6352

CCL5

chemokine (C-C motif) ligand 5;CCL5;chemokine (C-C motif) ligand 5

C-C motif chemokine 5|T-cell specific protein p288|beta-chemokine RANTES|eosinophil chemotactic cytokine|regulated upon activation, normally T-expressed, and presumably secreted|small inducible cytokine subfamily A (Cys-Cys), member 5

17q12

protein-coding

This study examined the role of regulated upon activation normal T cell expressed and secreted (RANTES) and its receptor C-C chemokine receptor type 5 (CCR5) in gastric cancer metastasis and the associated mechanism. The expression of RANTES and CCR5 was detected by using immunohistochemical staining and Western blotting in the gastric cancer tissues obtained from 60 gastric cancer patients with or without lymph node metastasis (n=30 in each). The results showed that the expression levels of RANTES and CCR5 were higher in gastric cancer with lymph node metastasis than in that without metastasis (P<0.05). The expression levels of RANTES in 30 lymph nodes with cancerous invasion were higher than in 30 normal lymph nodes (P<0.05). Chemotactic test revealed that the number of migrating gastric cancer cells (n=295.0 +/- 54.6) induced by the protein of cancer-invading lymph nodes was greater than that by the protein mixture from cancer-invading lymph nodes and RANTES antibody (n=42.5 +/- 11.6) (P<0.05). RT-PCR showed that the expression levels of the main Th1 cytokines (IL-2, Gamma-IFN) were lower in gastric cancer with lymph node metastasis (2.22 +/- 0.90, 3.26 +/- 1.15 respectively) than in that without metastasis (3.07 +/- 1.67, 4.77 +/- 1.52 respectively) (P<0.05), but the expression level of the main Th 2 cytokine (IL-10) was higher in gastric cancer with lymph nodes metastasis (6.06 +/- 2.04) than in that without metastasis (4.88 +/- 1.87) (P<0.05). It was concluded that RANTES and its receptor CCR5 may contribute to gastric cancer metastasis through influencing the balance of Th1/Th2. RANTES and CCR5 may become a marker of gastric cancer metastasis.

Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment.

Although the contribution of the bone marrow mesenchymal stem cells (BM-MSCs) in cancer progression is emerging, their potential roles in prostate cancer (PCa) remain unclear. Here, we showed that PCa cells could recruit BM-MSCs and consequently the metastatic ability of PCa cells was increased. We also found that the increased metastatic ability of PCa cells could be due to the increased PCa stem cell population. Mechanism dissection studies found that the upregulation of Chemokine ligand 5 (CCL5) expression in BM-MSCs and PCa cells, after MSCs infiltrated into the PCa cells, subsequently downregulated androgen receptor (AR) signaling, which was due to inhibition of AR nuclear translocation. Interruption of such signaling led to suppression of the BM-MSCs-induced PCa stem cell population increase and thereby inhibited the metastatic ability of PCa cells. The PCa stem cell increase then led to the upregulation of matrix metalloproteinase 9, ZEB-1, CD133 and CXCR4 molecules, and enhanced the metastatic ability of PCa cells. Therefore, we conclude that the BM-MSCs-mediated increased metastatic ability of PCa cells can be due to the PCa stem cell increase via alteration of the CCL5-AR signaling pathway. Together, these results uncover the important roles of BM-MSCs as key components in the prostate tumor microenvironment to promote PCa metastasis and may provide a new potential target to suppress PCa metastasis by blocking BM-MSCs infiltration into PCa.