Abstract
A tumor microenvironment may promote tumor metastasis and progression through the dynamic interplay between neoplastic cells and stromal cells. In this work, the most representative and significant stromal cells, fibroblasts, endothelial cells, and macrophages were used as vital component elements and combined with bladder cancer cells to construct a bladder cancer microenvironment simulation system. This is the first report to explore bladder cancer microenvironments based on 4 types of cells co-cultured simultaneously. This simulation system comprises perfusion equipment, matrigel channel units, a medium channel and four indirect contact culture chambers, allowing four types of cells to simultaneously interact through soluble biological factors and metabolites. With this system, bladder cancer cells (T24) with a tendency to form a 'reticular' structure under 3 dimensional culture conditions were observed in real time. The microenvironment characteristics of paracrine interactions and cell motility were successfully simulated in this system. The phenotype change process in stromal cells was successfully reproduced in this system by testing the macrophage effector molecule Arg-1. Arg-1 was highly expressed in the simulated tumor microenvironment group. To develop "precision medicine" in bladder cancer therapy, bladder cancer cells were treated with different clinical 'neo-adjuvant' chemotherapy schemes in this system, and their sensitivity differences were fully reflected. This work provides a preliminary foundation for neo-adjuvant chemotherapy in bladder cancer, a theoretical foundation for tumor microenvironment simulation and promotes individual therapy in bladder cancer patients.
Highlights
Bladder cancer is one of the most common malignant urologic diseases with high mortality and ranks eleventh in morbidity among human tumors worldwide.[1]
Each straight matrigel channel connected with 7 pairs of lateral microchannels was connected to the adjacent cell co-culture chambers to maintain cytokine spreading from one cell culture chamber to others
Unlike a co-culture with two types of cells or a monoculture, in this study, more elements involved in a microenvironment were introduced into the system
Summary
Bladder cancer is one of the most common malignant urologic diseases with high mortality and ranks eleventh in morbidity among human tumors worldwide.[1]. A tumor microenvironment is pivotal for mutationally corrupted cell proliferation, progression, and metastasis and can determine the malignant phenotype of bladder cancer.[3] A tumor microenvironment consists of tumor cells, non-neoplastic cells and an extracellular www.impactjournals.com/oncotarget matrix. Resident and recruited cells are crucial nonneoplastic cells for the tumor microenvironment and are mainly composed of endothelial cells, fibroblasts, macrophages and other inflammatory cells. Paracrine interactions between tumor cells and non-neoplastic cells are one of the driving forces of fibroblast and macrophage phenotypic alterations, which are referred to as cancer-associated-fibroblasts (CAFs) and tumor-associated-macrophages (TAM). Macrophages, fibroblasts and endothelial cells are vital components of a tumor microenvironment and enhance tumor drug resistance in tumors.[8,9,10,11,12]
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