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Microenvironment and Immunology

Dermatan Sulfate Is Involved in the Tumorigenic Properties of Esophagus Squamous Cell Carcinoma

Martin A. Thelin, Katrin J. Svensson, Xiaofeng Shi, Mariam Bagher, Jakob Axelsson, Anna Isinger-Ekstrand, Toin H. van Kuppevelt, Jan Johansson, Mef Nilbert, Joseph Zaia, Mattias Belting, Marco Maccarana and Anders Malmström
Martin A. Thelin
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Katrin J. Svensson
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Xiaofeng Shi
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Mariam Bagher
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Jakob Axelsson
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Anna Isinger-Ekstrand
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Toin H. van Kuppevelt
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Jan Johansson
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Marco Maccarana
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Anders Malmström
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DOI: 10.1158/0008-5472.CAN-11-1351
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Abstract

Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue. The main IdoA-producing enzyme, DS epimerase 1 (DS-epi1), together with the 6-O- and 4-O-sulfotransferases, were highly upregulated in ESCC biopsies. Importantly, CS/DS structure in patient tumors was significantly altered compared with normal tissue, as determined by sensitive mass spectrometry. To further understand the roles of IdoA in tumor development, DS-epi1 expression, and consequently IdoA content, was downregulated in ESCC cells. IdoA-deficient cells exhibited decreased migration and invasion capabilities in vitro, which was associated with reduced cellular binding of hepatocyte growth factor, inhibition of pERK-1/2 signaling, and deregulated actin cytoskeleton dynamics and focal adhesion formation. Our findings show that IdoA in DS influences tumorigenesis by affecting cancer cell behavior. Therefore, downregulation of IdoA by DS-epi1 inhibitors may represent a new anticancer therapy. Cancer Res; 72(8); 1–10. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received April 19, 2011.
  • Revision received January 10, 2012.
  • Accepted January 30, 2012.
  • ©2012 American Association for Cancer Research.
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Published OnlineFirst April 10, 2012
doi: 10.1158/0008-5472.CAN-11-1351

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Dermatan Sulfate Is Involved in the Tumorigenic Properties of Esophagus Squamous Cell Carcinoma
Martin A. Thelin, Katrin J. Svensson, Xiaofeng Shi, Mariam Bagher, Jakob Axelsson, Anna Isinger-Ekstrand, Toin H. van Kuppevelt, Jan Johansson, Mef Nilbert, Joseph Zaia, Mattias Belting, Marco Maccarana and Anders Malmström
Cancer Res April 10 2012 DOI: 10.1158/0008-5472.CAN-11-1351

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Dermatan Sulfate Is Involved in the Tumorigenic Properties of Esophagus Squamous Cell Carcinoma
Martin A. Thelin, Katrin J. Svensson, Xiaofeng Shi, Mariam Bagher, Jakob Axelsson, Anna Isinger-Ekstrand, Toin H. van Kuppevelt, Jan Johansson, Mef Nilbert, Joseph Zaia, Mattias Belting, Marco Maccarana and Anders Malmström
Cancer Res April 10 2012 DOI: 10.1158/0008-5472.CAN-11-1351
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Cancer Research Online ISSN: 1538-7445
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