The Extracellular Matrix: An Accomplice in Gastric Cancer Development and Progression

Abstract

The extracellular matrix (ECM) is a dynamic and highly organized tissue structure, providing support and maintaining normal epithelial architecture. In the last decade, increasing evidence has emerged demonstrating that alterations in ECM composition and assembly strongly affect cellular function and behavior. Even though the detailed mechanisms underlying cell-ECM crosstalk are yet to unravel, it is well established that ECM deregulation accompanies the development of many pathological conditions, such as gastric cancer. Notably, gastric cancer remains a worldwide concern, representing the third most frequent cause of cancer-associated deaths. Despite increased surveillance protocols, patients are usually diagnosed at advanced disease stages, urging the identification of novel diagnostic biomarkers and efficient therapeutic strategies. In this review, we provide a comprehensive overview regarding expression patterns of ECM components and cognate receptors described in normal gastric epithelium, pre-malignant lesions, and gastric carcinomas. Important insights are also discussed for the use of ECM-associated molecules as predictive biomarkers of the disease or as potential targets in gastric cancer.

Keywords: ECM biomarkers; ECM deregulation; ECM targeting; cell-ECM interaction; extracellular matrix; gastric cancer; integrin.

Figure 1

The extracellular matrix (ECM) contribution to cancer pathogenesis. The ECM mediates cancer development through several mechanisms, including formation of a physical barrier to anti-cancer drugs (A), provision of growth factor and cytokines reserves (B), alteration of immune cell responses (C), stimulation of integrin-dependent signaling that promotes invasion and proliferation (D), and establishment of an advantageous niche for metastatic cells (E).

Figure 2

Representative image of major ECM-integrin alterations in gastric cancer. ECM composition, as well as integrin expression and signaling, are distinct in normal and in gastric cancer contexts. Relevant players for gastric carcinogenesis are depicted to illustrate aberrant features. Briefly, during gastric cancer development, the expression of some integrin heterodimers is lost (α6β4), whereas that of others is increased (α2β1, α5β1, and αvβ6). Moreover, the increased activity of several MMPs (MMP-2, MMP-7, and MMP-9) is associated with cancer cell invasion. Increased levels of collagens (Col I and Col IV) and laminin γ2 are also part of a specific gastric cancer ECM signature.