CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance
Autor: | Sam S. Yoon, Deirdre Jill Cohen, Benjamin Schmidt, Do Joong Park, Chang Hwan Yoon, Teresa S. Kim, Yelena Y. Janjigian, Hae-June Lee, Nicholas J. Thomas |
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Rok vydání: | 2014 |
Předmět: |
Cancer Research
Pyridines Leucovorin Fluorescent Antibody Technique Apoptosis medicine.disease_cause Receptors G-Protein-Coupled Malignant transformation Mice Cell Movement Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured Anilides RNA Small Interfering Mice Inbred BALB C Flow Cytometry Prognosis Smoothened Receptor Hedgehog signaling pathway Survival Rate Hyaluronan Receptors Oncology Neoplastic Stem Cells Female Fluorouracil Signal Transduction medicine.drug Blotting Western Mice Nude Vismodegib Adenocarcinoma Biology Article Stomach Neoplasms Cancer stem cell Spheroids Cellular medicine Animals Humans Hedgehog Proteins Cell Proliferation CD44 Cancer medicine.disease Xenograft Model Antitumor Assays Drug Resistance Neoplasm Cancer cell Cancer research biology.protein Cisplatin Carcinogenesis |
Zdroj: | Clinical Cancer Research. 20:3974-3988 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells. Experimental Design: Gastric cancer cell lines, tumor xenografts, and patient tumors were examined. Results: Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival. Conclusions: HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels. Clin Cancer Res; 20(15); 3974–88. ©2014 AACR. |
Databáze: | OpenAIRE |
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