Heterogeneity and versatility of the extracellular matrix during the transition from pleomorphic adenoma to carcinoma ex pleomorphic adenoma: cumulative findings from basic research and new insights

Abstract

Pleomorphic adenoma (PA) is the most common salivary gland tumor, accounting for 50%-60% of these neoplasms. If untreated, 6.2% of PA may undergo malignant transformation to carcinoma ex-pleomorphic adenoma (CXPA). CXPA is a rare and aggressive malignant tumor, whose prevalence represents approximately 3%-6% of all salivary gland tumors. Although the pathogenesis of the PA-CXPA transition remains unclear, CXPA development requires the participation of cellular components and the tumor microenvironment for its progression. The extracellular matrix (ECM) comprises a heterogeneous and versatile network of macromolecules synthesized and secreted by embryonic cells. In the PA-CXPA sequence, ECM is formed by a variety of components including collagen, elastin, fibronectin, laminins, glycosaminoglycans, proteoglycans, and other glycoproteins, mainly secreted by epithelial cells, myoepithelial cells, cancer-associated fibroblasts, immune cells, and endothelial cells. Like in other tumors including breast cancer, ECM changes play an important role in the PA-CXPA sequence. This review summarizes what is currently known about the role of ECM during CXPA development.

Keywords: carcinogenesis; carcinoma ex pleomorphic adenoma (CXPA); extracellular matrix (ECM); pleomorphic adenoma (PA); review.

Figure 1

Schematic illustration of extracellular matrix (ECM) components in the tumor microenvironment of PA and CXPA. ECM is rich in macromolecules such as laminins, proteoglycan (PG) complex, collagen, and fibronectin. The interaction between cells and ECM is mainly mediated by cell receptors of the matrix components, such as integrins. Metalloproteinases (MMPs) promote the degradation and remodeling of ECM, favoring cell proliferation.