Excessive activation of IL‑33/ST2 in cancer‑associated fibroblasts promotes invasion and metastasis in ovarian cancer

Feng,Caixia; Kou,Li; Yin,Panyue; Jing,Yuan

doi:10.3892/ol.2022.13278

Excessive activation of IL‑33/ST2 in cancer‑associated fibroblasts promotes invasion and metastasis in ovarian cancer

Authors:
- Caixia Feng
- Li Kou
- Panyue Yin
- Yuan Jing
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Affiliations: Department of Obstetrics and Gynecology, Yulin First Hospital, Yulin, Shaanxi 719000, P.R. China, Department of Gynecology, Baoji People's Hospital, Baoji, Shaanxi 721000, P.R. China
Published online on: March 17, 2022 https://doi.org/10.3892/ol.2022.13278
Article Number: 158
Copyright: © Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ovarian cancer is highly prevalent and has high mortality rates due to metastasis and relapse. The cross communication between cancer‑associated fibroblasts (CAFs) and cancer‑associated macrophages (CAMs) in the ovarian tumor microenvironment leads to cancer cell invasion and metastasis. However, the role of overproduction of IL‑33/ST2 in the CAFs of ovarian cancer is still unclear. The expression of IL‑33, ST2, apoptosis‑related proteins and epithelial‑mesenchymal transition (EMT) markers was measured by western blotting. Primary normal fibroblasts and CAFs from ovarian cancerous tissue were isolated and cultured in vitro, and the medium was used to stimulate blood‑derived monocytes. Flow cytometry analysis was used to detect the frequency of M2‑like macrophages in blood‑derived monocytes from patients with ovarian cancer. Cell invasion were evaluated using Transwell assays. A xenograft model was used to study tumor growth in ST2‑knockout and wild‑type NOD‑SCID mice. The results demonstrated higher expression of IL‑33 and ST2 in carcinoma tissues compared with in para‑carcinoma tissues, and there was a survival improvement associated with elevated IL‑33. IL‑33 and culture supernatants from CAFs, rather than normal ovarian fibroblasts, led to a higher expression of M2 macrophage marker genes in human blood‑derived monocytes. Invasion and migration were aggravated in COC1 cells co‑cultured with CAF‑induced CAMs, and the EMT marker genes were upregulated. It was reported that EMT marker genes were downregulated and tumor volumes were significantly reduced in ST2‑deficient mice. Overall, the IL‑33/ST2 axis in ovarian cancer might integrate IL‑33‑expressing CAFs with M2 type‑like CAMs, which aggravated invasion and metastasis by promoting EMT.

