cancers Review Syndecan-4 in Tumor Cell Motility Aniko Keller-Pinter 1, *, Szuzina Gyulai-Nagy 1 , Daniel Becsky 1 , Laszlo Dux 1 and Laszlo Rovo 2   Citation: Keller-Pinter, A.; Gyulai-Nagy, S.; Becsky, D.; Dux, L.; Rovo, L. Syndecan-4 in Tumor Cell Motility. Cancers 2021, 13, 3322. https://doi.org/10.3390/cancers 13133322 Academic Editors: José I. López and Ildefonso M. de la Fuente Received: 30 April 2021 Accepted: 27 June 2021 Published: 1 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Biochemistry, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary; gyulai-nagy.szuzina@med.u-szeged.hu (S.G.-N.); becsky.daniel@med.u-szeged.hu (D.B.); dux.laszlo@med.u-szeged.hu (L.D.) 2 Department of Oto-Rhino-Laryngology and Head-Neck Surgery, University of Szeged, H-6725 Szeged, Hungary; office.orl@med.u-szeged.hu * Correspondence: keller.aniko@med.u-szeged.hu Simple Summary: Cell migration is crucial fReaor metastasis formation and a hallmark of malig- nancy. The primary cause of high mortality among oncology patients is the ability of cancer cells to metastasize. To form metastasis, primary tumor cells must be intrinsically able to move. The transmembrane, heparan sulfate proteoglycan syndecan-4 (SDC4) exhibits multiple functions in signal transduction by regulating Rac1 GTPase activity and consequently actin remodeling, as well as regulating focal adhesion kinase, protein kinase C-alpha and the level of intracellular calcium. By affecting several signaling pathways and biological processes, SDC4 is involved in cell migration un- der physiological and pathological conditions as well. In this review, we discuss the SDC4-mediated cell migration focusing on the role of SDC4 in tumor cell movement. Abstract: Syndecan-4 (SDC4) is a ubiquitously expressed, transmembrane proteoglycan bearing heparan sulfate chains. SDC4 is involved in numerous inside-out and outside-in signaling processes, such as binding and sequestration of growth factors and extracellular matrix components, regulation of the activity of the small GTPase Rac1, protein kinase C-alpha, the level of intracellular calcium, or the phosphorylation of focal adhesion kinase. The ability of this proteoglycan to link the extracellular matrix and actin cytoskeleton enables SDC4 to contribute to biological functions like cell adhesion and migration, cell proliferation, cytokinesis, cellular polarity, or mechanotransduction. The multiple roles of SDC4 in tumor pathogenesis and progression has already been demonstrated; therefore, the expression and signaling of SDC4 was investigated in several tumor types. SDC4 influences tumor progression by regulating cell proliferation as well as cell migration by affecting cell-matrix adhesion and several signaling pathways. Here, we summarize the general role of SDC4 in cell migration and tumor cell motility. Keywords: syndecan-4; proteoglycan; migration; EMT; metastasis; cancer; cell polarity; extracellular matrix; actin; calcium; centrosome 1. Introduction Cell migration is a hallmark of tumor cell malignancy and essential for the multistep process of metastasis formation. The capability of invasion and metastasis enables cancer cells to escape the primary tumor mass and colonize new terrain in the body [1]. Beyond its role in metastasis formation and tumor progression, cell motility is essential in a variety of physiological and pathological tasks, such as tissue regeneration, wound healing, angio- genesis, embryonic development, as well as immune cell responses [2]. To form metastasis, primary tumor cells must be intrinsically able to move. These motility mechanisms do not differ from the normal motility cycles [3]. Epithelial-mesenchymal transition (EMT) is defined as the transdifferentiation of epithelial cells into motile mesenchymal cells. EMT occurs during different biological processes, such as embryonic development, tissue regeneration or cancer progression. Cancers 2021, 13, 3322. https://doi.org/10.3390/cancers13133322 https://www.mdpi.com/journal/cancers