CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.

Macrophages have been suggested to contribute to constructing a cancer stem cell (CSC) niche. However, whether and how macrophages regulate the activity of CSCs through juxtacrine signaling are poorly understood. Here we report LSECtin, a transmembrane protein highly expressed on tumor-associated macrophages (TAMs), enhances stemness of breast cancer cells (BCCs). We identified BTN3A3, a B7 family member with previously unknown functions as the receptor for LSECtin on BCCs responsible for stemness-promoting effect of LSECtin. In mice bearing human tumor xenografts, either macrophage-specific ablation of LSECtin or silencing of BTN3A3 in BCCs decreased CSC frequency and tumor growth. Admixture of LSECtin-positive macrophages increased the tumorigenic activity of BCCs dependent on BTN3A3. Disruption of the LSECtin-BTN3A3 axis with BTN3A3-Fc or anti-BTN3A3 mAb has a therapeutic effect on breast cancer. These findings define a juxtacrine signaling mechanism by which TAMs promote cancer stemness. Targeting this axis in the CSC niche may provide potential therapies to breast cancer.

No abstract

No abstract

BackgroundNon-sentinel lymph node (NSLN) status prediction with molecular biomarkers may make some sentinel lymph node (SLN) positive breast cancer patients avoid the axillary lymph node dissection, but the available markers remain limited.MethodsSLN positive patients with and without NSLN invasion were selected, and genes differentially expressed or fused in SLN metastasis were screened by next-generation RNA sequencing.ResultsSix candidates (all ER/PR+, HER2−, Ki-67 <20 %) with metastatic SLNs selected from 305 patients were equally categorized as NSLN negative and positive. We identified 103 specifically expressed genes in the NSLN negative group and 47 in the NSLN positive group. Among them, FABP1 (negative group) and CYP2A13 (positive group) were the only 2 protein-encoding genes with expression levels in the 8th to 10th deciles. Using a false discovery rate threshold of <0.05, 62 up-regulated genes and 98 down-regulated genes were discovered in the NSLN positive group. Furthermore, 10 gene fusions were identified in this group with the most frequently fused gene being IGLL5.ConclusionsThe biomarkers screened in present study may broaden our understanding of the mechanisms of breast cancer metastasis to the lymph nodes and contribute to the axillary surgery selection for SLN positive patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12957-015-0642-2) contains supplementary material, which is available to authorized users.