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

Autor: Takahiro Osawa, Nako Maishi, Naoto Miyajima, Kyoko Hida, Kaname Ameda, Yoshihiro Matsuno, Masumi Sato, Ryo Takeda, Akira Kashiwagi, Hiroshi Kikuchi, Dorcas A. Annan, Mohammad Towfik Alam, Keita Ishizuka, Randa Dawood, Masahiro Morimoto, Katsushige Yamashiro, Nobuo Shinohara, Satoru Maruyama, Ryuji Matsumoto, Manabu Azuma, Kunihiko Tsuchiya, Tomoshige Akino, Yasuhiro Hida, Takashige Abe, Toru Harabayashi
Rok vydání: 2019
Předmět:
0301 basic medicine
CD31
Cancer Research
medicine.medical_treatment
Apoptosis
Drug resistance
Metastasis
chemistry.chemical_compound
Mice
0302 clinical medicine
Tumor Cells
Cultured
Medicine
Aged
80 and over
Mice
Inbred BALB C
Neovascularization
Pathologic
Induction Chemotherapy
Middle Aged
Prognosis
Drug Resistance
Multiple
Gene Expression Regulation
Neoplastic
Survival Rate
Oncology
Paclitaxel
030220 oncology & carcinogenesis
Female
Adult
ATP Binding Cassette Transporter
Subfamily B
TEC
education
Mice
Nude
Antineoplastic Agents
03 medical and health sciences
Biomarkers
Tumor
Animals
Humans
Aged
Cell Proliferation
Chemotherapy
business.industry
Interleukin-8
Induction chemotherapy
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
chemistry
Urinary Bladder Neoplasms
Tumor progression
Drug Resistance
Neoplasm
Cancer research
business
Zdroj: Cancer research. 80(14)
ISSN: 1538-7445
Popis: 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.
Databáze: OpenAIRE
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