M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer

Abstract

Clinical and experimental evidence has shown that tumorassociated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. Significance: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

“…Furthermore, our data also demonstrated that TGF-β1-containing CSC_EVs possibly participate in the transformation of NGFs into CAFs and might promote their metastatic potential, thereby transforming the TME. This is in part consistent with previous evidence that CAF-secreted EVs facilitate the tumorigenesis of oral cancer cells [36][37][38]. However, the observation that CSC_EVs promoted the transformation of NGFs to CAFs is unique to this study and is the first such documentation, to the best of our knowledge.…”

M2 Macrophages Enhance the Cementoblastic Differentiation of Periodontal Ligament Stem Cells via the Akt and JNK Pathways

“…Although the JNK pathway was involved in M2 Mφ-enhanced cementoblastic differentiation, JNK was not activated by the above factors in our study (Fig. 6A, 6B), suggesting that the contribution of the JNK pathway to M2 Mφ-enhanced cementoblastic differentiation may be mediated by other signals, such as exosomes [67,68]. There is evidence that the AKT signaling pathway plays a key role in the production of VEGF and IL-10 [69][70][71], and other cytokines, such as IFN-γ and TNF-α, can also regulate this process by activating the AKT or JNK signaling pathway [62][63][64][65][66][67][68][69][70][71][72][73], suggesting that the cytokine-cytokine and cytokine-pathway interactions are bidirectional and very complex.…”

“…6A, 6B), suggesting that the contribution of the JNK pathway to M2 Mφ-enhanced cementoblastic differentiation may be mediated by other signals, such as exosomes [67,68]. There is evidence that the AKT signaling pathway plays a key role in the production of VEGF and IL-10 [69][70][71], and other cytokines, such as IFN-γ and TNF-α, can also regulate this process by activating the AKT or JNK signaling pathway [62][63][64][65][66][67][68][69][70][71][72][73], suggesting that the cytokine-cytokine and cytokine-pathway interactions are bidirectional and very complex. Although further research is necessary before the signals involved in M2-enhanced cementoblastic differentiation can be clarified, the data obtained in the present study suggest that modulation of Mφs in an in vivo milieu to positively influence PDLSCs can be useful for true periodontal regeneration.…”

Exosomes in Bone Sarcomas: Key Players in Metastasis

“…In a study on CRC, exosomes from M2 macrophages were found to play a role in metastasis development. High levels of exosomal miR-21-5p and miR-155-5p were transferred from M2 macrophages to CRC cells, leading to an increase in migration and invasion via the direct downregulation of the BRG1 protein, which has been involved in CRC metastasis [67]. In a similar study, CRC-derived exosomes could educate macrophages to induce a pro-metastatic phenotype [68].…”