Abstract
BackgroundTo investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors.MethodsThe BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts.ResultsLA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate.ConclusionLA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC.DasE7LVW6tcKsMdapJmhMFVideo
Highlights
To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors
We demonstrated that LA facilitates metastatic niche formation in bone metastasis from CRC through overexpression of CXCL10 and Cadherin-11 in primary osteoclast precursors
Lactic acid facilitates the progression of osteolytic lesions in bone metastasis from CRC To confirm that LA can be produced by MC-38 cells, a murine colorectal cancer cell line, cells were cultured for 3 days, and the concentration of LA in the culture medium was examined by ELISA
Summary
To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. Metabolites derived from cancer cells were once thought to have no effect, it is well recognized that they contribute to the formation of the metabolic microenvironment and regulate intercellular interactions to impact tumor progression and metastasis in broad ways. Lactic acid (LA) is one of the predominant metabolites in the tumor microenvironment. The serum levels of several metabolites, including pyruvic acid, glucose, lactic acid, malic acid, fumaric acid, 3hydroxybutyric acid, tryptophan, phenylalanine, tyrosine, creatinine and ornithine, were found to be significantly different between CRC patients and control patients and could be good candidates for predicting the prognosis of CRC [6]. One clinical trial further analyzed the relationship between the serum level of LA and metastasis status in CRC, and the results showed that CRC patients with metastasis have higher levels of LA than patients without metastasis [7]
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