The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker

Journal of Translational Medicine

Research

Douglas M Noonan¹  Eraldo O Bucci²  Ornella Gottardi²  Massimo C Barberis³  Valentina Bertolini⁴  Fausto Sessa⁵  Cecilia Garlanda⁶  Luigi Laghi⁶  Rosaria Cammarota⁷  Giuseppina Pennesi⁷  Adriana Albini⁸ 

[1] Department of Experimental Medicine, Università degli Studi dell'Insubria, (viale Ottorino Rossi n9), (21100), Varese, Italy;Department of Oncology, IRCCS MultiMedica, (via Piemonte 70), (21053), Castellanza, Italy;Department of Pathology, Istituto Europeo Oncologico, (via Ripamonti 435), (20141), Milan, Italy;Department of Pathology, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), (20138), Milan, Italy;Department of Pathology, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), (20138), Milan, Italy;Department of Experimental Medicine, Università degli Studi dell'Insubria, (viale Ottorino Rossi n9), (21100), Varese, Italy;Istituto Clinico Humanitas IRCCS, (via Manzoni 56), (20089), Rozzano, Italy;Oncology Research Laboratory, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), (20138), Milan, Italy;Oncology Research Laboratory, Science and Technology Park, IRCCS MultiMedica, (via Fantoli 16/15), (20138), Milan, Italy;Department of Oncology, IRCCS MultiMedica, (via Piemonte 70), (21053), Castellanza, Italy;

关键词: Ulcerative Colitis;    Hepatocyte Growth Factor;    Immune Cell Infiltration;    Stromal Compartment;    Epithelial Compartment;   

DOI  :  10.1186/1479-5876-8-112

 received in 2010-07-15, accepted in 2010-11-08,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundColorectal 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.MethodsThe 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.ResultsThe 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.ConclusionsThese data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.

【 授权许可】

Unknown   
© Cammarota et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.