Laboratory of Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano, Milan, Italy.
Br J Cancer. 2013 Oct 29;109(9):2424-33. doi: 10.1038/bjc.2013.565. Epub 2013 Oct 1.
In pancreatic ductal adenocarcinoma (PDAC), fractalkine receptor CX3CR1 contributes to perineural invasion (PNI). We investigated whether CX3CR1 expression occurs early in PDAC and correlates with tumour features other than PNI.
We studied CX3CR1 and CX3CL1 expression by immunohistochemistry in 104 human PDAC and coexisting Pancreatic Intraepithelial Neoplasia (PanIN), and in PdxCre/LSL-Kras(G12D) mouse model of PDAC. CX3CR1 expression in vitro was studied by a spheroid model, and in vivo by syngenic mouse graft of tumour cells.
In total, 56 (53.9%) PDAC expressed CX3CR1, 70 (67.3%) CX3CL1, and 45 (43.3%) both. CX3CR1 expression was independently associated with tumour glandular differentiation (P=0.005) and PNI (P=0.01). Pancreatic Intraepithelial Neoplasias were more frequently CX3CR1+ (80.3%, P<0.001) and CX3CL1+ (86.8%, P=0.002) than matched cancers. The survival of PDAC patients was better in those with CX3CR1+ tumour (P=0.05). Mouse PanINs were also CX3CR1(+) and -CL1(+). In vitro, cytokines significantly increased CX3CL1 but not CX3CR1 expression. Differently, CX3CR1 was upregulated in tumour spheroids, and in vivo only in well-differentiated tumours.
Tumour differentiation, rather than inflammatory signalling, modulates CX3CR1 expression in PanINs and PDAC. CX3CR1 expression pattern suggests its early involvement in PDAC progression, outlining a potential target for interfering with the PanIN transition to invasive cancer.
在胰腺导管腺癌（PDAC）中，趋化因子受体 CX3CR1 有助于神经周围侵犯（PNI）。我们研究了 CX3CR1 表达是否在 PDAC 早期发生，以及是否与 PNI 以外的肿瘤特征相关。
我们通过免疫组织化学法研究了 104 例人 PDAC 和共存的胰腺上皮内瘤变（PanIN）以及 PDAC 的 PdxCre/LSL-Kras(G12D) 小鼠模型中 CX3CR1 和 CX3CL1 的表达。通过球体模型研究了 CX3CR1 的体外表达，通过同种异体小鼠肿瘤细胞移植研究了体内表达。
共有 56（53.9%）例 PDAC 表达 CX3CR1，70（67.3%）例表达 CX3CL1，45（43.3%）例同时表达两者。CX3CR1 的表达与肿瘤腺分化（P=0.005）和 PNI（P=0.01）独立相关。胰腺上皮内瘤变更常表达 CX3CR1（80.3%，P<0.001）和 CX3CL1（86.8%，P=0.002）。CX3CR1 阳性肿瘤患者的生存时间更好（P=0.05）。小鼠 PanIN 也表达 CX3CR1 和 -CL1。体外，细胞因子显著增加了 CX3CL1 但不增加 CX3CR1 的表达。相反，肿瘤球体中上调了 CX3CR1，体内仅在分化良好的肿瘤中上调。
肿瘤分化，而不是炎症信号，调节 PanIN 和 PDAC 中的 CX3CR1 表达。CX3CR1 的表达模式表明其在 PDAC 进展中的早期参与，为干扰 PanIN 向浸润性癌症的转变提供了一个潜在的靶点。
