Force-dependent breaching of the basement membrane

Abstract

Clinically, non-invasive carcinomas are confined to the epithelial side of the basement membrane and are classified as benign, whereas invasive cancers invade through the basement membrane and thereby acquire the potential to metastasize. Recent findings suggest that, in addition to protease-mediated degradation and chemotaxis-stimulated migration, basement membrane invasion by malignant cells is significantly influenced by the stiffness of the associated interstitial extracellular matrix and the contractility of the tumor cells that is dictated in part by their oncogenic genotype. In this review, we highlight recent findings that illustrate unifying molecular mechanisms whereby these physical cues contribute to tissue fibrosis and malignancy in three epithelial organs: breast, pancreas, and liver. We also discuss the clinical implications of these findings and the biological properties and clinical challenges linked to the unique biology of each of these organs.

Keywords: Breast cancer; Hepatocellular carcinoma; Matrix rigidity; Pancreatic cancer; Tumor invasion.

Figure 1

Inter-related and cross-regulating factors that promote basement membrane invasion in cancer progression. MMPs, matrix metalloproteinases.

Figure 2

Primary components of the basement membrane in healthy breast, pancreas, and liver tissue and the changes that occur in the basement membrane during development of fibrosis and cancer.

Figure 3

Malignant mammary epithelial cells cultured in reconstituted basement membrane as spherical multicellular organoids and then embedded in collagen hydrogels placed under either 0 (unstretched - soft) or 10% strain (stretched - stiff) in a tension bioreactor. After three days, cultures were fixed and stained for actin cytoskeleton (phalloidin) and nuclei (DAPI) to assess the extent of tumor cell invasion and migration (scale bar = 20 μm).