The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma

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Abstract

Background

In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. In the present study, we aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC.

Methods

The clinicopathological significance of Axin2 and Snail expression was investigated by immunohistochemistry in an OSCC cohort containing 217 tissue samples from patients with long-term follow-up. The influence of the Axin2-Snail axis on the biological behaviour of OSCC cells and CAFs was further investigated both in vitro and in vivo.

Results

Axin2 expression was significantly associated with Snail expression, the desmoplasia status, and bone invasion in patients with OSCC. In multivariate analysis, lymph node metastasis, desmoplasia, Axin2 expression, and Snail expression were independent poor prognostic factors in our cohort. Consistent with these findings, OSCC cells demonstrated attenuated oncogenic activity as well as decreased expression of Snail and various cytokines after Axin2 knockdown in vitro. Among the related cytokines, C-C motif chemokine ligand 5 (CCL5) and interleukin 8 (IL8) demonstrated a strong influence on the biological behaviour of CAFs in vitro. Moreover, both the desmoplastic reaction and osteolytic lesions in the calvaria were predominantly decreased after Axin2 knockdown in OSCC cells in vivo using a BALB/c athymic nude mouse xenograft model.

Conclusions

Oncogenic activities of the Axin2-Snail axis are not limited to the cancer cells themselves but rather extend to CAFs via regulation of the cytokine-mediated cancer-stromal interaction, with further implications for bone invasion as well as a poor prognosis in OSCC.

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Most cited references 42

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Cancer-associated fibroblasts (CAF) are components of the tumor microenvironment whose contributions to malignant progression are not fully understood. Here, we show that the fibroblast activation protein (FAP) triggers induction of a CAF subset with an inflammatory phenotype directed by STAT3 activation and inflammation-associated expression signature marked by CCL2 upregulation. Enforcing FAP expression in normal fibroblasts was sufficient to endow them with an inflammatory phenotype similar to FAP(+)CAFs. We identified FAP as a persistent activator of fibroblastic STAT3 through a uPAR-dependent FAK-Src-JAK2 signaling pathway. In a murine liver tumor model, we found that FAP(+)CAFs were a major source of CCL2 and that fibroblastic STAT3-CCL2 signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC). The CCL2 receptor CCR2 was expressed on circulating MDSCs in tumor-bearing subjects and FAP(+)CAF-mediated tumor promotion and MDSC recruitment was abrogated in Ccr2-deficient mice. Clinically, we observed a positive correlation between stromal expression of FAP, p-STAT3, and CCL2 in human intrahepatic cholangiocarcinoma, a highly aggressive liver cancer with dense desmoplastic stroma, where elevated levels of stromal FAP predicted a poor survival outcome. Taken together, our results showed how FAP-STAT3-CCL2 signaling in CAFs was sufficient to program an inflammatory component of the tumor microenvironment, which may have particular significance in desmoplasia-associated cancers. Cancer Res; 76(14); 4124-35. ©2016 AACR.

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Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

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Author and article information

Contributors

Junqi Ling: lingjq@mail.sysu.edu.cn

Xianglan Zhang: zhangxianglan@yuhs.ac

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 12 October 2020

Publication date PMC-release: 12 October 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 987

Affiliations

[1 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, Key laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, ; Guangzhou, Guangdong China

[2 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Department of Oral Pathology, , Yonsei University College of Dentistry, ; Seoul, Republic of Korea

[3 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, BK21 PLUS Project, , Yonsei University College of Dentistry, ; Seoul, South Korea

[4 ]GRID grid.15444.30, ISNI 0000 0004 0470 5454, Oral Cancer Research Institute, Yonsei University College of Dentistry, ; Seoul, Republic of Korea

[5 ]GRID grid.12981.33, ISNI 0000 0001 2360 039X, Department of Endodontics, , Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, ; 56 Lingyuanxi Road, Guangzhou, 510055 Guangdong China

[6 ]GRID grid.459480.4, ISNI 0000 0004 1758 0638, Department of Pathology, , Yanbian University Hospital, ; Yanji City, 133000 Jilin Province China

Article

Publisher ID: 7495

DOI: 10.1186/s12885-020-07495-9

PMC ID: 7552517

SO-VID: 30bd38da-a806-4fb4-b7ae-28115d79b23a

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 22 May 2020

Date accepted : 5 October 2020

Funding

Funded by: National Natural Science Foundation of China

Award ID: 81460408

Award Recipient : Xianglan Zhang

Funded by: National Research Foundation of Korea

Award ID: NRF-2017R1D1A1B03034921

Award ID: NRF-2017R1C1B1012464

Award ID: NRF-2020R1I1A1A01073437

Award Recipient : Eunae Cho Xianglan Zhang

Funded by: BK21 PLUS Project, Yonsei University College of Dentistry

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: axin2,snail,cytokine,cancer-stroma crosstalk,cafs,bone invasion,prognosis,oscc

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: axin2, snail, cytokine, cancer-stroma crosstalk, cafs, bone invasion, prognosis, oscc

The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma

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Abstract

Background

Methods

Results

Conclusions

Related collections

Karger: Oncology

Most cited references 42

Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging.

FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling.

Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

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