Fibroblast-associated tumour microenvironment induces vascular structure-networked tumouroid

Abstract

In vitro three-dimensional (3D) tumour models mimic natural cancer tissue in vivo, bridging the gap between conventional 2D in vitro testing and animal models. Stromal and cancer tissues with extracellular matrix (ECM) can provide a tumour microenvironment (TME) with cell-to-cell and cell-to-ECM interactions. These interactions induce the exchange of biophysical factors, contributing to the progression, metastasis, and drug resistance of cancer. Here, we describe a 3D in vitro lung cancer model cultured in a microfluidic channel that is able to confirm the role and function of various stromal cells in tumourigenesis, thereby representing an in vivo-like TME. We founded that biophysical factors contribute to the role of fibroblast cells in tumour formation, especially, producing a nascent vessel-like tubular structure, resulting in the formation of vascularized tumour tissue. Fibroblast cells altered the gene expression of the cancer cells to enhance metastasis, survival, and angiogenesis. The device could be used for developing and screening anti-cancer drugs through the formation of the same multicellular tumour spheroids under TME interactions. We believe this microfluidic system provides interaction of TME for cancer research by culturing stromal tissue.

Tumor microenvironment complexity and therapeutic implications at a glance

“…Cancer-associated fibroblasts (CAFs) in the immediate vicinity of cancer cells play an important role in tumorigenesis in various physicochemical ways by reducing apoptosis and improving the proliferation, migration and viability of cancer cells [58,59]. CAFs residing in TME are heterogeneous cells with different origins, different functions (pro or anti-tumor activities) and different surface markers such as alpha-smooth muscle actin (α-SMA), myosin light chain 9 (MYL9), myosin light chain kinase (MYLK), matrix metalloproteinase 2 (MMP2), decorin (DCN) and collagen type I alpha 2 (COL1A2) [60][61][62][63].…”

Paracrine signalling of AGR2 stimulates RhoA function in fibroblasts and modulates cell elongation and migration

“…It has been reported by many researchers that fibroblasts are important constituents of tumour stroma [4,[31][32][33]. NIH3T3 has been used to study tumour progression in heterotypic tumour models [2,[34][35][36][37]. Based on this research, we explored the gradient effect of extracellular AGR2 on NIH3T3 fibroblasts.…”

“…The detailed analysis of these mechanisms is mandatory in the context of understanding mechanical processes such as cell adhesion, cell movements and motility, and the generation of forces within TME. Specifically, conventional two-dimensional (2D) and 3D in vitro models reveal that cancer-associated fibroblasts (CAFs) are involved in developing protective effect in order to contribute stroma formation and progression of TME development [1][2][3][4]. The stromal alterations are caused by an increased accumulation of fibroblasts and collagenized ECM.…”

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

“…The tumor ECM provides structural foundation for efficient cell migration [70], but it also needs to be remodeled via proteolysis for tumor cell migration by microenvironmental proteases [64,[71][72][73]. In this work, we assume that the tumor ECM is degraded by the TAN-secreted NEs [74] and TAN-secreted MMPs [4,35,63,64] as in the invasion experiments [27].…”