Podoplanin Expression Identified in Stromal Fibroblasts as a Favorable Prognostic Marker in Patients with Colorectal Carcinoma
Podoplanin Expression Identified in Stromal Fibroblasts as a Favorable Prognostic Marker in Patients with Colorectal Carcinoma
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DOI：
10.1159/000226112
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发表时间：
2009-01-01
期刊：
影响因子：
3.5
通讯作者：
Hirohashi, Setsuo
中科院分区：
文献类型：
--
作者：
Yamanashi, Takahiro;Nakanishi, Yukihiro;Hirohashi, Setsuo
目的：肿瘤微环境在其发展过程中起着至关重要的作用。然而，与癌细胞相比，人们对癌症相关成纤维细胞（CAFs）的分子特征了解较少。我们研究了结直肠癌（CRC）患者间质成纤维细胞中podoplanin表达的临床病理意义。方法：我们从DNA芯片实验中选择podoplanin作为CAF的上调标记物。因此，podoplanin被确定为一个上调基因。在日本东京国立癌症中心医院对120例晚期结直肠癌患者的podoplanin表达进行免疫组化研究，并探讨其临床病理意义。通过与CRC细胞系（如HCT116和HCT15）共培养侵袭试验，还评估了podoplanin表达的生物学功能。结果：Podoplanin仅在间质成纤维细胞中表达，在肿瘤细胞中不表达。除淋巴管外，正常基质中不存在足平面蛋白。当超过30%的癌间质染色时，认为染色呈阳性。podoplanin阳性表达与肿瘤远端定位（p = 0.013）和肿瘤侵袭深度浅（p = 0.011）显著相关。单因素分析显示，间质成纤维细胞中podoplanin的阴性表达与疾病特异性生存（p = 0.0017）和无病生存（p < 0.0001）的降低显著相关。多因素分析显示，podoplanin阴性表达（p = 0.016）和淋巴结转移（p = 0.027）与无病生存显著相关。结直肠癌细胞侵袭通过与用siRNA处理过的CAFs共培养而增强。结论：我们的研究结果表明，间质成纤维细胞中podoplanin的阳性表达可能对CRC细胞侵袭具有保护作用，是晚期CRC患者预后良好的重要指标，生物学分析表明，CAFs中podoplanin的表达与CRC细胞侵袭减少有关。版权所有(C) 2009 S. Karger AG，巴塞尔
Objective: The microenvironment of cancer plays a critical role in its progression. However, the molecular features of cancer-associated fibroblasts (CAFs) are less well understood than those of cancer cells. We investigated the clinicopathological significance of podoplanin expression in stromal fibroblasts in patients with colorectal cancer (CRC). Methods: We selected podoplanin as an upregulated marker in CAF from a DNA microarray experiment. Consequently, podoplanin was identified as an upregulated gene. Immunohistochemical podoplanin expression was investigated at the National Cancer Center Hospital, Tokyo, Japan, in 120 patients with advanced CRC, and its clinicopathological significance was examined. The biological function of podoplanin expression was also assessed by a coculture invasion assay with CRC cell lines such as HCT116 and HCT15. Results: Podoplanin expression was exclusively confined to stromal fibroblasts and absent in tumor cells. Podoplanin is absent in normal stroma except for lymphatic vessels. Staining was considered positive when over 30% of the cancer stroma was stained. Positive podoplanin expression was significantly correlated with a more distal tumor localization (p = 0.013) and a shallower depth of tumor invasion (p = 0.011). Univariate analysis revealed that negative podoplanin expression in stromal fibroblasts was significantly associated with reduced disease-specific survival (p = 0.0017) and disease-free survival (p < 0.0001). Multivariate analysis revealed that negative podoplanin expression (p = 0.016) and lymph node metastasis (p = 0.027) were significantly associated with disease-free survival. CRC cell invasion was augmented by coculture with CAFs that were treated with siRNA for podoplanin. Conclusions: Our results suggest that a positive podoplanin expression in stromal fibroblasts could have a protective role against CRC cell invasion and is a significant indicator of a good prognosis in patients with advanced CRC, supported by biological analysis showing that podoplanin expression in CAFs is associated with decreased CRC cell invasion. Copyright (C) 2009 S. Karger AG, Basel