Blocking the Notch signal transduction pathway promotes tumor growth in osteosarcoma by affecting polarization of TAM to M2 phenotype

Abstract

Background: Osteosarcoma is a primary malignant tumor that seriously affects the health and life of patients. It is of great clinical significance to explore the molecular mechanism of osteosarcoma development and develop the corresponding therapeutic targets. Th1/Th2 cytokines in the normal human body are in a state of dynamic balance. When this balance is destroyed, it is related to many diseases such as a tumor, autoimmune disease, microbial infection, transplant rejection, among many others. Method:The model of mouse tumor-associated macrophage (TAM) was induced by being co-cultured with inducer granulocyte-macrophage colony stimulating factor (GM-CSF) and osteosarcoma S180 cells. The Notch1 knockout mice were obtained by gene targeting technology. The distribution of M1-and M2-type TAMs in the tumor was visualized by immunofluorescence staining. And the western-blot testing was used to detect and quantified the protein level of Notch1 and Th1/Th2-type cytokines.Results: In this study, the polarization of TAMs to the M2 phenotype occurred after coculture with osteosarcoma S180 cells and secretion level Th1/Th2-type cytokines changed. Also, the expression level of Notch1 reduced significantly. Further, the critical transcription factor Notch1 of the Notch signaling pathway was knocked out in mice. The tumor volume of Notch1 knockout mice was significantly more extensive than of the control mice. The results of microstructural observation on tumor showed that M2type TAMs infiltrated into tumor increased with increased expression of Th2-type cytokines, but M1-type TAMs reduced with reduced expression of Th1-type cytokines.Conclusions: According to our results, the Notch signal transduction pathway participates in tumor occurrence and growth with a negative role by maintaining Th1/Th2 balance.

The Roles of Tumor-Associated Macrophages in Prostate Cancer

“…When the Notch transduction is blocked, macrophages exhibit functional characteristics of an M2-like phenotype. However, in the absence of myeloid Klf4, bone marrow–derived macrophages (BMDMs) express fewer M2-like indicators, like Arg-1, mannose receptor (MR), and display a pro-inflammatory gene expression signature supporting M1 differentiation [ 104 ].…”

Human umbilical vein endothelial cells derived-exosomes promote osteosarcoma cell stemness by activating Notch signaling pathway

“…A previous report has found that Notch signaling pathway is abnormally expressed in osteosarcoma [ 31 ]. Inhibition of Notch signaling pathway accelerates the tumor growth of osteosarcoma by regulating the balance between Th1 and Th2 cells and promoting M2 polarization of tumor-associated macrophages [ 32 ]. Jin et al have found that activation of Notch signaling pathway is contribute to cell stemness of osteosarcoma, and CSC-induced recurrence in osteosarcoma by activating Notch signaling pathway [ 33 ].…”

Evaluation of the Chemotherapy Drug Response Using Organotypic Cultures of Osteosarcoma Tumours from Mice Models and Canine Patients

“…Numerous studies have previously implicated TAMs in osteosarcoma metastasis, with a higher density of M2-type TAMs in lung metastases compared to primary tumours, and enhanced invasive capability in osteosarcoma cells through TAM activation of the COX-2/STAT3 axis and epithelial to mesenchymal transition (EMT) [ 15 ]. Osteosarcoma cells drive the polarisation of TAMs to M2-phenotype through inhibition of Notch signaling, promoting tumour growth and metastasis [ 16 ]. Inhibition of M2-polarisation was correlated with decreased metastatic potential and stem cell-like properties in osteosarcoma [ 44 ].…”

“…Macrophages present in the tumour microenvironment (TME) are referred to as tumour-associated macrophages (TAMs); they resemble M2 polarised cells, display anti-inflammatory properties, and play a pivotal role in modulating tumour survival [ 13 , 14 ]. The role of TAMs in osteosarcoma is uncertain; they have been shown to promote tumour growth and spread, as well as suppressing anti-tumour immune responses [ 15 , 16 , 17 ]; however, they have also been associated with reduced metastasis and improved survival [ 18 , 19 ].…”