Regulation of the basement membrane by epithelia generated forces

Abstract

Tumor metastasis involves a progressive loss of tissue architecture and dissolution of structural boundaries between the epithelium and connective tissue. The basement membrane (BM), a specialized network of extracellular matrix proteins forms a barrier that physically restricts pre-invasive lesions such that they remain as local insults. The BM is not a static structure, but one that is constantly regenerated and remodeled in the adult organism. Matrix organization also regulates cell function. Thus alterations in the balance of synthesis, remodeling and proteolytic degradation of the extracellular matrix proteins may contribute to a loss of structural integrity. However, the de novo assembly and maintenance of the complex structural properties of in vivo basement membranes remain elusive. Here, this paper highlights the current understanding on the structural properties and the establishment of the BM, and discusses the potential role of self-generated forces in adult tissue remodeling and the maintenance of the BM as a malignancy suppressor.

Figure 1

Schematic showing the malignant transformation of a spherical acinus where there is a progressive loss of normal architecture and loss of the basement membrane.

Figure 2

3D lrECM culture of the HMT3522 cancer progression series. Non malignant and reverted malignant cells form growth arrested spheres when cultured in 3D while malignant cells continuously proliferate and form disorganized aggregates. Micrographs of the median cross- section are shown where immunofluorescence delineates the nuclei (white), endogenous pan-laminin (green), endogenous collagen IV (blue) and actin (red). White scale bar is 100μm.

Figure 3

Left panel a) shows the realized geometry of 3D culture of non- malignant cells treated with a specific pharmacological inhibitor. b) Right panel shows indicates the signaling pathways regulating traction forces via actin polymerization.