Correlation between CD105 expression and postoperative recurrence and metastasis of hepatocellular carcinoma

BACKGROUND: Angiogenesis is one of the mechanisms most critical to the postoperative recurrence and metastasis of hepatocellular carcinoma (HCC). Thus, finding the molecular markers associated with angiogenesis may help identify patients at increased risk for recurrence and metastasis of HCC. This study was designed to investigate whether CD105 or CD34 could serve as a valid prognostic marker in patients with HCC by determining if there is a correlation between CD105 or CD34 expression and postoperative recurrence or metastasis. METHODS: Immunohistochemical staining for the CD105, CD34 and vascular endothelial growth factor (VEGF) antibodies was performed in 113 HCC tissue specimens containing paracarcinomatous tissue and in 14 normal liver tissue specimens. The quantitation of microvessels identified by anti-CD105 and anti-CD34 monoclonal antibodies and the semiquantitation of VEGF expression identified by anti-VEGF monoclonal antibody were analyzed in conjunction with the clinicopathological characteristics of the HCC and any available follow-up information about the patients from whom the specimens were obtained. RESULTS: CD105 was not expressed in the vascular endothelial cells of any normal liver tissue or paracarcinomatous liver tissue but was expressed in the vascular endothelial cells of all HCC tissue. In contrast, CD34 was expressed in the vascular endothelial cells of normal liver tissue, paracarcinomatous tissue, and HCC tissue in the following proportions of specimens: 86.7%, 93.8%, and 100%, respectively. The microvascular densities (MVDs) of HCC determined by using an anti-CD105 mAb (CD105-MVD) and an anti-CD34 mAb (CD34-MVD), were 71.7 ± 8.3 (SD) and 106.3 ± 10.4 (SD), respectively. There was a significant correlation between CD105-MVD and CD34-MVD (r = 0.248, P = 0.021). Although CD34-MVD was significantly correlated with VEGF expression (r = 0.243, P = 0.024), CD105-MVD was more closely correlated (r = 0.300, P= 0.005). The correlation between microscopic venous invasion and CD105-MVD, but not CD34-MVD, was also statistically significant (r = 0.254, P = 0.018). Univariate analysis showed that CD105-MVD was significantly correlated with the 2-year overall survival rate (P = 0.014); CD34-MVD was not (P = 0.601). Multivariate analysis confirmed that CD105-MVD was an independent prognostic factor and that CD34-MVD was not. CONCLUSION: The anti-CD105 mAb is an ideal instrument to quantify new microvessels in HCC as compared with anti-CD34 mAb. CD105-MVD as compared with CD34-MVD is relevant a significant and independent prognostic indicator for recurrence and metastasis in HCC patients

Tumoral CD105 is a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma

International audienceBackground: Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker.Methods: A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan–Meier method, t-test and Cox proportional hazard model.Results: We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002).Conclusions: We have shown for the first time that tumoral CD105 is an independent predictive marker for death risk and unfavourable prognosis in patients with ccRCC after curative resection

Biochemical Properties of a Novel Cysteine Protease of Plasmodium vivax, Vivapain-4

Plasmodium vivax affects hundreds of millions each year and results in severe morbidity and mortality. Plasmodial cysteine proteases (CPs) play crucial roles during the progression of malaria since inhibition of these molecules impairs parasite growth. These CPs might be targeted for new antimalarial drugs. We characterized a novel P. vivax CP, vivapain-4 (VX-4), which appeared to evolve differentially among primate Plasmodium species. VX-4 showed highly unique substrate preference depending on surrounding micro-environmental pH. It effectively hydrolyzed benzyloxycarbonyl-Leu-Arg-4-methyl-coumaryl-7-amide (Z-Leu-Arg-MCA) and Z-Phe-Arg-MCA at acidic pH and Z-Arg-Arg-MCA at neutral pH. Three amino acids (Ala90, Gly157 and Glu180) that delineate the S2 pocket were found to be substituted in VX-4. Alteration of Glu180 abolished hydrolytic activity against Z-Arg-Arg-MCA at neutral pH, indicating Glu180 is intimately involved in the pH-dependent substrate preference. VX-4 hydrolyzed actin at neutral pH and hemoglobin at acidic pH, and participated in plasmepsin 4 activation at neutral/acidic pH. VX-4 was localized in the food vacuoles and cytoplasm of the erythrocytic stage of P. vivax. The differential substrate preferences depending on pH suggested a highly efficient mechanism to enlarge biological implications of VX-4, including hemoglobin degradation, maturation of plasmepsin, and remodeling of the parasite architecture during growth and development of P. vivax

Positron Emission Tomography Imaging of CD105 Expression with a 64Cu-Labeled Monoclonal Antibody: NOTA Is Superior to DOTA

