Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis

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; Cancer; SFRP2; Therapeutic target; Tumor vasculature; Wnt signaling.

Fig. 1

The SFRP family members contain a signal peptide (green), frizzled-like cysteine-rich domain (Fz/CRD; blue), and netrin domain (NTR; purple). Synonyms for each protein are indicated between brackets

Fig. 2

SFRP2 and the canonical Wnt signaling pathway. a In the absence of Wnt ligands, an activated destruction complex consisting of proteins such as DvL and APC enables β-catenin ubiquitination by β-TrCP and subsequent degradation of β-catenin in the proteasome. b When Wnt ligands binds to FzD receptors, LRP becomes phosphorylated and the destruction complex moves towards the plasma membrane. By this means, the destruction complex remains inactive and, therefore, β-catenin is not ubiquitinated and degraded. Finally, β-catenin translocates to the nucleus and transcription of Wnt target genes is initiated. c Several studies suggest that the effect of SFRP2 on Wnt signaling is dependent on the concentration. High concentrations are described to drive towards Wnt antagonism. SFRP2 is able to sequester Wnt ligands and prevent binding to FzD receptors. d At low concentrations of SFRP2, SFRP2 is able to synergize with Wnt ligands, enhancing their ability to activate Wnt signaling. Interestingly, SFRP2 is also described to directly bind to FzD receptors, activating the signaling cascade. The agonistic effect of SFRP2 might also be context dependent, where the expression of FzD5 is crucial for SFRP2 to function as potent Wnt activator. This figure was prepared using Servier Medical Art under a Creative Commons Attribution 3.0 Unported License

Fig. 3

SFRP2 and noncanonical Wnt signaling. a The Wnt/PCP pathway is characterized by the recruitment of DvL upon Wnt binding. Via two parallel signaling pathways, ROCK and JNK become activated. b In the Wnt/Ca²⁺ pathway, a cascade via several molecules eventually leads to the release of calcium from the endoplasmic reticulum. In turn, this activates calcineurin to dephosphorylate NFAT and regulates gene transcription. This figure was prepared using Servier Medical Art under a Creative Commons Attribution 3.0 Unported License

Fig. 4

SFRP2 overexpression in tumor endothelium leads to enhanced tumor angiogenesis via the Wnt/Ca2⁺ signaling pathway. SFRP2 is overexpressed on tumor endothelial cells (TEC) in several types of cancer. SFRP2 can directly bind to an FzD5 receptor, activating the Wnt/Ca²⁺ pathway. Eventually, the transcription factor NFATc3 will activate several gene transcription events, leading to enhanced tumor angiogenesis. This figure was prepared using Servier Medical Art under a Creative Commons Attribution 3.0 Unported License