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Invasive front of colorectal cancer:Dynamic interface of pro-/anti-tumor factors

World Journal of Gastroenterology 2009年第47期15卷 5898-5906页

作者： inti zlobec Alessandro Lugli Institute for Pathology University Hospital BaselSchnbeinstrasse 40CH-4031 BaselSwitzerland

Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding" ,a feature which can be highly specific for tumors showing an inf iltrating tumor growth pattern. Importantly,tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact,several tumor-associated antigens such as CD3,CD4,CD8,CD20,Granzyme B,FOXP3 and other immunological or inflammatory cell types have been identified as poten-tially prognostic in patients with this disease. Evidence seems to suggest that the balance between protumor (including budding and inf iltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand,the inf iltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other,the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features,such as the BRE and Gleason scores,the ratio of pro-and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer whi

关键词： Colorectal cancer Prognosis Tumor invasive front Tumor budding Tumor growth pattern Tumor infiltrating lymphocytes Tumor immunity Microsatellite instability

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ABCG5-positivity in tumor buds is an indicator of poor prognosis in node-negative colorectal cancer patients

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World Journal of Gastroenterology 2010年第6期16卷 732-739页

作者： lsabel Hostettler inti zlobec Luigi Terracciano Alessandro Lugli Institute for Pathology University Hospital of Basel

AIM:To analyze the expression of 8 putative cancer stem cell(CSC) markers within colorectal cancer tumor buds and to determine their prognostic impact in patients with this disease. METHODS:Immunohistochemistry was performed on 101 colorectal cancer resections for CK22(to identify tumor buds) as well as CD133,CD166,CD24,CD44s,CD90,EpCAM,ALDH1,and ABCG5,and their expression within tumor buds was evaluated. RESULTS:CD90,CD44s,and CD133 expression in tumor buds was found in less than 5%of all cases. ALDH1,CD24,CD166 were expressed in 16.5%,16.2%,and 34%cases,respectively,while ABCG5 and EpCAM expression was more frequent and found in 35%and 69%of cases,*** the 8 markers studied,EpCAM and ABCG5 positivity in tumor buds were significantly associated with poor prognosis(P=0.023,P=0.038,respectively) in multivariable analysis with pT and pN classificationP=0.048;hazard ratio(HR) :2.64;95%CI:1.0-6.9,for EpCAM and P=0.029;HR:2.22;95%CI:1.0-4.5,for *** survival time was particularly striking for lymph node-negative patients with ABCG5-positive buds(P<0.001) . CONCLUSION:Expression of putative stem cell markers EpCAM and ABCG5 within the tumor buds of colorectal cancer are frequently noted and are associated with poor prognosis.

关键词： Colorectal cancer Cancer stem cells Tumor budding ABCG5 Prognosis

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Tumor budding predicts response to anti-EGFR therapies in metastatic colorectal cancer patients

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World Journal of Gastroenterology 2010年第38期16卷 4823-4831页

作者： inti zlobec Francesca Molinari Vittoria Martin Luca Mazzucchelli Piercarlo Saletti Rosangela Trezzi Sara De Dosso Tatjana Vlajnic Milo Frattini Alessandro Lugli Institute for Pathology University Hospital Basel Institute of Pathology Division of Medical Oncology Institute of Southern Switzerland

AIM:To investigate whether the evaluation of tumor budding can complement K-RAS analysis to improve the individualized prediction of response to anti-epidermal growth factor receptor based therapies in metastatic colorectal cancer (mCRC) patients. METHODS:Forty-three patients with mCRC treated with cetuximab or panitumumab were entered into this study. According to the Response Evaluation Criteria in Solid Tumors criteria, 30 patients had stable or progressive disease (non-responsive), while 13 patients had a partial response. Tumor buds were evaluated from whole tissue sections stained for pan-cytokeratin, evaluated in the densest region using a 40 × objective and "high-grade" tumor budding was defi ned as 15 buds/high-power f ***: Tumor buds and K-RAS mutation both correctly classif ied 68% of patients. All patients with K-RAS mutation (n=7) or high-grade tumor budding (n=11) were non-responsive, of which 4 patients had both features. All 13 partial responders were K-RAS wild-type with low-grade tumor budding. Combined, the predictive value of K-RAS and tumor budding was 80%. Additionally, high-grade tumor budding was significantly related to worse progression-free survival [HR (95% CI): 2.8 (1.3-6.0, P=0.008)].CONCLUSION: If confirmed in larger cohorts, the addition of tumor budding to K-RAS analysis may represent an effective approach for individualized patient management in the metastatic setting.

关键词： Anti-epidermal growth factor receptor therapy Colorectal cancer K-RAS Prognosis Tumor budding

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