CD44 Expression a Marker for Chemotherapy Resistance in Gastric Cancer, Overcome by Hedgehog Inhibition

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CD44 is a gastric cancer stem cell marker, and the hedgehog signaling pathway can be dysregulated by cancer stem cells during tumorigenesis. In a study reported in Clinical Cancer Research, Yoon and colleagues found that high CD44 expression was associated with chemotherapy resistance and poorer survival in gastric cancer and that hedgehog inhibition could reverse resistance and improve survival.

Gastric cancer cell lines (AGS, MKN-45, and NCI-N87) grown as spheroids or sorted for CD44-positivity exhibited upregulation of hedgehog pathway proteins. Inhibition of the hedgehog pathway by Smoothened shRNA or vismodegib (Erivedge) resulted in reduced spheroid and colony formation. Resistance to fluorouracil and cisplatin treatment was observed in CD44-positive cells compared with unselected cells; resistance was reversed in vitro and in xenograft models by Smoothened shRNA or vismodegib treatment.

Hedgehog inhibition also prevented migration, invasion, and anchorage-independent growth associated with CD44-positive cells. Analysis of tumor samples from patients receiving chemotherapy with or without vismodegib for advanced gastric cancer showed that high CD44 expression was associated with reduced survival in patients receiving chemotherapy alone, but improved survival in those also receiving vismodegib.

The investigators concluded, “[Hedgehog] signaling maintains [cancer stem cell] phenotypes and malignant transformation phenotypes in CD44[-positive] gastric cancer cells, and [hedgehog] inhibition can reverse chemotherapy resistance in CD44[-positive] cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with [hedgehog] inhibition may only be effective in tumors with high CD44 levels.” ■

Yoon C, et al: Clin Cancer Res 20:3974-3988, 2014.




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