Two Distinct Types of Blood Vessels in Clear Cell Renal Cell Carcinoma Have Contrasting Prognostic Implications

Yao, Xin; Qian, Chao Nan; Zhang, Zhong Fa; Tan, Min; Kort, Eric J.; Yang, Ximing J.; Resau, James H.; Teh, Bin Tean

doi:10.1158/1078-0432.ccr-06-0774

Cited by 80 publications

(102 citation statements)

References 41 publications

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“…These findings suggest that CC-RCC with high MVD and low ECP% may have a more stabilised and mature vasculature than their counterpart. Our finding is concordant with a recent study, which described differentiated and undifferentiated types of blood vessels in CC-RCC (Yao et al, 2007). They found that an increased density of undifferentiated vessels significantly correlated with higher pathological grades and shorter patient survival.…”

Section: Discussionsupporting

confidence: 93%

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

et al. 2007

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Clear cell renal cell carcinoma (CC-RCC) is a highly vascularised tumour and is therefore an attractive disease to study angiogenesis and to test novel angiogenesis inhibitors in early clinical development. Endothelial cell proliferation plays a pivotal role in the process of angiogenesis. The aim of this study was to compare angiogenesis parameters in low nuclear grade (n ¼ 87) vs high nuclear grade CC-RCC (n ¼ 63). A panel of antibodies was used for immunohistochemistry: CD34/Ki-67, carbonic anhydrase IX, hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF). Vessel density (MVD -microvessel density), endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. mRNA expression levels of angiogenesis stimulators and inhibitors were determined by quantitative RT -PCR. High-grade CC-RCC showed a higher ECP% (P ¼ 0.049), a higher TCP% (P ¼ 0.009), a higher VEGF protein expression (Po0.001), a lower MVD (Po 0.001) and a lower HIF-1a protein expression (P ¼ 0.002) than low-grade CC-RCC. Growth factor mRNA expression analyses revealed a higher expression of angiopoietin 2 in low-grade CC-RCC. Microvessel density and ECP% were inversely correlated (Rho ¼ À0.26, P ¼ 0.001). Because of the imperfect association of nuclear grade and ECP% or MVD, CC-RCC was also grouped based on low/high MVD and ECP%. This analysis revealed a higher expression of vessel maturation and stabilisation factors (placental growth factor, PDGFB1, angiopoietin 1) in CC-RCC with high MVD, a group of CC-RCC highly enriched in low nuclear grade CC-RCC, with low ECP%. Our results suggest heterogeneity in angiogenic activity and vessel maturation of CC-RCC, to a large extent linked to nuclear grade, and, with probable therapeutic implications.

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Section: Discussionsupporting

confidence: 93%

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

et al. 2007

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“…For example, in tumors such as clear cell renal cell carcinoma, both differentiated and undifferentiated vessels (i.e. vessels made up of cells that have grown to the normal mature stage of development and vessels made up of cells that remain in an immature or ''primitive'' stage) coexist, which could serve as a basis for an alternative classification (Yao et al, 2007). Therefore, it seems to us that the studies aiming at determining a fractal dimension from 2D thin tissue sections of tumor tissues (for example Weyn et al, 2004) must be interpreted with great caution until these methodological issues are resolved.…”

