Editors' ChoiceGastric cancer

A potential gut punch to gastric cancer

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Science Translational Medicine  08 Jan 2020:
Vol. 12, Issue 525, eaba2906
DOI: 10.1126/scitranslmed.aba2906

Abstract

Combination chemotherapies that also inhibit the proline isomerase Pin1 may overcome the notorious drug resistance of gastric cancer.

Our stomachs hold sway during the festive season: It is well known that the average American gains more than half a percent of their body weight over the holidays. A lesser known and somber fact is that gastric cancer claims about 800,000 lives each year. Gastric tumors contain cancer stem cells (CSCs) that have an unlimited potential for self-renewal and differentiation and are believed to play a central role in the development of resistance to chemotherapy. A recent report by Zhang et al. from the Fujian Medical University may have identified a strategy to address the poor response of gastric cancers to chemotherapy.

Canonical Wnt signaling regulates CSCs’ self-renewal and differentiation by transducing the accumulation of β-catenin in the cytoplasm. β-Catenin subsequently translocates to the nucleus, wherein it induces gastric epithelial dysplasia. The Wnt signaling cascade is regulated by a proline isomerase called Pin1 that has also been implicated in the activation and repression of oncoproteins and tumor suppressors, respectively. Hypothesizing a link between Pin1 overexpression and gastric tumorigenesis, Zhang et al. studied primary tumors from 180 patients and determined that Pin1 overexpression is highly and positively correlated with advanced stages and greater drug resistance of the disease. Knocking down or inhibiting the expression of Pin1 using short hairpin RNA (shRNA) or all-trans retinoic acid (ATRA), respectively, reduced migration and invasion of tumors and reversed epithelial dysplasia in cultures of HGC-27 and MKN-45 gastric cancer cells. Down-regulating Pin1 reduced expression of β-catenin and several CSC markers, whereas expression of E-cadherin, which is essential for maintenance of epithelial integrity of tissues, was up-regulated. Tumor formation was also inhibited in three-dimensional cultures of gastric cancer cells treated with shRNA or ATRA, which reduced the abundance of CSCs. Treated cells formed fewer and smaller lung metastases than control cells in a mouse model of pulmonary metastasis.

To corroborate their therapeutic strategy, Zhang et al. tested combination therapies of shRNA or ATRA and the chemotherapeutics oxaliplatin or fluorouracil. Apoptosis was higher in gastric cancer cells treated with the combination therapies compared with cells treated solely with either anticancer drug. Likewise, in the mouse metastatic model, they observed tumor weight reductions of 30% and 70% for the oxaliplatin and the oxaliplatin-ATRA combination therapy, respectively, and improved survival for all combination therapies compared with the control group. These results are promising; however, some questions still remain. The long-term consequences of knocking down or inhibiting Pin1 are uncertain. For instance, Pin1 down-regulation has been implicated in neurodegeneration. Future studies should aim to put these concerns at ease.

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