Oncology Research Laboratory, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), Milan, (20138), Italy.
J Transl Med. 2010 Nov 8;8:112. doi: 10.1186/1479-5876-8-112.
Colorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers.
The presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control.
The differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels.
These data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.
结直肠癌在早期发现时可以得到有效治疗，因此寻找新的标志物至关重要。由于炎症与癌症的进展和血管生成有关，我们研究了细胞因子如白细胞介素 6（IL-6）和其他在先天免疫系统中起关键作用的介质在不同阶段结肠疾病进展的病变微环境中的表达，从溃疡性结肠炎到腺瘤和腺癌，以寻找有用的标志物。
通过免疫组织化学，在特定的组织隔室（上皮、基质、内皮）中定量检测炎症过程中关键细胞因子的存在和表达。使用 Tir8（炎症反应的负调节剂）缺失的鼠氧化偶氮甲烷/葡聚糖硫酸盐模型来证实临床观察结果。对 116 例不同阶段结直肠疾病患者的存档组织样本进行研究：13 例溃疡性结肠炎（UC），34 例管状或管状绒毛状腺瘤（AD）和 53 例浸润性腺癌。使用与癌组织一起切除的 16 例健康黏膜组织作为对照。
健康组织与不同病变之间的差异特征是明显的炎症-血管生成反应，所有病变组织中 CD68、CD15 和 CD31 表达细胞数量明显（P < 0.05）升高，与恶性程度的增加相关。我们注意到所有病变组织中潜在的调节分子肝细胞生长因子的下调（P < 0.05）。在人类样本和鼠模型中，肿瘤微环境中 TLR-4 和 IL6 的表达与腺癌相关。我们发现，肿瘤基质中 TLR-4 表达较高的腺癌患者（pT1-4）疾病进展的风险显著增加。在诊断为 pT3（33 例）结肠癌的患者中，肿瘤基质中 TLR-4 水平非常高的患者复发时间明显早于表达水平较低的患者。
这些数据表明，肿瘤微环境中 TLR-4 的高表达可能是结肠癌疾病进展的一个潜在标志物。
