Vascular Endothelial Growth Factors, Angiogenesis, and Survival in Human Ileal Enterochromaffin Cell Carcinoids

Abstract

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.

The Expression of the Hypoxia Markers CA9 and CXCR4 Is Correlated with Survival in Patients with Neuroendocrine Tumours of the Ileum

“…We also found a trend toward an association between higher vascularization and presence of liver metastasis, which suggests that the development of angiogenesis parallels IET growth. However, this result contrasts with a recent study [23], where the vascularization was lower in metastatic cases although not reaching statistical significance (p = 0.08). These discrepant results probably underline that the counting of vessels is heterogeneous in the different layers of the ileal wall.…”

“…Moreover, they are frequently aggressive and metastatic to lymph nodes and the liver and resistant to chemotherapy. Recent evidence suggested that angiogenesis is important for tumorigenesis of IET [23]. New therapeutic strategies, including antiangiogenic therapy targeting, are needed in order to treat patients with disseminated metastatic disease.…”

Everolimus Reduces 89Zr-Bevacizumab Tumor Uptake in Patients with Neuroendocrine Tumors

“…VEGF-A expression was similar between tumor lesions and healthy ileal mucosa. In contrast, VEGF-B and VEGF-D levels were higher in tumors than in normal mucosa (31). This might explain why several of the NET lesions in our study did not show uptake of 89 Zr-bevacizumab.…”

Radionuclide imaging and therapy in patients with neuroendocrine tumors

“…Выполнение лимф-аденэктомии достоверно улучшает общую выживаемость. Адекватным объемом лимфо-диссекции при НЭО тонкой кишки, по мне-нию некоторых авторов, необходимо считать удаление как минимум 8 лимфатических узлов [64][65][66][67][68][69][70][71][72][73][74][75][76].…”