YKL40/Integrin β4 Axis Induced by the Interaction between Cancer Cells and Tumor-Associated Macrophages Is Involved in the Progression of High-Grade Serous Ovarian Carcinoma

• Published in: International journal of molecular sciences Vol. 25; no. 19; p. 10598
• Main Authors: Yamanaka, Keitaro, Koma, Yu-Ichiro, Urakami, Satoshi, Takahashi, Ryosuke, Nagamata, Satoshi, Omori, Masaki, Torigoe, Rikuya, Yokoo, Hiroki, Nakanishi, Takashi, Ishihara, Nobuaki, Tsukamoto, Shuichi, Kodama, Takayuki, Nishio, Mari, Shigeoka, Manabu, Yokozaki, Hiroshi, Terai, Yoshito
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.10.2024; MDPI
• Subjects: Cancer therapies; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemotherapy; Chitinase-3-Like Protein 1 - genetics; Chitinase-3-Like Protein 1 - metabolism; Coculture Techniques; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; Cytokines; Disease Progression; epithelial ovarian cancer; Female; Fibroblasts; high-grade serous ovarian carcinoma; Humans; Integrin beta4 - genetics; Integrin beta4 - metabolism; Medical prognosis; Middle Aged; Mortality; Neoplasm Grading; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Prognosis; Signal Transduction; Tumor Microenvironment; tumor-associated macrophages; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - pathology; YKL40; epithelial ovarian cancer; tumor microenvironment; high-grade serous ovarian carcinoma; YKL40; tumor-associated macrophages
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms251910598

Macrophages in the tumor microenvironment, termed tumor-associated macrophages (TAMs), promote the progression of various cancer types. However, many mechanisms related to tumor-stromal interactions in epithelial ovarian cancer (EOC) progression remain unclear. High-grade serous ovarian carcinoma (HGSOC) is the most malignant EOC subtype. Herein, immunohistochemistry was performed on 65 HGSOC tissue samples, revealing that patients with a higher infiltration of CD68 , CD163 , and CD204 macrophages had a poorer prognosis. We subsequently established an indirect co-culture system between macrophages and EOC cells, including HGSOC cells. The co-cultured macrophages showed increased expression of the TAM markers CD163 and CD204, and the co-cultured EOC cells exhibited enhanced proliferation, migration, and invasion. Cytokine array analysis revealed higher YKL40 secretion in the indirect co-culture system. The addition of YKL40 increased proliferation, migration, and invasion via extracellular signal-regulated kinase (Erk) signaling in EOC cells. The knockdown of integrin β4, one of the YKL40 receptors, suppressed YKL40-induced proliferation, migration, and invasion, as well as Erk phosphorylation in some EOC cells. Database analysis showed that high-level expression of YKL40 and integrin β4 correlated with a poor prognosis in patients with serous ovarian carcinoma. Therefore, the YKL40/integrin β4 axis may play a role in ovarian cancer progression.