Chemotherapy-Induced IL8 Upregulates MDR1/ABCB1 in Tumor Blood Vessels and Results in Unfavorable Outcome.

Autor:	Kikuchi H; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan., Maishi N; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.; Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan., Annan DA; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.; Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan., Alam MT; Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan.; Department of Dental Radiology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan., Dawood RIH; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan., Sato M; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan., Morimoto M; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.; Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan., Takeda R; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan., Ishizuka K; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan., Matsumoto R; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.; Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan., Akino T; Department of Urology, Sapporo City General Hospital, Sapporo, Hokkaido, Japan.; Department of Urology, Tonan Hospital, Sapporo, Hokkaido, Japan., Tsuchiya K; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.; Department of Urology, KKR Sapporo Medical Center, Sapporo, Hokkaido, Japan., Abe T; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan., Osawa T; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan., Miyajima N; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.; Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan., Maruyama S; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.; Department of Urology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan., Harabayashi T; Department of Urology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan., Azuma M; Department of Pathology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan., Yamashiro K; Department of Pathology, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan., Ameda K; Hokkaido Hinyokika Kinen Hospital, Sapporo, Hokkaido, Japan., Kashiwagi A; Department of Urology, Teine Keijinkai Hospital, Sapporo, Hokkaido, Japan., Matsuno Y; Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan., Hida Y; Department of Cardiovascular and Thoracic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan., Shinohara N; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan., Hida K; Vascular Biology, Frontier Research Unit, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. khida@den.hokudai.ac.jp.; Department of Vascular Biology and Molecular Pathology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Hokkaido, Japan.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Jul 15; Vol. 80 (14), pp. 2996-3008. Date of Electronic Publication: 2020 Jun 14.
DOI:	10.1158/0008-5472.CAN-19-3791
Abstrakt:	Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues ( n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo , the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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