Open Access

ARTICLE

Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers

Hitoshi Takamatsu^*1, Ken-ichi Yamamoto^*1, Nahoko Tomonobu^*, Hitoshi Murata^*, Yusuke Inoue^†, Akira Yamauchi^‡, I Wayan Sumardika^*§, Youyi Chen^*, Rie Kinoshita^*, Masahiro Yamamura^¶, Hideyo Fujiwara^#, Yosuke Mitsui^{*, **}, Kota Araki^*††, Junichiro Futami^‡‡, Ken Saito^§§, Hidekazu Iioka^§§, I Made Winarsa Ruma^§, Endy Widya Putranto^¶¶, Masahiro Nishibori^##, Eisaku Kondo^§§, Yasuhiko Yamamoto^***, Shinichi Toyooka^††, Masakiyo Sakaguchi^*

* Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
† Faculty of Science and Technology, Division of Molecular Science, Gunma University, Kiryu, Gunma, Japan
‡ Department of Biochemistry, Kawasaki Medical School, Kurashiki, Okayama, Japan
§ Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
¶ Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Okayama, Japan
# Department of Pathology, Kawasaki Medical School, Kurashiki, Okayama, Japan
** Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
†† Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
‡‡ Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama, Japan
§§ Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
¶¶ Department of Pediatrics, Dr. Sardjito Hospital/Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
## Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
*** Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

Oncology Research 2019, 27(6), 713-727. https://doi.org/10.3727/096504018X15433161908259

Abstract

The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE⁺ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11–RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE–MyD88–mTOR–p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

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