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The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer


Autoři: Kenji Kuroda aff001;  Masakazu Yashiro aff001;  Tomohiro Sera aff001;  Yurie Yamamoto aff002;  Yukako Kushitani aff001;  Atsushi Sugimoto aff001;  Syuhei Kushiyama aff001;  Sadaaki Nishimura aff001;  Shingo Togano aff001;  Tomohisa Okuno aff001;  Tatsuro Tamura aff001;  Takahiro Toyokawa aff001;  Hiroaki Tanaka aff001;  Kazuya Muguruma aff001;  Masaichi Ohira aff001
Působiště autorů: Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka city, Japan aff001;  Molecular Oncology and Therapeutics, Osaka City University Graduate School of Medicine, Osaka city, Japan aff002;  Cancer Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka city, Japan aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224727

Souhrn

Introduction

Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC).

Materials and methods

We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.

Results

THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.

Conclusion

THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.

Klíčová slova:

Carcinomas – Fibroblast growth factor – Fibroblasts – Gastric cancer – Metastasis – Prognosis – Stromal cells


Zdroje

1. Chen X, Huang Y, Wang Y, Wu Q, Hong S, Huang Z. THBS4 predicts poor outcomes and promotes proliferation and metastasis in gastric cancer. J Physiol Biochem. 2019;75(1):117–23. Epub 2019/02/13. doi: 10.1007/s13105-019-00665-9 30746617.

2. Global Burden of Disease Cancer C, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3(4):524–48. Epub 2016/12/06. doi: 10.1001/jamaoncol.2016.5688 27918777; PubMed Central PMCID: PMC6103527.

3. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. Epub 2015/02/06. doi: 10.3322/caac.21262 25651787.

4. Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, et al. Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. Gastroenterology. 2017;153(1):191–204 e16. Epub 2017/04/10. doi: 10.1053/j.gastro.2017.03.046 28390866.

5. Muppala S, Xiao R, Krukovets I, Verbovetsky D, Yendamuri R, Habib N, et al. Thrombospondin-4 mediates TGF-beta-induced angiogenesis. Oncogene. 2017;36(36):5189–98. Epub 2017/05/10. doi: 10.1038/onc.2017.140 28481870; PubMed Central PMCID: PMC5589494.

6. Stenina-Adognravi O, Plow EF. Thrombospondin-4 in tissue remodeling. Matrix Biol. 2019;75–76:300–13. Epub 2017/11/16. doi: 10.1016/j.matbio.2017.11.006 29138119; PubMed Central PMCID: PMC6005712.

7. Adams JC, Lawler J. The thrombospondins. Cold Spring Harb Perspect Biol. 2011;3(10):a009712. Epub 2011/08/31. doi: 10.1101/cshperspect.a009712 21875984; PubMed Central PMCID: PMC3179333.

8. McCart Reed AE, Song S, Kutasovic JR, Reid LE, Valle JM, Vargas AC, et al. Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. Virchows Arch. 2013;463(4):535–45. Epub 2013/08/15. doi: 10.1007/s00428-013-1468-3 23942617.

9. Liu J, Cheng G, Yang H, Deng X, Qin C, Hua L, et al. Reciprocal regulation of long noncoding RNAs THBS4003 and THBS4 control migration and invasion in prostate cancer cell lines. Mol Med Rep. 2016;14(2):1451–8. Epub 2016/07/01. doi: 10.3892/mmr.2016.5443 27357608; PubMed Central PMCID: PMC4940078.

10. Forster S, Gretschel S, Jons T, Yashiro M, Kemmner W. THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling. Mod Pathol. 2011;24(10):1390–403. Epub 2011/06/28. doi: 10.1038/modpathol.2011.99 21701537.

11. Lin X, Hu D, Chen G, Shi Y, Zhang H, Wang X, et al. Associations of THBS2 and THBS4 polymorphisms to gastric cancer in a Southeast Chinese population. Cancer Genet. 2016;209(5):215–22. Epub 2016/05/11. doi: 10.1016/j.cancergen.2016.04.003 27160021.

