Sporadic cell death in macroscale 3D tumor grafts with high drug resistance by activating cell-ECM interactions

Abstract

In the tumor microenvironment (TME), the extracellular matrix (ECM) provides a dynamic structure for cell adhesion and cancer cell motility, such as migration and invasion, as well as remodeling. Matrix metalloproteinases (MMPs) promote cancer cell motility, which contributes to inducing drug resistance and thereby acquiring aggressive features. The drug resistance-induced 3D in vitro tumor model can be an effective model for therapeutic strategies for anticancer drugs targeting aggressive cancer cells. Here, we describe highly drug-resistant multicellular tumoroids (MCTs)-ECM tumor grafts under a macroscale dense 3D in vitro model through a combination of numerous MCTs and a collagen matrix. MCTs-ECM tumor grafts promote the high activity of MMP2 and MMP9 compared to general MCTs and induced cancer cell motility. Then, after the administration of anticancer drugs, the tumor grafts show increased drug resistance, with both the sporadic distribution of necrotic cells and the reduction of apoptotic portions, by activating cancer cell motility. MCTs-ECM tumor graft could be useful as a macroscale tumor graft model for inducing drug resistance by activating cancer cell motility and evaluating the efficacy of anticancer drugs targeting cancer with aggressive features.

Protective Mechanism of Ethyl Gallate against Intestinal Ischemia‐Reperfusion Injury in Mice by in Vivo and in Vitro Studies Based on Transcriptomics

“…), proteoglycans, growth factors, and enzymes [38] . Matrix metalloproteinases (MMPs) were a class of zinc‐dependent proteases that were abundant in cancerous and inflammatory tissues and whose main function was to degrade and remodel the ECM [39–41] . MMP9 is a type of gelatinase whose main function is to degrade type IV collagen, modulate adhesion factor activity, and degrade and disrupt basement membrane (BM) structure, leading to degradation and remodeling of the ECM, and promoting migration and invasion of cancer cells [42,43] .…”

“…[38] Matrix metalloproteinases (MMPs) were a class of zincdependent proteases that were abundant in cancerous and inflammatory tissues and whose main function was to degrade and remodel the ECM. [39][40][41] MMP9 is a type of gelatinase whose main function is to degrade type IV collagen, modulate adhesion factor activity, and degrade and disrupt basement membrane (BM) structure, leading to degradation and remodeling of the ECM, and promoting migration and invasion of cancer cells. [42,43] In intestinal tissues, MMP9 promoted ECM degradation and inflammation, leading to disruption of intestinal barrier function and structure, which in turn triggered intestinal tissue damage.…”

Artificial tumor matrices and bioengineered tools for tumoroid generation

“…Highly drug-resistant MCTs-ECM tumor grafts were analyzed in a 3D in vitro model by combining MCTs and collagen matrix. Compared with general MCTs, MCTs-ECM tumor grafts promoted the high activity of MMP2 and MMP9 and induced cancer cell motility [178]. Through the embedding of collagen gel, PANC-1 cells (human pancreatic epithelioid carcinoma cell line) cultured into tumor spheres are co-cultured with pancreatic stellate cells, which can be used for ECM fiber network, cancer cell invasive migration, and EMT-related proteins expression effects [179].…”