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Item A C-X-C Chemokine Receptor Type 2–Dominated Cross-talk between Tumor Cells and Macrophages Drives Gastric Cancer Metastasis(AACR, 2019-06) Zhou, Zhijun; Xia, Guanggai; Xiang, Zhen; Liu, Mingyang; Wei, Zhewei; Yan, Jie; Chen, Wei; Zhu, Jintao; Awasthi, Niranjan; Sun, Xiaotian; Fung, Kar-Ming; He, Yulong; Li, Min; Zhang, Changhua; Surgery, School of MedicinePurpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear. Experimental Design: The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A coculture system was established, and functional assays, including ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis. A xenograft gastric cancer model and a lymph node metastasis model were established to study the function of CXCR2 in vivo. Results: CXCR2 expression is associated with the prognosis of patients with gastric cancer (P = 0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells. Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop. Gastric cancer cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer in vitro and in vivo. Conclusions: Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.Item CCL2/CCR2 signaling elicits itch- and pain-like behavior in a murine model of allergic contact dermatitis(Elsevier, 2019) Jiang, Haowu; Cui, Huan; Wang, Tao; Shimada, Steven G.; Sun, Rui; Tan, Zhiyong; Ma, Chao; LaMotte, Robert H.; Pharmacology and Toxicology, School of MedicineSpontaneous itch and pain are the most common symptoms in various skin diseases, including allergic contact dermatitis (ACD). The chemokine (C-C motif) ligand 2 (CCL2, also referred to as monocyte chemoattractant protein 1 (MCP-1)) and its receptor CCR2 are involved in the pathophysiology of ACD, but little is known of the role of CCL2/CCR2 for the itch- and pain-behaviors accompanying the murine model of this disorder, termed contact hypersensitivity (CHS). C57BL/6 mice previously sensitized to the hapten, squaric acid dibutyl ester, applied to the abdomen were subsequently challenged twice with the hapten delivered to either the cheek or to the hairy skin of the hind paw resulting in CHS at that site. By 24 h after the 2nd challenge to the hind paw CCL2 and CCR2 mRNA, protein, and signaling activity were upregulated in the dorsal root ganglion (DRG). Calcium imaging and whole-cell current-clamp recordings revealed that CCL2 directly acted on its neuronal receptor, CCR2 to activate a subset of small-diameter, nociceptive-like DRG neurons retrogradely labeled from the CHS site. Intradermal injection of CCL2 into the site of CHS on the cheek evoked site-directed itch- and pain-like behaviors which could be attenuated by prior delivery of an antagonist of CCR2. In contrast, CCL2 failed to elicit either type of behavior in control mice. Results are consistent with the hypothesis that CHS upregulates CCL2/CCR2 signaling in a subpopulation of cutaneous small diameter DRG neurons and that CCL2 can activate these neurons through neuronal CCR2 to elicit itch- and pain-behavior. Targeting the CCL2/CCR2 signaling might be beneficial for the treatment of the itch and pain sensations accompanying ACD in humans.