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Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids
Sophie Besig1, Petra Voland, Dorothee M Baur
12nd Medical Department, Technical University of Munich, Munich, Germany.
Background And Aims:
Well-differentiated neuro-endocrine ileal carcinoids are composed of serotonin-producing enterochromaffin (EC) cells. Life expectancy is determined by metastatic spread to the liver because medical treatment options are still very limited. Selective inhibition of angiogenesis or lymphangiogenesis might prevent tumour growth and metastatic spread. We examined the role of the vascular endothelial growth factors (VEGFs) A, B, C, D, and their receptors (VEGFRs) 1, 2, 3 in angiogenesis and lymphangiogenesis of ileal EC cell carcinoids with and without liver metastases.
Methods:
The expression of various VEGFs and VEGFRs was determined by quantitative real-time RT-PCR in healthy mucosa, primary tumour, lymph node metastases and liver metastases of 25 patients with ileal EC cell carcinoids. Microvessel density (MVD) was determined by CD-31 staining in primary tumours and lymphatic vessel density (LVD) by LYVE-1 staining. VEGF expression levels, MVD, LVD, and patients' survival time were correlated using logistic regression and Kaplan-Meier survival analysis.
Results:
VEGF-A was highly expressed with no difference between normal mucosa and tumours. VEGF-B and -D as well as VEGFR-1 and -2 expression levels were significantly increased in the tumours when compared to normal mucosa. Patients with liver metastasis, however, had a significantly lower expression of the factors A, B, and C and the receptors 2 and 3. MVD in primary tumours positively correlated with the expression of VEGF ligands and their receptors, except for VEGF-D. LVD did not correlate with any VEGF ligand or receptor. Interestingly, low expression levels of VEGF-B were associated with poor survival.
Conclusion:
Patients with more aggressive metastatic spreading had relatively decreased expression levels of VEGF ligands and receptors. Thus, anti-angiogenic therapy may not be a suitable target in metastatic ileal EC cell carcinoids.
Insights
Vascular endothelial growth factors (VEGFs) and their receptors are involved in ileal carcinoid tumor growth. However, decreased expression in metastatic patients suggests anti-angiogenic therapy may not be effective for metastatic ileal neuroendocrine tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Well-differentiated neuroendocrine ileal carcinoids originate from serotonin-producing enterochromaffin (EC) cells.
- Metastatic spread to the liver significantly impacts life expectancy due to limited treatment options.
- Targeting angiogenesis and lymphangiogenesis presents a potential strategy to inhibit tumor growth and metastasis.
Purpose of the Study:
- To investigate the expression of vascular endothelial growth factors (VEGFs) A, B, C, D, and their receptors (VEGFRs) 1, 2, 3.
- To determine the role of these factors in angiogenesis and lymphangiogenesis in ileal EC cell carcinoids.
- To correlate VEGF/VEGFR expression with tumor characteristics and patient survival, particularly in the context of liver metastases.
Main Methods:
- Quantitative real-time RT-PCR was used to measure VEGF and VEGFR expression in healthy mucosa, primary tumors, and metastases from 25 patients.
- Microvessel density (MVD) was assessed using CD-31 staining, and lymphatic vessel density (LVD) using LYVE-1 staining.
- Statistical analyses, including logistic regression and Kaplan-Meier survival analysis, were employed to correlate expression levels, MVD, LVD, and survival.
Main Results:
- VEGF-A expression was similar in normal mucosa and tumors, while VEGF-B, VEGF-D, VEGFR-1, and VEGFR-2 were significantly upregulated in tumors.
- Patients with liver metastases showed significantly lower expression of VEGF-A, VEGF-B, VEGF-C, VEGFR-2, and VEGFR-3.
- MVD positively correlated with most VEGF ligands and receptors, but LVD did not correlate with any VEGF factors. Low VEGF-B expression was linked to poorer survival.
Conclusions:
- Aggressive metastatic ileal carcinoids exhibit relatively decreased expression of VEGF ligands and receptors.
- The findings suggest that anti-angiogenic therapy might not be an effective treatment strategy for metastatic ileal neuroendocrine tumors.
- Further research into alternative therapeutic targets is warranted for advanced disease stages.
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