Second Department of Pathology, University of Athens, 12464 Athens, Greece.
Hum Pathol. 2011 Dec;42(12):1888-96. doi: 10.1016/j.humpath.2010.06.020. Epub 2011 Jun 12.
In colorectal cancer, the functional impact of proteins from different signaling pathways varies between tumor center and tumor front. Our objective was to identify differential protein expression profiles between the tumor center and the tumor front of colorectal cancer. Twenty proteins from different signaling pathways (epidermal growth factor receptor [EGFR], phosphorylated extracellular signal regulated kinase [pERK], receptor for hyalouronic acid mediated motility [RHAMM], Raf-1 kinase inhibitor protein [RKIP], β-catenin, E-cadherin, phosphorylated AK transforming [pAKT], p16, p21, Ki-67, B-cell Lymphoma-2 [BCL2], vascular endothelial growth factor, apoptosis protease activating factor 1 [APAF-1], mucin1 [MUC1], ephrin B2 receptor [EphB2], matrix metalloproteinase 7 [MMP7], phosphorylated mothers against decapentaplegic 2 [pSMAD2], caudal type homeobox transcription factor 2 [CDX2], Laminin5γ2, and mammalian sterile 20-like kinase 1 [MST1]) involved in colorectal cancer progression were studied immunohistochemically on 220 well-characterized patients using a multiple-punch tissue microarray including 437 and 430 samples from the tumor center and the invasive front, respectively. Mean expression between the tumor center and the tumor front varied statistically significantly for pSMAD2, pERK, Raf-1 kinase inhibitor protein, E-cadherin, pAKT, BCL2, vascular endothelial growth factor, EphB2, matrix metalloproteinase 7, CDX2, Laminin5γ2, MST1, and APAF-1. Overexpression of pAKT, BCL2, vascular endothelial growth factor, APAF-1, pERK, EphB2, Raf-1 kinase inhibitor protein, CDX2, E-cadherin, MST1 (P < .001 each), and pSMAD2 (P = .002) was more frequently observed in the tumor center, whereas matrix metalloproteinase 7 and Laminin5γ2 (P < .001 each) overexpression was associated with the invasive front. In multivariate analysis, vascular endothelial growth factor (P < .001), Raf-1 kinase inhibitor protein (P = .009), and Laminin5γ2 (P < .001) were the most relevant proteins with the multimarker phenotypes positive/positive/negative and negative/negative/positive being most discriminating between the tumor center and the tumor front. Moreover, the combination negative/negative/positive vascular endothelial growth factor/Raf-1 kinase inhibitor protein/Laminin5γ2 at the tumor front was associated with vascular/lymphatic invasion (P = .014), distant metastasis (P = .019), higher tumor grade (P < .001), and poorer survival (P = .05). Our findings show that, in colorectal cancer progression, vascular endothelial growth factor overexpression seems to play a role in the tumor center, whereas Laminin5γ2-positivity combined with Raf-1 kinase inhibitor protein loss is associated with tumor invasion at the front.
在结直肠癌中，不同信号通路的蛋白质的功能影响在肿瘤中心和肿瘤前缘之间有所不同。我们的目的是鉴定结直肠癌肿瘤中心和肿瘤前缘之间的差异蛋白表达谱。研究了来自不同信号通路的 20 种蛋白质（表皮生长因子受体[EGFR]、磷酸化细胞外信号调节激酶[pERK]、透明质酸介导运动受体[RHAMM]、Raf-1 激酶抑制剂蛋白[RKIP]、β-连环蛋白、E-钙粘蛋白、磷酸化 AK 转化[pAKT]、p16、p21、Ki-67、B 细胞淋巴瘤-2[BCL2]、血管内皮生长因子、凋亡蛋白酶激活因子 1[APAF-1]、粘蛋白 1[MUC1]、 EphB2 受体、基质金属蛋白酶 7[MMP7]、磷酸化母亲对抗 decapentaplegic 2[pSMAD2]、尾型同源盒转录因子 2[CDX2]、层粘连蛋白 5γ2 和哺乳动物无菌 20 样激酶 1[MST1]）在结直肠癌进展中涉及，使用包括肿瘤中心和侵袭前缘的 437 和 430 个样本的多个打孔组织微阵列，对 220 个特征明确的患者进行了免疫组织化学研究。pSMAD2、pERK、Raf-1 激酶抑制剂蛋白、E-钙粘蛋白、pAKT、BCL2、血管内皮生长因子、EphB2、基质金属蛋白酶 7、CDX2、层粘连蛋白 5γ2、MST1 和 APAF-1 之间的肿瘤中心和肿瘤前缘之间的平均表达在统计学上有显著差异。pAKT、BCL2、血管内皮生长因子、APAF-1、pERK、EphB2、Raf-1 激酶抑制剂蛋白、CDX2、E-钙粘蛋白、MST1（P <.001）和 pSMAD2（P =.002）的过度表达在肿瘤中心更常见，而基质金属蛋白酶 7 和层粘连蛋白 5γ2（P <.001）的过度表达与侵袭前缘有关。在多变量分析中，血管内皮生长因子（P <.001）、Raf-1 激酶抑制剂蛋白（P =.009）和层粘连蛋白 5γ2（P <.001）是与多标记表型阳性/阳性/阴性和阴性/阴性/阳性最相关的蛋白，最能区分肿瘤中心和肿瘤前缘。此外，肿瘤前缘的阴性/阴性/阳性血管内皮生长因子/Raf-1 激酶抑制剂蛋白/层粘连蛋白 5γ2 组合与血管/淋巴管浸润（P =.014）、远处转移（P =.019）、更高的肿瘤分级（P <.001）和较差的生存（P =.05）相关。我们的研究结果表明，在结直肠癌的进展中，血管内皮生长因子的过度表达似乎在肿瘤中心起作用，而层粘连蛋白 5γ2 阳性与 Raf-1 激酶抑制剂蛋白缺失相结合与肿瘤前缘的侵袭有关。
