The role of CCN4/WISP-1 in the cancerous phenotype

Abstract

CCN proteins are secreted into the extracellular environment where they interact with both components of the extracellular matrix and with cell surface receptors to regulate cellular function. Through these interactions, CCNs act as extracellular ligands to activate intracellular signal transduction pathways. CCN4/WISP-1, like other CCNs, plays multiple physiologic roles in development and also participates in pathogenesis. CCN4 is of particular interest with respect to cancer, showing promise as a biomarker or prognostic factor as well as a potential therapeutic target. This review focuses on recent work addressing the role of CCN4 in cancer. While CCN4 has been identified as an oncogene in a number of cancers, where it enhances cell migration and promoting epithelial-mesenchymal transition, there are other cancers where CCN4 appears to play an inhibitory role. The mechanisms underlying these differences in cellular response have not yet been delineated, but are an active area of investigation. The expression and activities of CCN4 splice variants are likewise an emerging area for study. CCN4 acts as an autocrine factor that regulates the cancer cells from which it is secreted. However, CCN4 is also a paracrine factor that is secreted by stromal fibroblasts, and can affect the function of vascular endothelial cells. In summary, current evidence is abundant in regard to establishing potential roles for CCN4 in oncogenesis, but much remains to be learned about the functions of this fascinating protein as both an autocrine and paracrine regulator in the tumor microenvironment.

Keywords: extracellular matrix; matricellular proteins; oncogenesis; signal transduction; tumor microenvironment.

Figure 1

Domain structure of CCN4/WISP-1 and splice variants. Notes: The following are the highly conserved domains in CCN proteins: SP, IGFBP, VWC, TSP1, and CT. WISP-1v is a splice variant that lacks exon 3, which contains the VWC domain. WISP-1vx contains a truncated IGFBP domain, creating a frameshift that results in loss of the VWC and TSP1 domains. Abbreviations: SP, signaling peptide; IGFBP, insulin-like growth factor binding protein; VWC, von Willebrand factor type C; TSP1, thrombospondin 1; CT, C-terminal.

Figure 2

CCN4 as an autocrine and paracrine mediator within the tumor microenvironment. Notes: CCN4 is produced and secreted (blue arrows) by tumor cells as well as by stromal fibroblasts. Secreted CCN4 is then available to exert effects (red arrows) on tumor cells and vascular endothelial cells through both paracrine and autocrine mechanisms. CCN4 is able to bind to extracellular matrix proteins (eg, fibronectin; green shapes), as well as to integrins (blue shapes) in the cell membrane, thereby modulating cell interactions with the extracellular matrix. Integrins are expressed by all of the cell types depicted.