12. Su F, Zhao J, Qin S, Wang R, Li Y, Wang Q, et al. Over-expression of Thrombospondin 4 correlates with loss of miR-142 and contributes to migration and vascular invasion of advanced hepatocellular carcinoma. Oncotarget. 2017;8(14):23277–88. Epub 2017/02/09. doi: 10.18632/oncotarget.15054 28177895; PubMed Central PMCID: PMC5410303.

13. Wu H, Zhang G, Li Z, Ma J, Han X, Xiang T, et al. Thrombospondin-4 expression as a prognostic marker in hepatocellular carcinoma. Gene. 2019;696:219–24. Epub 2019/02/26. doi: 10.1016/j.gene.2019.02.049 30802535.

14. Greco SA, Chia J, Inglis KJ, Cozzi SJ, Ramsnes I, Buttenshaw RL, et al. Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation. BMC Cancer. 2010;10:494. Epub 2010/09/18. doi: 10.1186/1471-2407-10-494 20846368; PubMed Central PMCID: PMC2946314.

15. van Doorn R, Zoutman WH, Dijkman R, de Menezes RX, Commandeur S, Mulder AA, et al. Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. J Clin Oncol. 2005;23(17):3886–96. Epub 2005/05/18. doi: 10.1200/JCO.2005.11.353 15897551.

16. Fuyuhiro Y, Yashiro M, Noda S, Matsuoka J, Hasegawa T, Kato Y, et al. Cancer-associated orthotopic myofibroblasts stimulates the motility of gastric carcinoma cells. Cancer Sci. 2012;103(4):797–805. Epub 2012/02/11. doi: 10.1111/j.1349-7006.2012.02209.x 22320235.

17. Dakhova O, Ozen M, Creighton CJ, Li R, Ayala G, Rowley D, et al. Global gene expression analysis of reactive stroma in prostate cancer. Clin Cancer Res. 2009;15(12):3979–89. Epub 2009/06/11. doi: 10.1158/1078-0432.CCR-08-1899 19509179; PubMed Central PMCID: PMC2734921.

18. Yashiro M, Hirakawa K. Cancer-stromal interactions in scirrhous gastric carcinoma. Cancer Microenviron. 2010;3(1):127–35. Epub 2011/01/07. doi: 10.1007/s12307-010-0036-5 21209779; PubMed Central PMCID: PMC2990484.

19. Song J, Lee HJ, Cho GS, Han SU, Kim MC, Ryu SW, et al. Recurrence following laparoscopy-assisted gastrectomy for gastric cancer: a multicenter retrospective analysis of 1,417 patients. Ann Surg Oncol. 2010;17(7):1777–86. Epub 2010/02/13. doi: 10.1245/s10434-010-0932-4 20151217.

20. Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–12. Epub 2011/05/17. doi: 10.1007/s10120-011-0041-5 21573743.

21. Yashiro M, Shinto O, Nakamura K, Tendo M, Matsuoka T, Matsuzaki T, et al. Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int J Cancer. 2010;126(4):1004–16. Epub 2009/07/22. doi: 10.1002/ijc.24763 19621385.

22. Nakazawa K, Yashiro M, Hirakawa K. Keratinocyte growth factor produced by gastric fibroblasts specifically stimulates proliferation of cancer cells from scirrhous gastric carcinoma. Cancer Res. 2003;63(24):8848–52. 14695201.

23. Huang T, Liu D, Wang Y, Li P, Sun L, Xiong H, et al. FGFR2 Promotes Gastric Cancer Progression by Inhibiting the Expression of Thrombospondin4 via PI3K-Akt-Mtor Pathway. Cell Physiol Biochem. 2018;50(4):1332–45. Epub 2018/10/26. doi: 10.1159/000494590 30355943.


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