Chuan Lan1,2, Yuki Kitano1, Yo-Ichi Yamashita1, Takanobu Yamao1, Kiyoshi Kajiyama3, Tomoharu Yoshizumi4, Kengo Fukuzawa5, Keishi Sugimachi6, Yasuharu Ikeda7, Hiroshi Takamori8, Nobutomo Miyanari9, Masahiko Hirota10, Hideo Baba11. 1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. 2. Department of Hepatobiliary Surgery and Center of Severe Acute Pancreatitis, The Affiliated Hospital of North Sichuan Medical College, 637100, Nanchong, P. R. China. 3. Department of Surgery, Iizuka Hospital, 3-83 Yoshiomachi, Iizuka City, Fukuoka, 820-8505, Japan. 4. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812‑8582, Japan. 5. Department of Surgery, Oita Red Cross Hospital, 3-2-37, Chiyo-machi, Oita, 870-0033, Japan. 6. Department of Hepatobiliary-Pancreatic Surgery, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan. 7. Department of Surgery, Fukuoka City Hospital, 13-1 Yoshizuka-honmachi, Hakata-ku, Fukuoka, 812‑0046, Japan. 8. Department of Surgery, Saiseikai Kumamoto Hospital, 5-3-1 Chikami, Minami-ku, Kumamoto, 861-4193, Japan. 9. Department of Surgery, National Hospital Organization Kumamoto Medical Center, 1-5 Ninomaru, Chuo-ku, Kumamoto, 860-0008, Japan. 10. Department of Surgery, Kumamoto Regional Medical Center, 5-16-10 Honjyo, Chuo-cho, Kumamoto, 860-8556, Japan. 11. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. hdobaba@kumamoto-u.ac.jp.
Abstract
BACKGROUND: Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. METHODS: Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. RESULTS: CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. CONCLUSION: Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.
BACKGROUND: Caveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients. METHODS: Consecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated. RESULTS: CAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors. CONCLUSION: Cellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.
Authors: Barbara Chiavarina; Diana Whitaker-Menezes; Gemma Migneco; Ubaldo E Martinez-Outschoorn; Stephanos Pavlides; Anthony Howell; Herbert B Tanowitz; Mathew C Casimiro; Chenguang Wang; Richard G Pestell; Philip Grieshaber; Jaime Caro; Federica Sotgia; Michael P Lisanti Journal: Cell Cycle Date: 2010-09-04 Impact factor: 4.534
Authors: Agnieszka K Witkiewicz; Jessica Kline; Maria Queenan; Jonathan R Brody; Aristotelis Tsirigos; Erhan Bilal; Stephanos Pavlides; Adam Ertel; Federica Sotgia; Michael P Lisanti Journal: Cell Cycle Date: 2011-06-01 Impact factor: 4.534
Authors: Paul C Tumeh; Christina L Harview; Jennifer H Yearley; I Peter Shintaku; Emma J M Taylor; Lidia Robert; Bartosz Chmielowski; Marko Spasic; Gina Henry; Voicu Ciobanu; Alisha N West; Manuel Carmona; Christine Kivork; Elizabeth Seja; Grace Cherry; Antonio J Gutierrez; Tristan R Grogan; Christine Mateus; Gorana Tomasic; John A Glaspy; Ryan O Emerson; Harlan Robins; Robert H Pierce; David A Elashoff; Caroline Robert; Antoni Ribas Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Maximilian N Kinzler; Christina Klasen; Falko Schulze; Eva Herrmann; Andreas A Schnitzbauer; Jörg Trojan; Stefan Zeuzem; Peter J Wild; Dirk Walter Journal: J Clin Med Date: 2022-04-06 Impact factor: 4.241