Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid-binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11bF4/80MHCIILy6C phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NFκB/ pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM. These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. .
The cytokine milieu dictates whether TGF-β induces naïve CD4 cells to become adaptive regulatory cells or pro-inflammatory Th17 cells. We have found previously that while NOD CD4+CD25- cells convert into CD4+CD25+Foxp3+ cells in vivo, these cells are unable to regulate. The conversion defect in NOD mice appears to reside in the APC, and not the T cell, compartment, and transfer of B6.g7 or Idd3/5 DCs can reconstitute effective conversion in NOD mice. We report here preliminary results indicating that NOD DCs cultured with BDC2.5 CD4+CD25- cells, antigen and varying doses of TGF-β are less effective mediators of conversion into Foxp3+CD4+ cells than B6.g7 or Idd3/5 DCs. Furthermore, NOD DCs produce more IL-6 than either B6.g7 or Idd3/5 DCs both constitutively and after LPS stimulation in vitro. Interestingly, spleen and LNs (including pancreatic) from NOD mice contain higher (albeit small) numbers of IL-17+CD4+ cells than control mice. Taken together, these data could indicate that IL-6 produced by APC in NOD mice may interfere with the conversion of naïve CD4+ cells into functional adaptive regulatory T cells by driving these cells toward an Th17-like pathway. Funded by NIH R01 AI064421.
Interactions between chemokines and their receptors are involved in organ-specific homing and propagation of metastatic breast cancer (BrCa) cells. BrCa cells express higher levels of CXCR4 and CXCR7 mRNA and cell surface protein, than normal human mammary epithelial cells (HMECs). Recent studies show CXCR7 is highly expressed by activated endothelial cells (i.e., neovasculature), fetal liver cells, and many tumors, but not by non-transformed (or normal) human tissues. Unlike other chemokine receptors, activation of CXCR7 does not cause Ca2+ mobilization/flux or cell migration. However, CXCR7 activation by its ligands provides signals for growth, survival, and adhesion. CXCR4, CXCR7, and CXCL12 mRNAs and proteins are differentially expressed by BrCa cell lines (MCF-7 and MDA-MB-231) and breast tumor, than compared to HMEC or benign mammary tissue, respectively. Using selective G protein inhibitors, CXCR4/CXCR7-specific siRNAs as well as Amnis ImageStream, real time PCR, and active matrix metalloproteinase assays, we tested the hypothesis that CXCR7 and its interactions with CXCR4 and CXCL12 promote BrCa cell collagenase expression, alter NF-κB and ERK1/2 localization to the nucleus, and correlates with cell cycle. CXCL12-induced CXCR4 mRNA upregulation required Gβγ protein and/or JAK/STAT signal transduction; CXCL12 expression was negatively regulated by the presence of CXCR4. CXCL12-mediated CXCR7 mRNA expression in a pertussis toxin-sensitive manner. Lastly, CXCL12-dependent MMP-1 and MMP-13 mRNA expression was Gα protein-, Gβ protein-, and Gγ protein-dependent presumably through CXCR4, while elevated expression of CXCR7 suppressed these effects. Together, this study suggests that differential and cell cycle-dependent CXCR7 and CXCR4 expression plays a critical role in enhancing BrCa cell invasion and survival cell signals, which were CXCL12-dependent, but often G protein-independent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1907.
Standard treatment modalities for breast cancer has improved the outlook for women afflicted with it. However, 40% of breast cancer patients still die from the disease, primarily due to metastasis. In this regard, chemokines and their corresponding receptor interactions in metastasis is an area of intense pre-clinical and clinical research. Our lab has demonstrated higher expression of CXCR6 in breast cancer cell lines (MCF-7 and MDA-MB-231) compared to the normal mammary epithelial cell line (MCF-10A), and expression by breast cancer tissue. We investigated the role of CXCR6 in breast cancer cell migration and invasion, which are key steps used by cancer cells to achieve metastatic goals. Breast cancer cells showed higher migratory and invasive potential towards the chemotactic gradients of CXCL16, which was significantly inhibited after CXCR6 blockade. Because our antibody array data showed phosphorylation of Src, FAK, and ERK1/2 in breast cancer cells following CXCL16 treatment, we used inhibitors against these molecules after CXCL16 treatment to determine the molecular mechanisms by which CXCR6 mediates migration and invasion. The results showed a significant decrease in migration and invasion, a reduction in F-actin polymerization, and decreased phosphorylation of Vav1, ezrin, cortactin, and paxillin. Taken together, this data suggests that Src, FAK, and ERK1/2 are required for CXCR6-mediated migration and invasion.
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