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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

See all articles by Ming Wang

Ming Wang

Shanghai Jiao Tong University (SJTU)

Bo Ni

Shanghai Jiao Tong University (SJTU)

Chun Zhuang

Shanghai Jiao Tong University (SJTU)

Wen-yi Zhao

Shanghai Jiao Tong University (SJTU)

Lin Tu

Shanghai Jiao Tong University (SJTU)

Xin-Li Ma

Sun Yat-sen University (SYSU) - Department of Public Health; Shanghai Jiao Tong University (SJTU)

Lin-xi Yang

Shanghai Jiao Tong University (SJTU)

Zhi-gang Zhang

Shanghai Jiao Tong University (SJTU) - School of Chemistry and Chemical Engineering

Hui Cao

Shanghai Jiao Tong University (SJTU) - Department of Gastrointestinal Surgery

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

Suggested Citation

Wang, Ming and Ni, Bo and Zhuang, Chun and Zhao, Wen-yi and Tu, Lin and Ma, Xin-Li and Ma, Xin-Li and Yang, Lin-xi and Zhang, Zhi-gang and Cao, Hui, Aberrant Accumulation of DKK4 Promotes Tumor Progression via Forming the Immune Suppressive Microenvironment in Gastrointestinal Stromal Tumor (August 1, 2019). Available at SSRN: https://ssrn.com/abstract=3314418 or http://dx.doi.org/10.2139/ssrn.3314418

Ming Wang

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Bo Ni

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Chun Zhuang

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Wen-yi Zhao

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Lin Tu

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Xin-Li Ma

Sun Yat-sen University (SYSU) - Department of Public Health

China

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Lin-xi Yang

Shanghai Jiao Tong University (SJTU)

KoGuan Law School
Shanghai 200030, Shanghai 200052
China

Zhi-gang Zhang

Shanghai Jiao Tong University (SJTU) - School of Chemistry and Chemical Engineering ( email )

Shanghai, 200240
China

Hui Cao (Contact Author)

Shanghai Jiao Tong University (SJTU) - Department of Gastrointestinal Surgery ( email )

160 Pujian Road
Shanghai, 200127
China

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