The SPARC protein: an overview of its role in lung cancer and pulmonary fibrosis and its potential role in chronic airways disease

Abstract

The SPARC (secreted protein acidic and rich in cysteine) protein is matricellular molecule regulating interactions between cells and their surrounding extracellular matrix (ECM). This protein thus governs fundamental cellular functions such as cell adhesion, proliferation and differentiation. SPARC also regulates the expression and activity of numerous growth factors and matrix metalloproteinases essential for ECM degradation and turnover. Studies in SPARC-null mice have revealed a critical role for SPARC in tissue development, injury and repair and in the regulation of the immune response. In the lung, SPARC drives pathological responses in non-small cell lung cancer and idiopathic pulmonary fibrosis by promoting microvascular remodelling and excessive deposition of ECM proteins. Remarkably, although chronic airway conditions such as asthma and chronic obstructive pulmonary disease (COPD) involve significant remodelling in both the airway and vascular compartments, the role of SPARC in these conditions has thus far been overlooked. In this review, we discuss the role of SPARC in lung cancer and pulmonary fibrosis, as well as potential mechanisms by which it may contribute to the disease process in asthma and COPD.

Figure 1

Proposed role of SPARC in airway and vascular remodelling in asthma and COPD: TGF‐β induces SPARC mRNA and protein expression in various cell types, including lung cells. We propose that many of the pro‐remodelling effects of TGF‐β in asthma and COPD are mediated by SPARC. Acting downstream of the transcription factor Snail, SPARC may potentially drive TGF‐β‐induced EMT (A). Increased deposition of a non‐degradative ECM within the airway wall may also be attributed to SPARC's ability to enhance collagen deposition and augment PAI‐1 expression (B). SPARC inhibits the expression and secretion of the pro‐angiogenic factor VEGF. However, cleavage of SPARC may potentially lead to the generation of SPARC peptide fragments with –KGHK sequence, which may confer pro‐angiogenic activity. The balance of these processes may be an important determinant of angiogenic activity in airways disease (C).