Sox2 Communicates with Tregs Through CCL1 to Promote the Stemness Property of Breast Cancer Cells

Abstract

As an important component of tumor microenvrionment, CD4+CD25+ Tregs reduce antitumor immunity, promote angiogenesis and metastasis in breast cancer. However, their function in regulating the “sternness” of tumor cells and the communication between Tregs and cancer stem cells (CSCs) remain elusive. Here, we disclose that the primarily cultured Tregs isolated from breast-tumor-bearing Foxp3-EGFP mouse upregulate the stemness property of breast cancer cells. Tregs increased the side-population and the Aldehyde dehydrogenase-bright population of mouse breast cancer cells, promoted their sphere formation in a paracrine manner, and enhanced the expression of stemness genes, such as Sox2 and so forth. In addition, Tregs increased tumorigenesis, metastasis and chemoresistance of breast cancer cells. Furthermore, Sox2-overexpression tumor cells acitivated NF-κB-CCL1 signaling to recruit Tregs through reducing the binding of H3K27Me3 on promoter regions of p65 and Ccl1. These findings reveal the functional interaction between Tregs and CSCs and indicate that targeting on the communication between them is a promising strategy in breast cancer therapy.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…In solid tumors, CCL1 is produced by CAF [ 241 , 242 ], TAM [ 243 ], CCR8 - CD11b + myeloid cells [ 244 ], and T reg [ 245 ]. The expression of this chemokine has also been demonstrated in breast cancer stem cells [ 246 ], bladder cancer tumors [ 244 , 247 ], and renal cell carcinomas [ 244 ].…”

“…In addition to the effect on a cancer cell, CCL1 causes angiogenesis on vascular endothelial cells via CCR8 [ 238 , 250 ]. It is involved in the recruitment of CCR8 - CD11b + myeloid cells [ 244 ] and T reg [ 246 , 251 , 252 ] to a tumor niche. However, CCL1 can also participate in the conversion of CD4 + T cells into T reg [ 245 ], in a process dependent on transforming growth factor-β (TGF-β), which increases the expression of CCL1 in CD4 + T cells.…”

Targeting cytokines secreted by CD4+CD25highCD127low regulatory T cells inhibits ovarian cancer progression

“…https://www.ncbi.nlm.nih.gov/pubmed/?term=MaoL[Author]&cauthor=true&cauthor_uid=29047105 et al showed that tumour immune evasion severely hampered the desired anti‐tumour effect in multiple cancers and investigated the role of Tregs in immune evasion in head and neck squamous cell carcinoma (HNSCC) microenvironments. https://www.ncbi.nlm.nih.gov/pubmed/?term=XuY[Author]&cauthor=true&cauthor_uxml:id=29044882 et al researched the function of CD4 + CD25 + Tregs in regulating the "stemness" of tumour cells and the communication between Tregs and cancer stem cells (CSCs). Our studies linked the high number of CD4 + CD25 + CD127 low Tregs in the tumour microenvironment of EOC with lymphatic invasion, which highlighted the vital role of Tregs in tumour metastasis and progression.…”

“…Mao L et al 22 showed that tumour immune evasion severely hampered the desired anti-tumour effect in multiple cancers and investigated the role of Tregs in immune evasion in head and neck squamous cell carcinoma (HNSCC) microenvironments. Xu Y et al 23 researched the function of CD4 + CD25 + Tregs in regulating the "stemness" of tumour cells and the communication between Tregs and cancer stem cells (CSCs). Our studies linked the high number of CD4 + CD25 + CD127 low Tregs in the tumour microenvironment of EOC with The inhibitory cytokines such as IL-10 and TGF-β1 were indispensable for suppression of the immune response by CD4 + Tregs.…”

WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC

“…4 The stemness-related proteins SOX2, OCT4, NANOG, KLF4, and c-Myc induce pluripotency in somatic cells, 5 and also contribute to tumorigenesis [5][6][7][8][9][10][11][12][13][14][15][16] and CSCs 6-10 in cancers, including NSCLC. SOX2 has increased expression and promotes tumorigenesis in lung, breast, ovarian, and prostate cancers, 6,7,[9][10][11][12][13][14][17][18][19] and is required for CSCs and tumorigenesis in NSCLC. 8 The p38 MAPK pathway was initially identified as a mediator of inflammation and stress responses, and was later found to regulate other conditions, including cancer.…”