Shimada Yoshihisa, Ishii Genichiro, Nagai Kanji, Atsumi Naho, Fujii Satoshi, Yamada Atsushi, Yamane Yuki, Hishida Tomoyuki, Nishimura Mitsuyo, Yoshida Junji, Ikeda Norihiko, Ochiai Atsushi
Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Cancer Sci. 2009 Nov;100(11):2054-9. doi: 10.1111/j.1349-7006.2009.01295.x. Epub 2009 Jul 21.
Recent molecular biological studies have identified podoplanin as a candidate cancer stem cell (CSC) marker in squamous cell carcinoma (SqCC). The purpose of this study was to examine the expression pattern of podoplanin, and the other stem cell markers CD44 and p63, and their relationship to clinico-pathological features including survival in pulmonary SqCC. We examined histologically the expression of podoplanin, CD44, and p63 in 162 consecutive SqCC by immunostaining. Podoplanin expression was observed in 107 (66%) tumors, CD44 in 145 (89.5%), and p63 in 151 (93.2%), respectively. In 95.3% of the podoplanin-positive tumors, tumor cells showing strong expression were localized in the periphery of the tumor nests. However, this peripheral localization was observed in only 55.9% of the CD44-positive and 43% of p63-positive tumors. In 88.8% of the podoplanin-positive tumors, positive cells were localized more peripherally in the tumor nests than CD44- or p63-positive cells and when CD44 and p63 expressions were compared in these podoplanin-positive tumors, p63-positive layers in the periphery of the tumor nests were broader compared to CD44-positive layers. These findings suggest tumor cells are aligned in the "hierarchical distribution pattern" according to the expression of these three markers. Patients who had podoplanin-positive tumors with the "hierarchical pattern" resulted in significantly better overall survival than those who had podoplanin-negative tumors (P = 0.043). These results suggest that podoplanin expression would reflect the most immature status in the differentiation process of SqCC, and SqCC with hierarchical expression would be a well-organized tumor group with lower biological aggressiveness based on the CSC concept.
近期分子生物学研究已将血小板反应蛋白-1确定为鳞状细胞癌（SqCC）中一种潜在的癌症干细胞（CSC）标志物。本研究旨在检测血小板反应蛋白-1、其他干细胞标志物CD44和p63的表达模式，以及它们与肺SqCC临床病理特征（包括生存率）的关系。我们通过免疫染色对162例连续性SqCC进行组织学检查，检测血小板反应蛋白-1、CD44和p63的表达。分别在107例（66%）肿瘤中观察到血小板反应蛋白-1表达，145例（89.5%）中观察到CD44表达，151例（93.2%）中观察到p63表达。在95.3%的血小板反应蛋白-1阳性肿瘤中，显示强表达的肿瘤细胞位于肿瘤巢的周边。然而，仅在55.9%的CD44阳性肿瘤和43%的p63阳性肿瘤中观察到这种周边定位。在88.8%的血小板反应蛋白-1阳性肿瘤中，阳性细胞在肿瘤巢中的定位比CD44或p63阳性细胞更靠外周，并且在这些血小板反应蛋白-1阳性肿瘤中比较CD44和p63表达时，肿瘤巢周边的p63阳性层比CD44阳性层更宽。这些发现表明肿瘤细胞根据这三种标志物的表达呈“分层分布模式”排列。具有“分层模式”的血小板反应蛋白-1阳性肿瘤患者的总生存率显著高于血小板反应蛋白-1阴性肿瘤患者（P = 0.043）。这些结果表明血小板反应蛋白-1表达可反映SqCC分化过程中最不成熟的状态，基于CSC概念，具有分层表达的SqCC将是一个生物学侵袭性较低、组织良好的肿瘤组。
