Editorial Comment on: DPP9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer
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EDITORIAL – COLORECTAL CANCER
Editorial Comment on: DPP9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer Takehiko Yokobori, MD, PhD1,2 Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan; 2Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan
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Colorectal cancer (CRC) is a common cancer worldwide.1 In a period without effective anticancer drugs, patients with advanced CRC have a poor prognosis. However, even in advanced cases, long-term survival may be achieved by using the latest established surgical techniques, radiotherapy, and systemic chemotherapies. Chemotherapy currently includes novel cytotoxic agents, targeted molecular antibodies, and evolving immune checkpoint inhibitors (ICI).2–7 In contrast, patients with significantly advanced or recurrent CRC who do not respond to available chemotherapeutic agents do not exhibit improved outcomes. Further research is required to identify new therapeutic targets to counter therapeutic resistance in patients with CRC. The dipeptidyl peptidase (DPP) subfamily 9b includes six members: DPP4, DPP9, DPP8, fibroblast activation protein alpha, DPP4-like protein 1, and DPP4-like protein 2.8 DPP4 is the best-known DPP family protein. It serves as a multifunctional protein involved in T cell activation and modulation of several chemokines, neuropeptides, and peptide hormones, such as neuropeptide Y, substance P, glucagon-like peptide 1, GIP, and glucagon. Several DPP4 inhibitors are currently used clinically as antidiabetic agents.9
Ó Society of Surgical Oncology 2020 First Received: 11 May 2020 T. Yokobori, MD, PhD e-mail: [email protected]
DPP9 has attracted attention as an inflammasome repressor in human autoinflammatory diseases.10 The inflammasome is associated with cancer progression, chemosensitivity, and regulation of immune cells in the tumor microenvironment.11–14 In this issue of Annals of Surgical Oncology, Saso et al.15 focused on the significance of DPP9 expression and the potential of DPP9 targeting for chemosensitizing tumors to conventional cytotoxic agents. The authors demonstrate that the DPP9 expression levels in CRC are higher than those in noncancerous tissues and that, in patients with CRC, high DPP9 expression levels are associated with poor prognosis compared with patients with low DPP9 expression levels. Moreover, DPP9 suppression by RNA interference (RNAi) and compounds such as talabostat and vildagliptin inhibits CRC cell viability, and the combination of existing cytotoxic agents with compounds that target DPP9 increases the sensitivity of CRC cells to chemotherapy. These data suggest that DPP9 levels in CRC tissues might be a useful marker for poor prognosis and that targeting DPP9 might be useful for chemosensitizing refractory CRC. Interestingly, the authors discussed drug repositioning of talabostat and vildagliptin, the latter already
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