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1	Machida H, Matsuo K, Yamagami W, Ebina Y, Kobayashi Y, Tabata T, Kanauchi M, Nagase S, Enomoto T and Mikami M: Trends and characteristics of epithelial ovarian cancer in Japan between 2002 and 2015: A JSGO-JSOG joint study. Gynecol Oncol. 153:589–596. 2019. View Article : Google Scholar : PubMed/NCBI
2	Rose PG, Java JJ, Salani R, Geller MA, Secord AA, Tewari KS, Bender DP, Mutch DG, Friedlander ML, Van Le L, et al: Nomogram for predicting individual survival after recurrence of advanced-stage, high-grade ovarian carcinoma. Obstet Gynecol. 133:245–254. 2019. View Article : Google Scholar : PubMed/NCBI
3	Zhang J, Silva EG, Sood AK, et al: Ovarian epithelial carcinogenesis[M]//gynecologic and obstetric pathology, Volume 2. Springer; Singapore: pp. 121–139. 2019
4	Hwang JY, Lim WY, Tan CS, Lim SL, Chia J, Chow KY and Chay WY: Ovarian cancer incidence in the multi-ethnic asian city-state of Singapore 1968–2012. Asian Pac J Cancer Prev. 20:3563–3569. 2019. View Article : Google Scholar : PubMed/NCBI
5	Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al: A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 20:174–186. 2020. View Article : Google Scholar : PubMed/NCBI
6	Tsang M, Quesnel K, Vincent K, Hutchenreuther J, Postovit LM and Leask A: Insights into fibroblast plasticity: Cellular communication network 2 is required for activation of cancer-associated fibroblasts in a murine model of melanoma. Am J Pathol. 190:206–221. 2020. View Article : Google Scholar : PubMed/NCBI
7	Ling J and Chiao PJ: Two birds with one stone: Therapeutic targeting of IL-1β signaling pathways in pancreatic ductal adenocarcinoma and the cancer-associated fibroblasts. Cancer Discov. 9:173–175. 2019. View Article : Google Scholar : PubMed/NCBI
8	Neri S, Hashimoto H, Kii H, Watanabe H, Masutomi K, Kuwata T, Date H, Tsuboi M, Goto K, Ochiai A and Ishii G: Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts. J Cancer Res Clin Oncol. 142:437–446. 2016. View Article : Google Scholar : PubMed/NCBI
9	Teng F, Tian WY, Wang YM, Zhang YF, Guo F, Zhao J, Gao C and Xue FX: Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 9:82016. View Article : Google Scholar : PubMed/NCBI
10	Ogawa K, Lin Q, Li L, Bai X, Chen X, Chen H, Kong R, Wang Y, Zhu H, He F, et al: Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis. Cancer Lett. 481:63–75. 2020. View Article : Google Scholar : PubMed/NCBI
11	Arai K, Ishimatsu H, Iwasaki T, Tsuchiya C, Sonoda A and Ohata K: Membranous S100A10 involvement in the tumor budding of colorectal cancer during oncogenesis: Report of two cases with immunohistochemical analysis. World J Surg Oncol. 18:2892020. View Article : Google Scholar : PubMed/NCBI
12	Brunetto E, De Monte L, Balzano G, Camisa B, Laino V, Riba M, Heltai S, Bianchi M, Bordignon C, Falconi M, et al: The IL-1/IL-1 receptor axis and tumor cell released inflammasome adaptor ASC are key regulators of TSLP secretion by cancer associated fibroblasts in pancreatic cancer. J Immunother Cancer. 7:452019. View Article : Google Scholar : PubMed/NCBI
13	Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M and Worthley DL: Cancer-associated fibroblasts in gastrointestinal cancer. Nat Rev Gastroenterol Hepatol. 16:282–295. 2019. View Article : Google Scholar : PubMed/NCBI
14	Qian L, Tang Z, Yin S, Mo F, Yang X, Hou X, Liu A and Lu X: Fusion of dendritic cells and cancer-associated fibroblasts for activation of anti-tumor cytotoxic T lymphocytes. J Biomed Nanotechnol. 14:1826–1835. 2018. View Article : Google Scholar : PubMed/NCBI
15	Suklabaidya S, Dash P and Senapati S: Pancreatic fibroblast exosomes regulate survival of cancer cells. Oncogene. 36:3648–3649. 2017. View Article : Google Scholar : PubMed/NCBI
16	Kanada M, Bachmann MH and Contag CH: Signaling by extracellular vesicles advances cancer hallmarks. Trends Cancer. 2:84–94. 2016. View Article : Google Scholar : PubMed/NCBI
17	Yang F, Ning Z, Ma L, Liu W, Shao C, Shu Y and Shen H: Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts. Mol Cancer. 16:1482017. View Article : Google Scholar : PubMed/NCBI
18	Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S and Pouliot F: Exosomes induce fibroblast differentiation into Cancer-associated fibroblasts through TGF-β signaling. Mol Cancer Res. 16:1196–1204. 2018. View Article : Google Scholar : PubMed/NCBI
19	Wang H, Wei H, Wang J, Li L, Chen A and Li Z: MicroRNA-181d-5p-containing exosomes derived from CAFs promote EMT by regulating CDX2/HOXA5 in breast cancer. Mol Ther Nucleic Acids. 19:654–667. 2020. View Article : Google Scholar : PubMed/NCBI
20	Yeon JH, Jeong HE, Seo H, Cho S, Kim K, Na D, Chung S, Park J, Choi N and Kang JY: Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts. Acta Biomater. 76:146–153. 2018. View Article : Google Scholar : PubMed/NCBI
21	Qin X, Guo H, Wang X, Zhu X, Yan M, Wang X, Xu Q, Shi J, Lu E, Chen W and Zhang J: Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5. Genome Biol. 20:12–14. 2019. View Article : Google Scholar : PubMed/NCBI
22	Li K, Chen Y, Li A, Tan C and Liu X: Exosomes play roles in sequential processes of tumor metastasis. Int J Cancer. 144:1486–1495. 2019. View Article : Google Scholar : PubMed/NCBI
23	Liu T and Kong J: CAF-derived exosomes remodel ECM by targeting lung fibroblasts via integrin α2β1 at the pre-metastatic niche. J Extracellular Vesicles. 7:234–235. 2018.
24	Guo H, Ha C, Dong H, Yang Z, Ma Y and Ding Y: Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A. Cancer Cell Int. 19:3472019. View Article : Google Scholar : PubMed/NCBI
25	Wu HJ, Hao M, Yeo SK and Guan JL: FAK signaling in cancer-associated fibroblasts promotes breast cancer cell migration and metastasis by exosomal miRNAs-mediated intercellular communication. Oncogene. 39:2539–2549. 2020. View Article : Google Scholar : PubMed/NCBI
26	Allaoui R, Bergenfelz C, Mohlin S, Hagerling C, Salari K, Werb Z, Anderson RL, Ethier SP, Jirström K, Påhlman S, et al: Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat Commun. 7:130502016. View Article : Google Scholar : PubMed/NCBI
27	Becht E, de Reyniès A, Giraldo NA, Pilati C, Buttard B, Lacroix L, Selves J, Sautès-Fridman C, Laurent-Puig P and Fridman WH: Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res. 22:4057–4066. 2016. View Article : Google Scholar : PubMed/NCBI
28	Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, Lanciotti M, Serni S and Chiarugi P: Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 33:2423–2431. 2014. View Article : Google Scholar : PubMed/NCBI
29	Liu X, Hansen DM, Timko NJ, Zhu Z, Ames A, Qin C, Nicholl MB, Bai Q, Chen X, Wakefield MR, et al: Association between interleukin-33 and ovarian cancer. Oncol Rep. 41:1045–1050. 2019.PubMed/NCBI
30	Tong X, Barbour M, Hou K, Gao C, Cao S, Zheng J, Zhao Y, Mu R and Jiang HR: Interleukin-33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways. Mol Oncol. 10:113–125. 2016. View Article : Google Scholar : PubMed/NCBI
31	Larsen KM, Minaya MK, Vaish V and Peña MMO: The role of IL-33/ST2 pathway in tumorigenesis. Int J Mol Sci. 19:26762018. View Article : Google Scholar : PubMed/NCBI