Al-Nomani Lukman, Friedrichs Jacqueline, Schüle Roland, Büttner Reinhard, Friedrichs Nicolaus
Institute of Pathology, University of Cologne Medical School, Kerpener Str. 62, 50937 Cologne, Germany.
Center for Clinical Research, University of Freiburg Medical School, Breisacherstr. 66, 79106 Freiburg, Germany.
Pathol Res Pract. 2015 Feb;211(2):171-4. doi: 10.1016/j.prp.2014.12.001. Epub 2014 Dec 11.
Four and a half LIM domain protein-2 (FHL2) is part of the focal adhesion structures modulating cell motility. FHL2 may translocate into the nucleus serving as a transcriptional cofactor binding several transcription factors. Overexpression of FHL2 has been linked to cancer progression in various neoplasias. The aim of the present study was to determine, whether FHL2's function as nuclear cofactor plays a prognostic role in invading tumor cells of sporadic and HNPCC-associated colorectal cancer (CRC).
Immunohistochemical staining intensity of nuclear FHL2 was quantified by Remmele score analysing 47 sporadic and 42 HNPCC-associated colorectal cancers. Analysis was restricted to carcinoma cells of the tumoral invasion front.
Confocal microscopy detected nuclear expression of FHL2 in colon cancer cells and absence of nuclear FHL2 signal in normal colon enterocytes. In colon cancer, nuclear FHL2 expression was predominantly observed in low-differentiated, often mucinous tumor areas. 42.55% of sporadic and 54.76% of HNPCC-associated CRC showed enhanced (Remmele score 6-12) nuclear FHL2 expression in the carcinoma cells of the tumoral advancing edge. Enhanced nuclear FHL2 expression was significantly linked to lymphatic metastasis in sporadic CRC (p=0.0197) and almost reached significance in HNPCC-associated CRC (p=0.0545). In contrast, nuclear FHL2 expression was neither associated with hematogenic metastasis in sporadic (p=0.7087) nor in HNPCC-associated colorectal cancer (p=0.3007).
We recently demonstrated that enhanced nuclear FHL2 expression in tumor stroma of sporadic colon cancer is associated with lymphatic metastasis. The results of the present study indicate a synergistic effect of nuclear cofactor FHL2 in tumor cells as well as in peritumoral stroma cells promoting lymphatic metastasis in sporadic CRC. As HNPCC-associated tumors did not show a significant association between tumoral nuclear FHL2 expression and lymphatic metastasis we speculate, that the intensive lymphocytic immune response in HNPCC precludes a direct contact of tumor cells and stromal cells resulting in reduced lymphatic spread.
四又二分之一LIM结构域蛋白2（FHL2）是调节细胞运动的粘着斑结构的一部分。FHL2可能转位至细胞核，作为结合多种转录因子的转录辅因子。FHL2的过表达与多种肿瘤的癌症进展有关。本研究的目的是确定FHL2作为核辅因子的功能在散发性和HNPCC相关结直肠癌（CRC）的侵袭性肿瘤细胞中是否具有预后作用。
通过Remmele评分对47例散发性和42例HNPCC相关的结直肠癌进行分析，定量核FHL2的免疫组化染色强度。分析仅限于肿瘤侵袭前沿的癌细胞。
共聚焦显微镜检测到结肠癌细胞中FHL2的核表达，而正常结肠肠上皮细胞中无核FHL2信号。在结肠癌中，核FHL2表达主要见于低分化、常为黏液性的肿瘤区域。42.55%的散发性和54.76%的HNPCC相关CRC在肿瘤前沿的癌细胞中显示核FHL2表达增强（Remmele评分6 - 12）。散发性CRC中核FHL2表达增强与淋巴转移显著相关（p = 0.0197），在HNPCC相关CRC中几乎达到显著水平（p = 0.0545）。相反，散发性（p = 0.7087）和HNPCC相关结直肠癌（p = 0.3007）中核FHL2表达均与血行转移无关。
我们最近证明散发性结肠癌肿瘤基质中核FHL2表达增强与淋巴转移有关。本研究结果表明核辅因子FHL2在肿瘤细胞以及肿瘤周围基质细胞中具有协同作用，促进散发性CRC中的淋巴转移。由于HNPCC相关肿瘤的肿瘤细胞核FHL2表达与淋巴转移之间未显示出显著关联，我们推测HNPCC中强烈的淋巴细胞免疫反应阻止了肿瘤细胞与基质细胞的直接接触，从而导致淋巴扩散减少。
