CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance Journal Article

   

Authors:	Yoon, C.; Park, D. J.; Schmidt, B.; Thomas, N. J.; Lee, H. J.; Kim, T. S.; Janjigian, Y. Y.; Cohen, D. J.; Yoon, S. S.
Article Title:	CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance
Abstract:	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 orvismodegib (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. © 2014 American Association for Cancer Research.
Keywords:	signal transduction; cancer chemotherapy; cancer survival; controlled study; human tissue; major clinical study; fluorouracil; nonhuman; protein function; antigen expression; cell proliferation; mouse; phenotype; animal tissue; cell survival; sonic hedgehog protein; animal experiment; animal model; in vitro study; tumor xenograft; folinic acid; cancer cell; cell subpopulation; cell migration; stomach cancer; therapy resistance; upregulation; oxaliplatin; hermes antigen; smoothened protein; anchorage independent growth; cell invasion; short hairpin rna; stomach tumor; randomized controlled trial (topic); phase 2 clinical trial (topic); colony formation; vismodegib; tumor spheroid; human; male; priority journal; article; gastric cancer cell line
Journal Title:	Clinical Cancer Research
Volume:	20
Issue:	15
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2014-08-01
Start Page:	3974
End Page:	3988
Language:	English
DOI:	10.1158/1078-0432.ccr-14-0011
PROVIDER:	scopus
PMCID:	PMC4135312
PUBMED:	24947926
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84905444205&partnerID=40&md5=71bcc2b8f4c2c18143ad4be03cb7b4f7
Notes:	Export Date: 2 September 2014 -- CODEN: CCREF -- Source: Scopus

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