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
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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