Tumor Microvessel Density as a Predictor of Recurrence After Resection of Hepatocellular Carcinoma: A Prospective Study

Poon, Ronnie Tung‐Ping; Ng, Irene Oi–Lin; Lau, CK; Yu, Wun-Ching; Yang, Zhenfan; Fan, Sheung‐Tat; Wong, John

doi:10.1200/jco.2002.07.089

Cited by 266 publications

(226 citation statements)

References 44 publications

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“…[48][49][50] In HCC, several groups have reported that high tumor MVD by CD34 or vWF immunostaining may serve as an adverse prognostic marker for HCC less than 5 cm. 51,52 Some suggested that higher tumor MVD may predispose to micrometastasis and tumor angiogenesis may be one of the most important factors to influence tumor recurrence of small HCC. Therefore, it would be interesting to assess whether the MVD measured with the novel markers reported in the current study may prove to be a better and more reliable prognostic marker than CD34.…”

Section: Discussionmentioning

confidence: 99%

Novel endothelial cell markers in hepatocellular carcinoma

et al. 2004

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Hepatocellular carcinoma is characterized by hypervascularity and a propensity for vascular invasion. Detailed analysis of complementary DNA (cDNA) microarray global gene expression data and further validation on a smaller independent sample set by reverse transcription-polymerase chain reaction established the presence of two endothelial gene clusters in hepatocellular carcinoma. Cluster I, consists of 20 cDNA clones, representing 15 unique genes. Cluster II consists of nine unique genes. The expression of the cluster I genes appeared to be significantly upregulated in hepatocellular carcinoma compared with normal liver, cirrhotic liver, or nontumor liver tissues adjacent to the hepatocellular carcinoma. The pattern of gene expression of cluster I genes correlated positively with the 'proliferation gene cluster' and 'stromal cells cluster 2'. Expression of cluster II genes, in contrast, was not significantly different between hepatocellular carcinoma and non-neoplastic liver tissues. Studies conducted to localize the protein products of these genes by immunohistochemical staining of tissue arrays with up to 350 cores of tissues, and by in situ hybridization led to the discovery of novel sinusoidal endothelial cell markers in hepatocellular carcinoma: podocalyxin-like and regulator of G protein signaling-5. Our results underscore fundamental differences not only between neoplastic vs non-neoplastic liver cells but also between the hepatic sinusoidal endothelium of hepatocellular carcinoma and normal liver.

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Section: Discussionmentioning

confidence: 99%

Novel endothelial cell markers in hepatocellular carcinoma

et al. 2004

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“…Overexpression of CD151 or a high MVD alone was correlated with a poor prognosis for HCC patients. 6,27 To evaluate the prognostic significance of the overexpression profile of CD151, MMP9, and MVD together, immunohistochemical double-staining analysis of CD151, MMP9 expression, and MVD-CD34 staining was performed. Simultaneously higher levels of CD151, MMP9 expression, and MVD were observed in HCC tissues with a malignant phenotype (e.g., microvascular invasion, larger size, and dedifferentiation; Supporting Information Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…6 The MVD was evaluated as described elsewhere. 27 Statistical Analysis. Statistical analysis was performed with SPSS12.0 software (SPSS, Chicago, IL).…”

Section: Methodsmentioning

confidence: 99%

CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma

et al. 2010

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Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3b (GSK-3b)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151 high in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC. Conclusion: Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3b/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC. (HEPATOLOGY 2010;52:183-196) Abbreviations: AFP, alpha-fetoprotein; AKT, protein kinase B; bFGF, basic fibroblast growth factor; CDC42, cell division control protein 42 homologue; CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSK, glycogen synthase kinase; H&E, hematoxylin and eosin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HR, hazard ratio; HUVEC, human umbilical vein endothelial cell; LY294002, 2-morpholin-4-yl-8-phenylchromen-4-one; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; MVD, microvessel density; NA, not adopted; NS, not significant; OS, overall survival; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time polymerase chain reaction; RT-PCR, reverse transcription polymerase chain reaction; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNM, tumor node metastasis; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; VEGF, vascular endothelial growth factor.From the

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“…The preoperative clinical diagnosis of HCC met the diagnostic criteria of the American Association for the Study of Liver Diseases (Bruix and Sherman, 2005;Bridges et al, 2011 (Poon et al, 2002), (c) complete clinicopathologic and follow-up data. The exclusion criteria included (a) extra hepatic spread and (b) prior anticancer treatments before liver resection.…”

Section: Patients and Tissue Samplesmentioning

confidence: 99%

Roles of Fibroblast Growth Factor-inducible 14 in Hepatocellular Carcinoma

Hu²,

Shi³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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The prognostic value of the fibroblast growth factor-inducible 14 (Fn14) expression in hepatocellular carcinoma (HCC) is unknown. Real-time PCR (RT-PCR), western blot assays and immunohistochemistry analysis were here performed in order to compare Fn14 expressios in paired liver samples of HCC and normal liver tissue. Most of the tumor tissues expressed significantly higher levels of Fn14 compared to adjacent non-tumor tissues, with Fn14High accounting for 54.6% (142/260) of all patients. The Pearson χ 2 test indicated that Fn14 expression was closely associated with serum alpha fetal protein (AFP) (P=0.002) and tumor number (p=0.019). Univariate and multivariate analyses revealed that along with tumor diameter and portal vein tumor thrombosis (PVTT ) type, Fn14 was an independent prognostic factor for both overall survival (OS) (HR=1.398, p=0.008) and recurrence (HR=1.541, p=0.001) rates. Fn14 overexpression HCC correlated with poor surgical outcome, and this molecule may be a candidate biomarker for prognosis as well as a target for therapy.

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Tumor Microvessel Density as a Predictor of Recurrence After Resection of Hepatocellular Carcinoma: A Prospective Study

Abstract: This study shows that a high MVD-CD34 was predictive of early postresection recurrence in patients with HCCs < or = 5 cm and, therefore, may be a novel prognostic marker in this subset of patients.

Cited by 266 publications

References 44 publications

Novel endothelial cell markers in hepatocellular carcinoma

Novel endothelial cell markers in hepatocellular carcinoma

CD151 Modulates Expression of Matrix Metalloproteinase 9 and Promotes Neoangiogenesis and Progression of Hepatocellular Carcinoma

Roles of Fibroblast Growth Factor-inducible 14 in Hepatocellular Carcinoma

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