Extracellular Matrix-Mediated Breast Cancer Cells Morphological Alterations, Invasiveness, and Microvesicles/Exosomes Release.

Marco Franchi,Leonardo Franchi,Zoi Piperigkou,Konstantinos-Athanasios Karamanos,Valentina Masola

doi:10.3390/cells9092031

Marco Franchi, Leonardo Franchi + Show 3 more

Open Access

https://doi.org/10.3390/cells9092031

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Abstract

Breast cancer is a leading disease in women. Several studies are focused to evaluate the critical role of extracellular matrix (ECM) in various biochemical and molecular aspects but also in terms of its effect on cancer cell morphology and therefore on cancer cell invasion and metastatic potential. ECM fibrillar components, such as collagen and fibronectin, affect cell behavior and properties of mammary cancer cells. The aim of this study was to investigate using the scanning electron microscopy (SEM) how the highly invasive MDA-MB-231 breast cancer cells, interplaying with ECM substrates during cell migration/invasion, modify their morphological characteristics and cytoplasmic processes in relation to their invasive potential. In particular we reproduced and analyzed how natural structural barriers to cancer cell invasion, such as the basement membrane (Matrigel) and fibrillar components of dermis (fibronectin as well as the different concentrations/array of type I collagen), could induce morphological changes in 3D cultures. Interestingly, we demonstrate that, even with different effects, all collagen concentrations/arrays lead to morphological alterations of breast cancer cells. Intriguingly, the elongated mesenchymal shaped cells were more prominent in 3D cultures with a dense and thick substrate (thick Matrigel, high concentrated collagen network, and densely packed collagen fibers), even though cells with different shape produced and released microvesicles and exosomes as well. It is therefore evident that the peri-tumoral collagen network may act not only as a barrier but also as a dynamic scaffold which stimulates the morphological changes of cancer cells, and modulates tumor development and metastatic potential in breast cancer.

Highlights

Tumors are characterized by a loss of tissue organization with abnormal and uncontrolled behavior of cells that grow independently
Cancer cells interact with the surrounding tissues by inducing extracellular matrix (ECM) changes similar to those found in wounds that never heal [1,2,3,4]
To mimic structural ECM natural barriers opposing to cancer cell invasion (2.5 × 105 ) cells were seeded for 4 h on 20 similar filters coated with fibronectin (130 μg/mL, BD Becton Dickinson, East Rutherford, NJ, USA) or Matrigel (3.0 μg/μL, BD Biosciences, Milan, Italy) or type I Collagen solution in different concentrations (50,200 and 3000 μg/mL C3867, Sigma-Aldrich, Schnelldorf, Germany)

Summary

Introduction

Tumors are characterized by a loss of tissue organization with abnormal and uncontrolled behavior of cells that grow independently. In solid tumors the continuous expansion of the tumor mass exerts forces on the surrounding tissues so that cancer cells lose their adhesion with neighboring cells, spread out by invading and disseminating into the surrounding microenvironment and initiate the colonization process and metastasis [5,6,7]. At the time cancer cells lose their cell–cell junctions and develop a migrating capability they become able to cross natural barriers like the basement membrane, differentiating into dangerous invasive cells through the epithelial-to-mesenchymal transition (EMT) process [8,9,10]. Cells involved in EMT process display a spindle-like or mesenchymal shape, loss of cell adhesion, inhibition of E-cadherin expression, and increased cell mobility [11,12]

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