Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment

Zainab Al Shareef; Mai Nidal Asad Ershaid; Rula Mudhafar; Sameh S M Soliman; Robert M Kypta

doi:10.3390/cancers14235822

Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment

Cancers (Basel). 2022 Nov 25;14(23):5822. doi: 10.3390/cancers14235822.

Authors

Zainab Al Shareef^{1

2}, Mai Nidal Asad Ershaid², Rula Mudhafar², Sameh S M Soliman^{2

3}, Robert M Kypta^{4

5}

Affiliations

¹ College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
² Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
³ College of Pharmacy, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates.
⁴ CIC BioGUNE, Basque Research and Technology Alliance, BRTA, Bizkaia Technology Park, 48160 Derio, Spain.
⁵ Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.

Abstract

Dickkopf-3 (Dkk-3) is a member of the Dickkopf family protein of secreted Wingless-related integration site (Wnt) antagonists that appears to modulate regulators of the host microenvironment. In contrast to the clear anti-tumorigenic effects of Dkk-3-based gene therapies, the role of endogenous Dkk-3 in cancer is context-dependent, with elevated expression associated with tumor promotion and suppression in different settings. The receptors and effectors that mediate the diverse effects of Dkk-3 have not been characterized in detail, contributing to an ongoing mystery of its mechanism of action. This review compares the various functions of Dkk-3 in the tumor microenvironment, where Dkk-3 has been found to be expressed by subpopulations of fibroblasts, endothelial, and immune cells, in addition to epithelial cells. We also discuss how the activation or inhibition of Dkk-3, depending on tumor type and context, might be used to treat different types of cancers.

Keywords: DKK3 gene; Dickkopf-3 (Dkk-3) protein; secreted glycoprotein; stroma; tumor suppression.

Publication types

Review

Grants and funding

This work has been funded by University of Sharjah to Z.A.S. and S.S.M.S. R.M.K. is funded, in part, by the Ministry of Science and Innovation PID2020-117649RB-I00, the Department of Industry, Tourism and Trade (Elkartek), the Department of Innovation Technology of the Government of the Autonomous Community of the Basque Country and the Centre of Excellence Severo Ochoa and Prostate Cancer UK RIA19-ST2-009.