RETRACTED: CD44 Expression Denotes a Subpopulation of Gastric Cancer Cells in Which Hedgehog Signaling Promotes Chemotherapy Resistance

Abstract

Purpose Gastric cancers (GC) may harbor a small subset of cells with cancer stem cell (CSC) properties including chemotherapy (CT) resistance. 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(+) GC cells. Experimental Design GC cell lines, tumor xenografts, and patient tumors were examined. Results GC 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 Smo shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared to unselected cells, were also resistant to 5-fluorouracil and cisplatin CT, 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 for advanced GC of CT with or without VIS were analyzed for CD44 expression. In the CT alone group, high CD44 expression was associated with decreased survival, while in the CT plus VIS group, high CD44 expression was associated with improved survival. Conclusions HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) GC cells, and HH inhibition can block CT resistance in CD44(+) cells. GC is a heterogeneous disease, and the strategy of combining CT with HH inhibition may only be effective in the subset with high CD44 levels.

Identifying and targeting cancer stem cells in the treatment of gastric cancer

“…Preclinical studies suggest that gastric tumors expressing the CSC marker CD44 are associated with up‐regulation of the Hedgehog pathway and with a worse outcome 50. A biomarker study of tumor samples from a phase 2 study with vismodegib plus FOLFOX in gastric cancer confirmed these findings 38. Further study of phase 2 tumor samples revealed that, when tumors were selected for positive CD44 expression, the combination of vismodegib and FOLFOX produced increased activity over FOLFOX alone 38.…”

“…In addition, CD44 is expressed in up to 80% of primary gastric cancer resection specimens and is associated with more advanced clinicopathologic features and a poorer prognosis 21. CD44 expression also denotes a subpopulation of gastric cancer cells in which Hedgehog signaling pathway proteins are up‐regulated and also promote chemotherapy resistance and thus a poorer prognosis 21, 38. A variant of CD44 (CD44v8‐10) was identified as the predominant CD44 variant expressed in gastric cancer cells and contributes to tumor initiation, possibly through enhancing oxidative stress defense 39.…”

“…Yoon et al examined 97 available tumor samples from patients in the phase 2 trial described above for CD44‐expressing cells 38. Those authors observed that CD44‐positive cells in gastric cancer cell lines had up‐regulation of Hedgehog pathway proteins.…”

Identifying therapeutic targets in gastric cancer: the current status and future direction

“…CD44(+) cells sorted from gastric cancer cell lines that were resistant to 5-Fu and cisplatin, had significantly more malignant properties, and had up-regulation of hedgehog pathway proteins. Moreover, hedgehog signaling inhibitor, vismodegib, can reverse chemotherapy resistance in CD44(+) cells [76]. Based on these and other studies, CSC-targeted treatment approaches appear to be promising to overcome drug resistance.…”

Gastric Cancer: A Stem Cell Disease?

“…Indeed, there is evidence that CD44v8-10 stabilizes the cystine-glutamate transporter subunit xCT and promotes the synthesis of glutathione, thereby protecting cancer cells from reactive oxygen species [70]. Depletion of the expression of CD44 leads to a decrease in the tumorigenicity of cancer cell lines [50], and Yoon et al demonstrated implication of the Hedgehog signaling in the maintenance, chemoresistance, and migration capacity of the GCSC CD44 + cells [74].…”