Optimizing the in vivo stability of positron emission tomography (PET) tracers is of critical importance to cancer diagnosis. In the case of 64Cu-labeled monoclonal antibodies (mAb), in vivo behavior and biodistribution is critically dependent on the performance of the bifunctional chelator used to conjugate the mAb to the radiolabel. This study compared the in vivo characteristics of 64Cu-labeled TRC105 (a chimeric mAb that binds to both human and murine CD105), through two commonly used chelators: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Flow cytometry analysis confirmed that chelator conjugation of TRC105 did not affect its CD105 binding affinity or specificity. PET imaging and biodistribution studies in 4T1 murine breast tumor-bearing mice revealed that 64Cu-NOTA-TRC105 exhibited better stability than 64Cu-DOTA-TRC105 in vivo, which resulted in significantly lower liver uptake without compromising the tumor targeting efficiency. In conclusion, this study confirmed that NOTA is a superior chelator to DOTA for PET imaging with 64Cu-labeled TRC105

Particular distribution and expression pattern of endoglin (CD105) in the liver of patients with hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Endoglin (CD105) has been considered a prognostic marker for hepatocellular carcinoma (HCC), and widely used as an appropriate targeting for antiangenesis therapy in some cancers. Our aim was to evaluate the distribution and expression of CD105 in the liver of patients with HCC, and to discuss whether CD105 may be used as an appropriate targeting for antiangenesis therapy in HCC.</p> <p>Methods</p> <p>Three parts of liver tissues from each of 64 patients with HCC were collected: tumor tissues (TT), adjacent non-tumor (AT) liver tissues within 2 cm, and tumor free tissues (TF) 5 cm far from the tumor edge. Liver samples from 8 patients without liver diseases served as healthy controls (HC). The distribution and expression of CD105 in tissues were evaluated by immunohistochemistry, Western blotting analysis, and real-time PCR. HIF-1alpha and VEGF₁₆₅protein levels in tissues were analyzed by Immunohistochemistry and Western blotting analysis or ELISA.</p> <p>Results</p> <p>CD105 was positively stained mostly in a subset of microvessels 'endothelial sprouts' in TT of all patients while CD105 showed diffuse positive staining, predominantly on hepatic sinus endothelial cells in the surrounding of draining veins in TF and AT. The mean score of MVD-CD105 (mean ± SD/0.74 mm²) was 19.00 ± 9.08 in HC, 153.12 ± 53.26 in TF, 191.12 ± 59.17 in AT, and 85.43 ± 44.71 in TT, respectively. Using a paired <it>t </it>test, the expression of CD105 in AT and TF was higher than in TT at protein (MVD, <it>p </it>= 0.012 and <it>p </it>= 0.007, respectively) and mRNA levels (<it>p </it>< 0.001 and <it>p </it>= 0.009, respectively). Moreover, distribution and expression of CD105 protein were consistent with those of HIF-1alpha and VEGF₁₆₅protein in liver of patients with HCC. The level of <it>CD105 </it>mRNA correlated with VEGF₁₆₅level in TF (r = 0.790, <it>p </it>= 0.002), AT (r = 0.723, <it>p </it>< 0.001), and TT (r = 0.473, <it>p </it>= 0.048), respectively.</p> <p>Conclusion</p> <p>It is demonstrated that CD105 was not only present in neovessels in tumor tissues, but also more abundant in hepatic sinus endothelium in non-tumor tissues with cirrhosis. Therefore, CD105 may not be an appropriate targeting for antiangenesis therapy in HCC, especially with cirrhosis.</p

Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopaty

The stratum lacunosum moleculare (SLM) is the connection hub between entorhinal cortex and hippocampus, two brain regions that are most vulnerable in Alzheimer’s disease. We recently identified a specific synaptic deficit of Nectin-3 in transgenic models for tauopathy. Here we defined cognitive impairment and electrophysiological problems in the SLM of Tau.P301L mice, which corroborated the structural defects in synapses and dendritic spines. Reduced diffusion of DiI from the ERC to the hippocampus indicated defective myelinated axonal pathways. Ultrastructurally, myelinated axons in the temporoammonic pathway (TA) that connects ERC to CA1 were damaged in Tau.P301L mice at young age. Unexpectedly, the myelin defects were even more severe in bigenic biGT mice that co-express GSK3β with Tau.P301L in neurons. Combined, our data demonstrate that neuronal expression of protein Tau profoundly affected the functional and structural organization of the entorhinal-hippocampal complex, in particular synapses and myelinated axons in the SLM. White matter pathology deserves further attention in patients suffering from tauopathy and Alzheimer’s disease