Angiogenesis and tumor progression in neuroendocrine digestive tumors.
BACKGROUND
Clinical observations suggest that in neuroendocrine digestive tumors a high intratumoral microvascular density is associated with good prognosis. We used an experimental orthotopic xenograft model to analyze the relations between angiogenic activity and tumor progression in this tumor subset.


METHODS
We compared 2 endocrine cell lines: STC-1, a low vascular endothelial growth factor (VEGF)-producing cell line, and INS-r3, a high VEGF-producing cell line. Tumor cells were grafted in the adventitial layer of the caecal wall of nude mice, sacrificed after 8 wk.


RESULTS
At 8 wk, "primary" tumors were present in all animals. STC-1 derived tumors were morphologically moderately differentiated, with high proliferative and apoptotic activities; in contrast, INS-r3 derived tumors were well differentiated, with low proliferative and apoptotic activities. VEGF was expressed in <50% grafted STC-1 cells but in >90% of grafted INS-r3 cells. Microvascular density was significantly higher in INS-r3 derived tumors than in STC-1 derived tumors. All STC-1 derived tumors (n = 8) have invaded the mucosa, in contrast to none of the INS-r3 derived tumors (n = 8); liver metastases were detected in 7/8 animals bearing STC-1 derived tumors and in 0/8 animals with INS-r3 derived tumors, despite the presence of lymph node metastases.


CONCLUSIONS
Our experimental data concur with clinical findings to suggest that in well differentiated digestive neuroendocrine tumors angiogenesis is disconnected from tumor progression: the development of a highly vascular tumor microenvironment is correlated with VEGF secretion but is not associated with invasive and metastatic properties; it must therefore be regarded as an indirect marker of differentiation.
Poncet
Gilles
G
INSERM, U865, IFR Lyon Est, Université Claude Bernard Lyon 1, Faculté Laennec, Lyon, France.
Villaume
Karine
K
Walter
Thomas
T
Pourreyron
Céline
C
Theillaumas
Aurélie
A
Lépinasse
Florian
F
Hervieu
Valérie
V
Cordier-Bussat
Martine
M
Scoazec
Jean-Yves
JY
Roche
Colette
C
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000098:blood supply / Q000473:pathology*; D045744:Cell Line, Tumor; D004067:Digestive System Neoplasms / Q000098:blood supply / Q000473:pathology*; D018450:Disease Progression; D005934:Glucagon / Q000235:genetics; D007328:Insulin / Q000235:genetics; D007414:Intestinal Neoplasms / Q000098:blood supply / Q000473:pathology*; D008207:Lymphatic Metastasis / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011401:Promoter Regions, Genetic; D051381:Rats; D013539:Simian virus 40 / Q000276:immunology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000957:Antigens, Viral, Tumor; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D005934:Glucagon