Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis
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NON-THEMATIC REVIEW
Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis Karlijn van Loon 1 & Elisabeth J. M. Huijbers 1 & Arjan W. Griffioen 1 Received: 9 September 2020 / Accepted: 26 October 2020 # The Author(s) 2020
Abstract Secreted frizzled-related proteins (SFRP) are glycoproteins containing a so-called frizzled-like cysteine-rich domain. This domain enables them to bind to Wnt ligands or frizzled (FzD) receptors, making potent regulators of Wnt signaling. As Wnt signaling is often altered in cancer, it is not surprising that Wnt regulators such as SFRP proteins are often differentially expressed in the tumor microenvironment, both in a metastatic and non-metastatic setting. Indeed, SFRP2 is shown to be specifically upregulated in the tumor vasculature of several types of cancer. Several studies investigated the functional role of SFRP2 in the tumor vasculature, showing that SFRP2 binds to FzD receptors on the surface of tumor endothelial cells. This activates downstream Wnt signaling and which is, thereby, stimulating angiogenesis. Interestingly, not the well-known canonical Wnt signaling pathway, but the noncanonical Wnt/Ca2+ pathway seems to be a key player in this event. In tumor models, the pro-angiogenic effect of SFRP2 could be counteracted by antibodies targeting SFRP2, without the occurrence of toxicity. Since tumor angiogenesis is an important process in tumorigenesis and metastasis formation, specific tumor endothelial markers such as SFRP2 show great promise as targets for anti-cancer therapies. This review discusses the role of SFRP2 in noncanonical Wnt signaling and tumor angiogenesis, and highlights its potential as anti-angiogenic therapeutic target in cancer. Keywords Angiogenesis . SFRP2 . Wnt signaling . Cancer . Therapeutic target . Tumor vasculature
Abbreviations APC Adenomatous polyposis coli CAM Chick chorioallantoic membrane CRC Colorectal cancer CRD Cysteine-rich domain CYR Cysteine-rich angiogenic inducer DAAM Dishevelled-associated activator of morphogenesis DAG Diacylglycerol DvL Dishevelled protein Fz Frizzled-like FzD Frizzled HCC Hepatocellular carcinoma JNK c-Jun N-terminal protein kinase LRP Low-density lipoprotein receptor–related protein
* Arjan W. Griffioen [email protected] 1
Angiogenesis Laboratory, Cancer Center Amsterdam, Department of Medical Oncology, VU University Medical Center, Amsterdam UMC, Amsterdam, The Netherlands
MMPs NFAT NTR PCP PLC ROCK Ror SARP SDF SFRP TEC VEGF Wnt β-TrCp
Matrix metalloproteinases Nuclear factor of activated T cells Netrin domain Planar cell polarity Phospholipase C Rho-associated protein kinase Receptor tyrosine kinase–like orphan receptor Secreted apoptosis-related protein Stromal cell–derived factor Secreted frizzled-related protein Tumor endothelial cell Vascular endothelial growth factor Wingless-related integration site F-box β-transducing repeat-containing protein
1 Introduction The secreted frizzled-related protein (SFRP) family consists of five secreted glycopr
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