Matrix stiffness and tumor-associated macrophages modulate epithelial to mesenchymal transition of human adenocarcinoma cells

Abstract

The tumor microenvironment (TME) is gaining increasing attention in oncology, as it is recognized to be functionally important during tumor development and progression. Tumors are heterogeneous tissues that, in addition to tumor cells, contain tumor-associated cell types such as immune cells, fibroblasts, and endothelial cells. These other cells, together with the specific extracellular matrix (ECM), create a permissive environment for tumor growth. While the influence of tumor-infiltrating cells and mechanical properties of the ECM in tumor invasion and progression have been studied separately, their interaction within the complex TME and the epithelial -to-mesenchymal transition (EMT) is still unclear. In this work, we develop a 3D co-culture model of lung adenocarcinoma cells and macrophages in an interpenetrating network hydrogel, to investigate the influence of the macrophage phenotype and ECM stiffness in the induction of EMT. Rising ECM stiffness increases both tumor cell proliferation and invasiveness. The presence of tumor-associated macrophages and the ECM stiffness jointly contribute to an invasive phenotype, and modulate the expression of key EMT-related markers. Overall, these findings support the utility of in vitro 3D cancer models that allow one to study interactions among key components of the TME.

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

“…Neoplastic cells induce polarization of M0 macrophages towards the M2 phenotype. On the other hand, physical properties of the cellular matrix may increase tumor invasiveness by regulating the transcription of EMT-related genes in the population of M2c macrophages [50]. TNF-α-releasing M2 macrophages promote the progression of HCC and induce EMT, which is associated with regulation of the Wnt/βcatenin pathway by cytokines [51].…”

Risk Evaluation of EMT and Inflammation in Metastatic Pancreatic Cancer Cells Following Plasma Treatment

“…This study now extends on the previous investigations of four different pancreatic cancer cell lines (MiaPaCa2, PaTuS, PaTuT, and Panc01) and tissue from in ovo-grown tumors, to a more detailed analysis of factors that can mediate an altered cell detachment and outgrowth. This includes (i) adhesion molecules, that are responsible for cell-cell and cell-matrix contact being essential to maintain tissue integrity [33][34][35], (ii) markers of the epithelialmesenchymal transition (EMT), that are associated with cancer cell polarization and transformation to a more metastatic phenotype [18,36,37], and (iii) molecules of inflammation known to drive or limit inflammation-mediated cellular escape from the bulk tumor mass. In a series of experiments, it was demonstrated that the plasma treatment regime using the kINPen argon plasma jet was safe with respect to the aspects mentioned above and the model systems employed in this study.…”

Identification of candidate genes and prognostic value analysis in patients with PDL1-positive and PDL1-negative lung adenocarcinoma

“…Our results reveal that the PDL1-positive group mainly demonstrated enrichment of adhesion-related biological processes and the PPAR signaling pathway. Adhesion-related biological processes have been previously reported to be associated with invasion and metastasis in patients with lung adenocarcinoma (Stevens et al, 2017;Alonso-Nocelo et al, 2018), resulting in relatively high levels of organ and tissue metastases and poor prognosis. Real-world studies have revealed similar results (Wang et al, 2015;Okita et al, 2017).…”