Cancer-Associated Fibroblasts in Gallbladder Cancer Modify the Migration and Invasion of Gallbladder Cancer Cells

Cancer-Associated Fibroblasts in Gallbladder Cancer Modify the Migration and Invasion of Gallbladder Cancer Cells

Kazuhiko Tsukuda,¹ Masaharu Ishida,¹ Takayuki Miura,¹ Shimpei Maeda,¹ Hideo Ohtsuka,¹ Masamichi Mizuma,¹ Kei Nakagawa¹ and Michiaki Unno¹

¹Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan

The importance of the microenvironment in cancer progression is widely recognized, and interactions between cancer cells and stromal cells play an important role in the progression of the disease. A major component of stromal cells are fibroblasts, known as cancer-associated fibroblasts (CAFs). CAFs are thought to enhance the malignant properties of cancer cells through various secreted proteins. It is also known that CAFs function as a leading cell in cancer invasion, and their migratory ability is involved in local cancer invasion. The aim of this study was to elucidate the function of CAF in gallbladder cancer, which is one of the gastrointestinal malignancies with the worst prognosis.

CAFs were primarily cultured from surgical specimens of gallbladder cancer patients. We investigated the migration ability of established CAFs and the effects of conditioned medium obtained from CAFs on the growth and invasion ability of gallbladder cancer cell lines. Functional analysis showed that the migration ability of certain CAFs was enhanced compared to control, and that conditioned medium enhanced the migration and invasion of gallbladder cancer cell lines. Gene expression analysis of CAFs revealed that tenascin-C (TNC) and podoplanin (PDPN) were highly expressed in CAFs with the enhancing functions. Immunohistochemical staining of TNC and PDPN on surgical specimens was performed to investigate the relationship with the prognosis. Disease-free survival and overall survival were found to be reduced in patients with high expression of those genes. The results of this study indicate that CAFs expressing TNC and PDPN promote cancer progression in gallbladder cancer.

Key words —— cancer-associated fibroblast; gallbladder cancer; invasion; podoplanin; tenascin-C

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Tohoku J. Exp. Med., 2025 May, 266(3), 279-293.

Correspondence: Michiaki Unno, Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: m_unno@surg.med.tohoku.ac.jp