Zipin-Roitman Adi, Meshel Tsipi, Sagi-Assif Orit, Shalmon Bruria, Avivi Camila, Pfeffer Raphael M, Witz Isaac P, Ben-Baruch Adit
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Cancer Res. 2007 Apr 1;67(7):3396-405. doi: 10.1158/0008-5472.CAN-06-3087.
CXCL10 was recently shown to exert antimalignancy functions by influencing the tumor microenvironment. Here, we have taken a different approach, investigating the effects of CXCL10 directly on tumor-promoting functions in colorectal carcinoma (CRC) cells. CXCL10 expression was detected in preferred metastatic sites of CRC (liver, lungs, and lymph nodes), and its CXCR3 receptor was expressed by eight CRC cell lines (detected: reverse transcription-PCR and/or flow cytometry). Detailed analysis was done on two cell lines derived from primary CRC tumors (SW480, KM12C) and their metastatic descendents (SW620 and KM12SM). The three known variants of CXCR3 (CXCR3-A, CXCR3-B, and CXCR3-alt) were detected in all four cell lines. CXCR3 expression was also observed on colorectal tumor cells in biopsies of CRC patients (immunohistochemistry). CXCL10 and CXCR3 expression were potently induced in CRC cells by Interferon gamma and all four CRC cell lines responded to CXCL10 by extracellular signal-regulated kinase 1/2 dephosphorylation. The chemokine did not affect tumor cell growth or angiogenesis-related functions in the tumor cells, such as CXCL8 and vascular endothelial growth factor secretion. Importantly, CXCL10 significantly up-regulated invasion-related properties in CRC cells: It promoted matrix metalloproteinase 9 expression and induced CRC cell migration. Of note, CXCL10-induced migration was detected only in the two metastatic cells and not in their primary counterparts. Also, CXCL10 promoted the adhesion of metastatic cells to laminin. These results suggest that CXCL10 can be exploited by CRC cells toward their progression, thus possibly antagonizing the antimalignancy effects of the chemokine on the tumor microenvironment. Therefore, care should be taken when considering CXCL10 as a therapeutic antitumor modality for CRC treatment.
最近研究表明，CXCL10可通过影响肿瘤微环境发挥抗癌功能。在此，我们采用了不同的方法，直接研究CXCL10对结直肠癌（CRC）细胞促肿瘤功能的影响。在CRC的优先转移部位（肝脏、肺和淋巴结）检测到CXCL10表达，其CXCR3受体在8种CRC细胞系中表达（检测方法：逆转录 - PCR和/或流式细胞术）。对源自原发性CRC肿瘤的两种细胞系（SW480、KM12C）及其转移后代（SW620和KM12SM）进行了详细分析。在所有四种细胞系中均检测到CXCR3的三种已知变体（CXCR3 - A、CXCR3 - B和CXCR3 - alt）。在CRC患者活检的结直肠肿瘤细胞上也观察到CXCR3表达（免疫组织化学）。干扰素γ可在CRC细胞中有效诱导CXCL10和CXCR3表达，并且所有四种CRC细胞系均通过细胞外信号调节激酶1/2去磷酸化对CXCL10产生反应。趋化因子不影响肿瘤细胞生长或肿瘤细胞中与血管生成相关的功能，如CXCL8和血管内皮生长因子分泌。重要的是，CXCL10显著上调CRC细胞中与侵袭相关的特性：它促进基质金属蛋白酶9表达并诱导CRC细胞迁移。值得注意的是，仅在两种转移细胞中检测到CXCL10诱导的迁移，而在其原发性对应细胞中未检测到。此外，CXCL10促进转移细胞与层粘连蛋白的粘附。这些结果表明，CRC细胞可利用CXCL10促进其进展，从而可能拮抗趋化因子对肿瘤微环境的抗癌作用。因此，在将CXCL10作为CRC治疗的治疗性抗肿瘤手段时应谨慎考虑。