Section: Discussionmentioning

confidence: 99%

Fractal analysis of vascular networks: Insights from morphogenesis

Lorthois

Cassot

2010

Journal of Theoretical Biology

130

119

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OATAO is an open access repository that collects the work of Toulouse researchers and makes it freely available over the web where possible. This is an author-deposited version published in : http://oatao. a b s t r a c t Considering their extremely complicated and hierarchical structure, a long standing question in vascular physio-pathology is how to characterize blood vessels patterns, including which parameters to use. Another question is how to define a pertinent taxonomy, with applications to normal development and to diagnosis and/or staging of diseases.To address these issues, fractal analysis has been applied by previous investigators to a large variety of healthy or pathologic vascular networks whose fractal dimensions have been sought. A review of the results obtained on healthy vascular networks first shows that no consensus has emerged about whether normal networks must be considered as fractals or not.Based on a review of previous theoretical work on vascular morphogenesis, we argue that these divergences are the signature of a two-step morphogenesis process, where vascular networks form via progressive penetration of arterial and venous quasi-fractal arborescences into a pre-existing homogeneous capillary mesh. Adopting this perspective, we study the multi-scale behavior of generic patterns (model structures constructed as the superposition of homogeneous meshes and quasi-fractal trees) and of healthy intracortical networks in order to determine the artifactual and true components of their multi-scale behavior. We demonstrate that, at least in the brain, healthy vascular structures are a superposition of two components: at low scale, a mesh-like capillary component which becomes homogeneous and space-filling over a cut-off length of order of its characteristic length; at larger scale, quasi-fractal branched (tree-like) structures. Such complex structures are consistent with all previous studies on the multi-scale behavior of vascular structures at different scales, resolving the apparent contradiction about their fractal nature.Consequences regarding the way fractal analysis of vascular networks should be conducted to provide meaningful results are presented. Finally, consequences for vascular morphogenesis or hemodynamics are discussed, as well as implications in case of pathological conditions, such as cancer.

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“…Our recent study demonstrated that within CCRCC there are at least 2 major categories of blood vessels having contrasting prognostic implications: the undifferentiated vessels (expressing CD31 but not CD34) and the differentiated vessels (expressing both CD31 and CD34). 34 The morphologic characteristics of undifferentiated vessels include no (or a small) lumen, a thicker vessel wall, and smaller size when compared with differentiated vessels. A higher density of undifferentiated vessels is correlated with shorter patient survival, higher grade tumors, and a more advanced primary tumor.…”

Section: Differential Analysis Of Tumor Vasculaturementioning

confidence: 99%

Complexity of tumor vasculature in clear cell renal cell carcinoma

Qian

Huang

Wondergem

et al. 2009

Cancer

Self Cite

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Clear cell renal cell carcinoma (CCRCC) is a highly vascularized cancer resistant to conventional chemotherapy and radiotherapy. Antiangiogenic therapy has achieved some effectiveness against this unique malignancy. The complexity of the tumor vasculature in CCRCC has led to differences in correlating tumor microvessel density with patient prognosis. The authors' recent findings demonstrated that there were at least 2 major categories of tumor vessels in CCRCC-namely, undifferentiated and differentiated-correlating with patient prognosis in contrasting ways, with higher undifferentiated vessel density indicating poorer prognosis, and higher differentiated vessel density correlating with better prognosis. Furthermore, the presence of pericytes supporting the differentiated vessels varied in CCRCC. The distributions of pericyte coverage and differentiated vessels in CCRCC were uneven. The tumor margin had a higher pericyte coverage rate for differentiated vessels than did the inner tumor area. The uneven distributions of pericyte coverage and differentiated vessels in CCRCC prompted the authors to revisit the mechanism of tumor central necrosis, which was also known to be a prognostic indicator for CCRCC. The discrepancy of prognostic correlation between protein and messenger RNA levels of vascular endothelial growth factor in CCRCC was discussed. The complexity of the tumor vasculature in CCRCC also led the authors to begin to re-evaluate the therapeutic effects of antiangiogenic agents for each type of tumor vessel, which will in turn significantly broaden understanding of tumor angiogenesis and improve therapeutic effect. Clear cell renal cell carcinoma (CCRCC) is a highly vascularized malignancy. As evaluated by 2-phase multidetector computed tomography angiography, CCRCC is found to be able to develop an aberrant capsular vascular supply with outflow through an ovarian vein or testicular vein, 1 although positron emission tomography shows that blood perfusion of the tumor is reduced compared with normal kidney tissues. 2 Our expression profiling study also indicated that the expression level of vascular endothelial growth factor (VEGF; a potent proangiogenesis factor) in CCRCC is 5-fold higher than in other types of kidney

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Two Distinct Types of Blood Vessels in Clear Cell Renal Cell Carcinoma Have Contrasting Prognostic Implications

Cited by 80 publications

References 41 publications

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

Fractal analysis of vascular networks: Insights from morphogenesis

Complexity of tumor vasculature in clear cell renal cell carcinoma

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