Prostate-specific membrane antigen expression in hepatocellular carcinoma,cholangiocarcinoma,and liver cirrhosis

BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prognosis and high mortality,so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer.Prostate-specific membrane antigen(PSMA)expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently,but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIM To study the expression of PSMA in HCC,CCA,and liver cirrhosis.METHODS A total of 446 formalin-fixed paraffin-embedded(FFPE)liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital.Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens(213 HCC,203 CCA,and 30 liver cirrhosis).The tumor compartment and the associated neovascular endothelium were separately analyzed.PSMA expression was examined by two certified pathologists,and the final results were presented in a 4-point scoring system(0-3 points).Correlation between PSMA expression and clinicopathological information was also assessed.RESULTS PSMA was expressed primarily in the neovascular endothelium associated with tumors.The positive rate of PSMA staining in HCC was significantly higher than that in CCA(86.8%vs 79.3%;P=0.001)but was only 6.6%in liver cirrhosis(P=0.000).HCC cases had more 3-score PSMA staining than CCA had(89/213,41.8%vs 35/203,17.2%;P=0.001).PSMA expression correlated positively with the stage and grade of HCC and CCA.In both liver cancer subtypes,there were more PSMA+cases in stages III–V diseases than in stages I and II.High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage.There was no significant association of PSMA expression with sex,age,region,α-fetoprotein,hepatitis B surface antigen,or tumor size in both tumor subtypes.CONCLUSION Neovascular PSMA may be a promising marker to differentiate HCC from liver cirrhosis and a prognostic marker for anti-tumor angiogenesis therapy for HCC.

Enhanced glioma-targeting and stability of ~LGICP peptide coupled with stabilized peptide ~DA7R

Malignant glioma is usually accompanied by vigorous angiogenesis to provide essential nutrients. An effective glioma targeting moiety should include excellent tumor-cell homing ability as well as good neovasculature-targeting efficiency, and should be highly resistant to enzyme degradation in the bloodstream. The phage display-selected heptapeptide, the glioma-initiating cell peptide(GICP), was previously reported as a ligand for the VAV3 protein(a Rho-GTPase guanine nucleotide exchange factor),which is mainly expressed on glioma cells; the stabilized heptapeptide ~DA7R has been shown to be the ligand of both vascular endothelial growth factor receptor 2(VEGFR2) and neuropilin-1(NRP-1), and has demonstrated good neovasculature-targeting ability. By linking ~DA7R and GICP, a multi-receptor targeting molecule was obtained. The stability of these three peptides was evaluated and their targeting efficiency on tumor-related cells and models was compared. The ability of these peptides to cross the blood–tumor barrier(BTB) was also determined. The results indicate that the coupled Y-shaped peptide ~DA7R–GICP exhibited improved tumor and neovasculature targeting ability and had higher efficiency in crossing the BTB than either individual peptide.