Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis

Abstract

Matricellular proteins have been classified as a family of non-structural matrix proteins capable of modulating a variety of biological processes within the extracellular matrix (ECM). These proteins are expressed dynamically and their cellular functions are highly dependent upon cues from the local environment. Recent studies have shown an increasing appreciation of the key roles these ECM proteins play within the tumour microenvironment. Induced by either tumour cells or tumour stromal components, matricellular proteins initiate downstream signalling events that lead to proliferation, invasion, matrix remodelling and dissemination to pre-metastatic niches in other organs. In this review, we summarise and discuss the current knowledge of the diverse roles these proteins play within the microenvironment that influences tumour progression and potential for future therapies targeting the tumour microenvironment.

Figure 1

Roles of matricellular proteins within the tumour microenvironment and metastatic niche. (A) After induction by soluble factors such as EGF and TGF-β as well as cytokines in the tumour microenvironment (red arrow), matricellular proteins act as ligands to activate integrin signalling or receptor tyrosine kinases such as EGFR or FAK receptors, which in turn induces downstream biological processes such as EMT, cell motility and invasion and ultimately metastasis. (B) Matricellular proteins induce ECM remodelling by activating intracellular ADAMTs or undergoing proteolytic cleavage by extracellular MMPs. These interactions promote downstream tumour cell signalling, invasion and metastasis. Matricellular proteins can also act as scaffolds for facilitating interactions with other matricellular/ECM proteins that promotes upregulation of LOXP activity and fibrillar collagen crosslinking. The resulting matrix remodelling and stiffness cluster receptor tyrosine kinases or integrins, which then initiate downstream cell signalling pathways for mediating invasion. (C) Matricellular proteins, derived from growth factors or cytokines secreted from primary tumours or stromal cells (red arrow), aid in maintenance of cancer stem cell (CSC) signalling such as Notch1 or Wnt signalling to maintain the metastatic niche. Matricellular proteins may also form interactions with other matricellular proteins to augment CSC survival in metastatic niche.