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Aberrant Accumulation of DKK4 Promotes Tumor Progression via Forming the Immune Suppressive Microenvironment in Gastrointestinal Stromal Tumor
32 Pages Posted: 15 Jan 2019
More...Abstract
Backgrounds: Drug resistance and tumor recurrence are most concerns in clinical practices of gastrointestinal stromal tumor (GIST), with the urgent requirement for exploring undiscovered pathways driving malignancy. To deal with these, recent studies have made many efforts to explore prognosis indicators and establish potential therapeutic targets.
Methods: Expression profiles of different risks of GISTs were described in this study. Then abundant clinical evidences involved in our study, combined with some public data, supported our findings. Exploration in vitro and verification in vivo were taken to elucidate the underlying mechanism, which drove the malignancy in GIST.
Findings: Dickkopf 4 (DKK4), as the canonical Wnt pathway antagonist, was unexpectedly and universally upregulated in high-risk GISTs, and aberrant accumulation of DKK4 was closely correlated with poor prognosis. Although separately deregulating DKK4 in vitro had little impact on tumor biological behavior, we found that tumor-derived DKK4 could decrease immune cells infiltrating and activating in tumor microenvironment, which partly accounted for the weak sensitivity to receptor tyrosine kinase (RTK) targeted therapy-imatinib, because of the necessity of immune-response participation in drug effect. And the phenomenon was recurrent in human tumor specimens.
Interpretation: Overall, our findings identified DKK4 as a proper tumor biomarker for prognosis predicting and recurrence monitoring, and suggested a potential therapeutic target to improve the effects of RTK inhibited therapy and combined immunotherapy.
Funding Statement: This work was supported by: 1. Shanghai Municipal Commission of Health and Family Planning (NO. 201540071); 2. Clinical research plan of SHDC (Shanghai hospital development center) (NO. 16CR3001A); 3. 2017 Shanghai Outstanding Academic Leaders Plan.
Declaration of Interests: The authors have declared that no conflict of interest exists.
Ethics Approval Statement: All patients and clinical specimens involved in this study came from Renji Hospital, Shanghai Jiaotong University School of Medicine, while the specimen-collecting process and study design were approved by the Renji Hospital Ethics Committee, with all patients’ informed consents. These specimens constitute four cohorts for different experimental design
Keywords: DKK4, prognosis indicator, immune suppression, GIST
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