Matricellular proteins in cancer: a focus on secreted Frizzled-related proteins

Abstract

Tumours are complex entities, wherein cancer cells interact with myriad soluble, insoluble and cell associated factors. These microenvironmental mediators regulate tumour growth, progression and metastasis, and are produced by cancer cells and by stromal components such as fibroblast, adipocytes and immune cells. Through their ability to bind to extracellular matrix proteins, cell surface receptors and growth factors, matricellular proteins enable a dynamic reciprocity between cancer cells and their microenvironment. Hence, matricellular proteins play a critical role in tumour progression by regulating where and when cancer cells are exposed to key growth factors and regulatory proteins. Recent studies suggest that, in addition to altering Wingless (Wnt) signalling, certain members of the Secreted Frizzled Related Protein (sFRP) family are matricellular in nature. In this review, we outline the importance of matricellular proteins in cancer, and discuss how sFRPs may function to both inhibit and promote cancer progression in a context-dependent manner. By considering the matricellular functionality of sFRPs, we may better understand their apparently paradoxical roles in cancers.

Keywords: cancer; matricellular; microenvironment; secreted Frizzled-Related Proteins; stroma.

Fig. 1

Cellular components of tumour heterogeneity. Tumours involve the co-evolution of tumour cells with an extracellular matrix, and stromal, immune and endothelial cells. Taken together this forms a specialized tumour niche that supports neoplastic progression

Fig. 2

Possible mechanisms by which sFRPs could modulate Wnt signalling. (a) In the absence of sFRPs, Wnt ligands are free to interact with Fz receptors and activate downstream Wnt signaling. (b) sFRPs can sequester Wnt ligands through the CRD or NTR domain, thereby acting as a classical Wnt antagonist. (c) sFRPs may bind Wnt ligands, and aid in their stability and diffusion in the extracellular space. (d) sFRPs may bind Fz receptors, and form signalling active or inactive complexes. (e) sFRPs interact with each other in the extracellular space and modulate one another’s activity