Cancer-Associated Fibroblasts Regulate Bladder Cancer Invasion and Metabolic Phenotypes through Autophagy

Abstract

Recently, both cancer-associated fibroblasts (CAFs) and autophagy have been proven to play an important role in tumor development, including bladder cancer (BCa). However, the real mechanisms remain largely unclear. Here, we reconstruct a mimic tumor microenvironment to explore the interaction between CAFs and the BCa cell line T24 using a coculture system. Autophagy in CAFs was induced or inhibited by rapamycin or siRNA, respectively. After coculture with CAFs, T24 cell proliferation, invasion, and aerobic glycolysis were tested in vitro. Rapamycin induced and siAtg5 inhibited autophagy in CAFs. Enhanced autophagy in CAFs promoted cell proliferation and invasion in T24 cells in vitro, while there was no significant difference between the autophagy-inhibited group and the controls. Lactate concentration was elevated in both rapamycin-treated and siAtg5-treated groups compared with the control group. In addition, the expression levels of MCT1, MCT4, HK2, SLC2A1, and MMP-9 were all increased in T24 cells in the autophagy-enhanced group. Our results indicated that CAFs could regulate BCa invasion and metabolic phenotypes through autophagy, providing us with new alternative treatments for BCa in the future.

Cytoskeleton regulator RNA expression on cancer-associated fibroblasts is associated with prognosis and immunotherapy response in bladder cancer

“…Moreover, the expression level of CYTOR was positively correlated with the expression levels of CD163 , MRC1 , MS4A4A and VSIG4 , which have been reported to promote the M2 polarization of macrophages [ [34] , [35] , [36] ]. CAFs are the most essential stromal components of the TME, and activated CAFs can promote tumor growth, invasion and metastasis, along with extracellular matrix remodeling and even chemoresistance [ 37 , 38 ]. Current studies have confirmed that CAFs interact with many immune components within the TME and shape an immunosuppressive TME, including restricting the recruitment of immune effector cells and facilitating the recruitment of inhibitory immune cells [ 37 ].…”

Exosomal miR-93-5p from cancer-associated fibroblasts confers malignant phenotypes on bladder cancer cells by targeting PAFAH1B1

“…Besides, highly infiltrated CAFs exacerbated tumor development and prognosis and led to RUNX2 upregulation in bladder urothelial cancer [31]. Moreover, the latest research revealed that enhanced autophagy of CAFs facilitated cell growth in T24 cells [32]. In addition to the direct gene regulation function, CAFs participate in tumor progression through paracrine, and exosomes are the primary products of CAFs.…”

Mechanism and Role of Tumor Microenvironment in the Initiation and Progression of Bladder Cancer

“…CAFs promote BC cell growth by secreting a variety of cytokines and increasing energy supply. Autophagy is a kind of behavior that realizes the metabolic needs of cells and the renewal of organelles.. Dong et al [19] enhanced autophagy in CAFs with rapamycin, and then co-cultured with bladder cancer cells, observed that enhanced autophagy in CAFs induced increased expression of matrix metalloproteinase-9 (MMP9) in cancer cells. The expression levels of proteases MCT1, MCT4, HK2 and SLC2A1 related to energy metabolism pathway such as glycolysis were increased, and lactic acid levels were increased in tumor microenvironment.…”