, Tsuchida J, Soma D, Hirose Y, et al. DNA damage response and sphingolipid signaling in liver diseases. Surg Today. 2016;46:995–1005.CrossRefPubMed
16.
Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, et al. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012;72:726–35.CrossRefPubMedPubMedCentral
17.
Zhang L, Wang X, Bullock AJ, Callea M, Shah H, Song J, et al. Anti-S1P antibody as a novel therapeutic strategy for VEGFR TKI-resistant renal cancer. Clin Cancer Res. 2015;21:1925–34.CrossRefPubMedPubMedCentral
18.
Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC Jr, LaPolla JP, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2004;13:1185–91.PubMed
19.
Sato Y, Motoyama S, Nanjo H, Ito S, Yoshino K, Sasaki T, et al. REG1A expression status suggests chemosensitivity among advanced thoracic esophageal squamous cell carcinoma patients treated with esophagectomy followed by adjuvant chemotherapy. Ann Surg Oncol. 2013;20:3044–51.CrossRefPubMed
20.
Matsumoto G, Yajima N, Saito H, Nakagami H, Omi Y, Lee U, et al. Cold shock domain protein A (CSDA) overexpression inhibits tumor growth and lymph node metastasis in a mouse model of squamous cell carcinoma. Clin Exp Metastasis. 2010;27:539–47.CrossRefPubMed
21.
Sasaki T, Motoyama S, Sato Y, Yoshino K, Matsumoto G, Minamiya Y, et al. C-reactive protein inhibits lymphangiogenesis and resultant lymph node metastasis of squamous cell carcinoma in mice. Surgery. 2013;154:1087–92.CrossRefPubMed
22.
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 2001;20:672–82.CrossRefPubMedPubMedCentral
23.
Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7:192–8.CrossRefPubMed
24.
Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001;7:186–91.CrossRefPubMed
25.
Holopainen T, Saharinen P, D’Amico G, Lampinen A, Eklund L, Sormunen R, et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J Natl Cancer Inst. 2012;104:461–75.CrossRefPubMedPubMedCentral
26.
Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood. 2005;105:4649–56.CrossRefPubMed
27.
Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45.CrossRefPubMed
28.
Björndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, et al. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci U S A. 2005;102:15593–8.CrossRefPubMedPubMedCentral
29.
Cao R, Björndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, et al. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood. 2006;107:3531–6.CrossRefPubMed
30.
Yoon CM, Hong BS, Moon HG, Lim S, Suh PG, Kim YK, et al. Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood. 2008;112:1129–38.CrossRefPubMedPubMedCentral
31.
Anelli V, Gault CR, Snider AJ, Obeid LM. Role of sphingosine kinase-1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro. FASEB J. 2010;24:2727–38.CrossRefPubMedPubMedCentral
32.
Ponnusamy S, Selvam SP, Mehrotra S, Kawamori T, Snider AJ, Obeid LM, et al. Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1/sphingosine 1-phosphate signalling to regulate tumour metastasis. EMBO Mol Med. 2012;4:761–75.CrossRefPubMedPubMedCentral
33.
Kawamori T, Kaneshiro T, Okumura M, Maalouf S, Uflacker A, Bielawski J, et al. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 2009;23:405–14.CrossRefPubMedPubMedCentral
34.
Pan J, Tao YF, Zhou Z, Cao BR, Wu SY, Zhang YL, et al. An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma. J Transl Med. 2011. doi:10.​1186/​1479-5876-9-157.
35.
Shirai K, Kaneshiro T, Wada M, Furuya H, Bielawski J, Hannun YA, et al. A role of sphingosine kinase 1 in head and neck carcinogenesis. Cancer Prev Res (Phila). 2011;4:454–62.CrossRef
36.
Hazar-Rethinam M, de Long LM, Gannon OM, Topkas E, Boros S, Vargas AC, et al. A novel E2F/sphingosine kinase 1 axis regulates anthracycline response in squamous cell carcinoma. Clin Cancer Res. 2015;21:417–27.CrossRefPubMed
37.
Sinha UK, Schorn VJ, Hochstim C, Chinn SB, Zhu S, Masood R. Increased radiation sensitivity of head and neck squamous cell carcinoma with sphingosine kinase 1 inhibition. Head Neck. 2011;33:178–88.CrossRefPubMed
38.
French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, Eberly JL, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003;63:5962–9.PubMed
39.
Ruckhäberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, Schiffmann S, et al. Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat. 2008;112:41–52.CrossRefPubMed
40.
Liu SQ, Su YJ, Qin MB, Mao YB, Huang JA, Tang GD. Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules. Int J Oncol. 2013;42:617–26.CrossRefPubMed
41.
Rosa R, Marciano R, Malapelle U, Formisano L, Nappi L, D’Amato C, et al. Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models. Clin Cancer Res. 2013;19:138–47.CrossRefPubMed
42.
Song L, Xiong H, Li J, Liao W, Wang L, Wu J, et al. Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-κB pathway in human non-small cell lung cancer. Clin Cancer Res. 2011;17:1839–49.CrossRefPubMed
43.
Malavaud B, Pchejetski D, Mazerolles C, de Paiva GR, Calvet C, Doumerc N, et al. Sphingosine kinase-1 activity and expression in human prostate cancer resection specimens. Eur J Cancer. 2010;46:3417–24.CrossRefPubMed
44.
Kim HS, Yoon G, Ryu JY, Cho YJ, Choi JJ, Lee YY, et al. Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer. Oncotarget. 2015;6:26746–56.CrossRefPubMedPubMedCentral
45.
Camp RL, Neumeister V, Rimm DL. A decade of tissue microarrays: progress in the discovery and validation of cancer biomarkers. J Clin Oncol. 2008;26:5630–7.CrossRefPubMed
46.
Camp RL, Charette LA, Rimm DL. Validation of tissue microarray technology in breast carcinoma. Lab Invest. 2000;80:1943–9.CrossRefPubMed
47.
Torhorst J, Bucher C, Kononen J, Haas P, Zuber M, Ko¨chli OR, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints. Am J Pathol. 2001;159:2249–56.CrossRefPubMedPubMedCentral
48.
49.
Liang J, Nagahashi M, Kim EY, Harikumar KB, Yamada A, Huang WC, et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–20.CrossRefPubMed
Metadata
Title
Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma
Authors
Yuta Kawakita
Satoru Motoyama
Yusuke Sato
Souichi Koyota
Akiyuki Wakita
Jiajia Liu
Hajime Saito
Yoshihiro Minamiya
Publication date
01-11-2017
Publisher
Springer Japan
Published in
Surgery Today / Issue 11/2017
Print ISSN: 0941-1291
Electronic ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-017-1514-x

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