Kan Jung-Yu, Wu Deng-Chyang, Yu Fang-Jung, Wu Cheng-Ying, Ho Ya-Wen, Chiu Yen-Jung, Jian Shu-Fang, Hung Jen-Yu, Wang Jaw-Yuan, Kuo Po-Lin
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Gastrointestinal and General Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
J Cell Physiol. 2015 Aug;230(8):1883-94. doi: 10.1002/jcp.24918.
Tumor micro-environment is a critical factor in the development of cancer. The aim of this study was to investigate the inflammatory cytokines secreted by tumor-associated dendritic cells (TADCs) that contribute to enhanced migration, invasion, and epithelial-to-mesenchymal transition (EMT) in colon cancer. The administration of recombinant human chemokine (C-C motif) ligand 5 (CCL5), which is largely expressed by colon cancer surrounding TADCs, mimicked the stimulation of TADC-conditioned medium on migration, invasion, and EMT in colon cancer cells. Blocking CCL5 by neutralizing antibodies or siRNA transfection diminished the promotion of cancer progression by TADCs. Tumor-infiltrating CD11c(+) DCs in human colon cancer specimens were shown to produce CCL5. The stimulation of colon cancer progression by TADC-derived CCL5 was associated with the up-regulation of non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), which subsequently increased the expression of Snail. Blocking MALAT-1 significantly decreased the TADC-conditioned medium and CCL5-mediated migration and invasion by decreasing the enhancement of Snail, suggesting that the MALAT-1/Snail pathway plays a critical role in TADC-mediated cancer progression. In conclusion, the inhibition of CCL5 or CCL5-related signaling may be an attractive therapeutic target in colon cancer patients.
肿瘤微环境是癌症发展的关键因素。本研究旨在探究肿瘤相关树突状细胞（TADC）分泌的炎性细胞因子，这些因子有助于增强结肠癌的迁移、侵袭和上皮-间质转化（EMT）。重组人趋化因子（C-C基序）配体5（CCL5）在TADC周围的结肠癌中大量表达，给予CCL5可模拟TADC条件培养基对结肠癌细胞迁移、侵袭和EMT的刺激作用。用中和抗体或siRNA转染阻断CCL5可减弱TADC对癌症进展的促进作用。人结肠癌标本中肿瘤浸润性CD11c(+)树突状细胞可产生CCL5。TADC来源的CCL5对结肠癌进展的刺激作用与非编码RNA转移相关肺腺癌转录本1（MALAT-1）的上调有关，MALAT-1随后增加Snail的表达。阻断MALAT-1可通过降低Snail的增强作用显著降低TADC条件培养基和CCL5介导的迁移和侵袭，这表明MALAT-1/Snail通路在TADC介导的癌症进展中起关键作用。总之，抑制CCL5或CCL5相关信号通路可能是结肠癌患者有吸引力的治疗靶点。
