Immunohistochemical demonstration of proliferating lymphatic vessels in colorectal carcinoma and its clinicopathological significance

Department of Surgery, Shinshu University, Shonai, Nagano, Japan
Cancer Letters (Impact Factor: 5.62). 03/2007; 246(1-2):167-72. DOI: 10.1016/j.canlet.2006.02.013
Source: PubMed


Lymphatic metastasis to the regional lymph nodes through the lymphatic vessels is an important indicator of poor prognosis in many types of malignant tumors. Recently, much attention has been paid to lymphangiogenesis for its possible role on tumor progression in various carcinomas. However, morphological evidence that lymphatic vessels actively proliferate in colorectal carcinoma has not been reported. Here, we first devised a triple immunostaining method to detect proliferating lymphatic vessels utilizing antibody to Ki-67 antigen as a marker of cell proliferation, antibody to cytokeratin as an epithelial cell marker, and antibody to podoplanin as a lymphatic vessel-specific marker. Ki-67/podoplanin-immunoreactivity enabled us to identify proliferating lymphatic vessels, while cytokeratin immunoreactivity allowed us to distinguish proliferating lymphatic vessels from Ki-67/cytokeratin-positive carcinoma cells in lymphatic lumens. Analyzing 64 colorectal carcinoma patients' samples using this technique, we showed that both lymphatic vessel density and proliferating activity of lymphatic vessels were significantly increased in colorectal carcinoma tissues compared with their normal counterparts. We then examined the correlation between the degree of lymphangiogenesis and patients' prognosis or clinicopathological variables, but no statistically significant differences were obtained in these analyses. Thus, these results combined together indicate that extensive lymphangiogenesis occurs in colorectal carcinoma, but that the degree of lymphangiogenesis alone is not an independent prognostic factor for this disease.

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    • "The study of lymphatics has been facilitated by the identification of the lymphatic marker LYVE-1 [13-17]. LYVE-1 is found in lymphatic endothelium and not in blood vascular endothelium except in the sinusoidal endothelium of liver and spleen where uptake and degradation of HA is known to occur [17]. "
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    ABSTRACT: The lymphatic system is a major route for cancer cell dissemination and also a potential target for antitumor therapy. To investigate whether increased lymphatic vessel density (LVD) is a prognostic factor for nodal metastasis and survival, we studied peritumoral LVD (P-LVD) and intratumoral LVD (I-LVD) in samples from 102 patients with endometrial carcinoma; Endometrial carcinoma tissues were analyzed for lymphatic vessels by immunohistochemical staining with an antibody against LYVE-1. Univariate analysis was performed with Kaplan-Meier life-table curves to estimate survival, and was compared using the log rank test. Prognostic models used multivariate Cox regression analysis for multivariate analyses of survival; Our study showed that P-LVD, but not I-LVD, was significantly correlated with lymph vascular space invasion (LVSI), lymph node metastasis, tumor stage, and CD44 expression in endometrial carcinoma. Moreover, P-LVD was an independent prognostic factor for progression-free survival and overall survival of endometrial carcinoma; P-LVD may serve as a prognostic factor for endometrial carcinoma. The peritumoral lymphatics might play an important role in lymphatic vessel metastasis.
    Full-text · Article · Apr 2010 · BMC Cancer
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    • "Similarly, the clinicopathologic significance of lymphatic vessel density (LVD) in CRC remains controversial. Some studies demonstrated that LVD was an indicator of lymph node metastasis or patient survival [12] [13] [14] [15] [16], while others could not confirm the findings [17] [18]. "
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    ABSTRACT: Angiogenesis and lymphangiogenesis are essential for tumour development and progression. However, in colorectal cancer (CRC), the relationship between angiogenesis and clinical outcome is controversial, and the prognostic significance of lymphangiogenesis is not well examined because of the lack of specific a marker for lymphatic vessels. To evaluate blood microvessel density (MVD) following the proposed standard method for MVD assessment given by the first international consensus and lymphatic vessel density (LVD), and investigate their clinicopathologic and biologic significance in CRC. MVD and LVD in primary tumours (n=210), along with their corresponding adjacent normal mucosa (n=105) and distant normal mucosa (n=27) specimens, were immunohistochemically examined by using CD31 and D2-40 antibodies. Both MVD and LVD were higher in tumour compared with the corresponding normal mucosa. In tumours, MVD was positively related to particular interesting new cysteine-histidine-rich protein (PINCH) expression (P=0.006), but not with clinicopathologic variables. LVD, in both intratumoural and peritumoural areas of tumours, was reversely related to Dukes' stage. There was no association between MVD or LVD and patients' survival (P>0.05). Angiogenesis and lymphangiogenesis occurred in CRC development, but were not related to CRC patient prognosis. PINCH may play a potential role in tumour angiogenesis.
    Preview · Article · Dec 2008 · Digestive and Liver Disease
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    • "Tissue sections on slides were deparaffinized, dehydrated and made free in endogenous peroxidase activity as described previously (Omachi et al., 2007). Antigen retrieval was carried out by incubating tissue sections in a microwave in 10 mM Tris- HCl (pH 8.0) buffer containing 1 mM EDTA. "
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    ABSTRACT: Reactive oxygen species (ROS)-generating enzyme Nox1 is important in the induction of oncogenic Ras transformation phenotypes, but it is not defined whether Nox1 is involved in Ras-induced upregulation of vascular endothelial growth factor (VEGF), a potent stimulator of tumor angiogenesis. Here we describe that ablation of the Nox1 activity by Nox1 small-interference RNAs (siRNAs) or diphenylene iodonium (DPI) inhibited synthesis of both VEGF proteins and VEGF mRNAs in K-Ras transformed normal rat kidney (KNRK) cells. Nox1siRNAs and DPI suppressed extracellular signal-regulated kinase (ERK)-dependent phosphorylation of a transcription factor Sp1 and Sp1 binding to a VEGF promoter. Furthermore, tumors derived from Nox1siRNA-transfected KNRK cells markedly decreased neovascularization. The Nox1 activity was required for VEGF production in human colon cancer CaCO-2 cells, as in the case of KNRK cells. However, since overexpression of Nox1 in normal rat kidney cells failed to induce VEGF, the Nox1 activity alone was not sufficient to upregulate VEGF expression, which suggests that unlike the previously proposed model, Nox1 may act in concert with other effectors integrated into the Ras network. We propose that Nox1 mediates oncogenic Ras-induced upregulation of VEGF and angiogenesis by activating Sp1 through Ras-ERK-dependent phosphorylation of Sp1.
    Preview · Article · Jun 2008 · Oncogene
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