Dataset Information

Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3.

ABSTRACT:

Background

Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.

Methods

Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM. Tissue microarrays were constructed from duplicate cores of tumor tissue and surrounding peritumoral tissue from each resected specimen. Immunohistochemistry and real-time polymerase chain reaction were used to evaluate the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-1(VEGFR-1), VEGFR-2, and VEGFR-3. Macrophage infiltration was determined by CD68 staining. Correlations between the expression of these factors and overall survival (OS) and time to recurrence (TTR) were studied.

Results

The peritumoral expression of VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were significantly higher than expression of these factors in tumors. VEGFR-1 was mostly located in peritumoral macrophages, while VEGF-C and VEGFR-3 were mostly located in peritumoral hepatocytes. HCC with high peritumoral co-expression of VEGF-C, VEGFR-1, and VEGFR-3 was associated with higher peritumoral distribution of macrophages (0.87%±0.26% versus 0.45%±0.20%), LNM (32.4% versus 12.0%), shorter TTR (10.2 months versus 34.5 months), and poor prognosis (19.4 months versus 49.3 months).

Conclusion

Expression of VEGF-C, VEGFR-1, and VEGFR-3 in peritumoral liver tissue is associated with a unique type of HCC that has a poorer outcome after hepatectomy.

SUBMITTER: Zhuang PY

PROVIDER: S-EPMC3667811 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3.

Zhuang Peng-Yuan PY Shen Jun J Zhu Xiao-Dong XD Lu Lu L Wang Lu L Tang Zhao-You ZY Sun Hui-Chuan HC

PloS one 20130530 5

<h4>Background</h4>Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.<h4>Methods</h4>Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patien ...[more]

PMID: 23737988

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Project description:Vascular endothelial growth factor-A (VEGF-A) acts via 2 vascular endothelial growth factor receptors, VEGFR-1 and VEGFR-2, that play important and distinct roles in tumor biology. We reasoned that selective imaging of these receptors could provide unique information for diagnostics and for monitoring and optimizing responses to anticancer therapy, including antiangiogenic therapy. Herein, we report the development of 2 first-in-class 89Zr-labeled PET tracers that enable the selective imaging of VEGFR-1 and VEGFR-2.MethodsFunctionally active mutants of scVEGF (an engineered single-chain version of pan-receptor VEGF-A with an N-terminal cysteine-containing tag for site-specific conjugation), named scVR1 and scVR2 with enhanced affinity to, respectively, VEGFR-1 and VEGFR-2, were constructed. Parental scVEGF and its receptor-specific mutants were site-specifically derivatized with the 89Zr chelator desferroxamine B via a 3.4-kDa PEG linker. 89Zr labeling of the desferroxamine B conjugates furnished scV/Zr, scVR1/Zr, and scVR2/Zr tracers with high radiochemical yield (>87%), high specific activity (≥9.8 MBq/nmol), and purity (>99%). Tracers were tested in an orthotopic breast cancer model using 4T1luc-bearing syngeneic BALB/c mice. For testing tracer specificity, tracers were coinjected with an excess of cold proteins of the same or opposite receptor specificity or pan-receptor scVEGF. PET imaging, biodistribution, and dosimetry studies in mice, as well as immunohistochemical analysis of harvested tumors, were performed.ResultsAll tracers rapidly accumulated in orthotopic 4T1luc tumors, allowing for the successful PET imaging of the tumors as early as 2 h after injection. Blocking experiments with an excess of pan-receptor or receptor-specific cold proteins indicated that more than 80% of tracer tumor uptake is VEGFR-mediated, whereas uptake in all major organs is not affected by blocking within the margin of error. Critically, blocking experiments indicated that VEGFR-mediated tumor uptake of scVR1/Zr and scVR2/Zr was mediated exclusively by the corresponding receptor, VEGFR-1 or VEGFR-2, respectively. In contrast, uptake of pan-receptor scV/Zr was mediated by both VEGFR-1 and VEGFR-2 at an approximately 2:1 ratio.ConclusionFirst-in-class selective PET tracers for imaging VEGFR-1 and VEGFR-2 were constructed and successfully validated in an orthotopic murine tumor model.

Dataset Information

Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3.

Background

Methods

Results

Conclusion

Publications

Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3.

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