Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors.
Lymphangiogenesis is thought to promote the progression of malignant tumors. Because the lymphangiogenic factors vascular endothelial factor (VEGF)-C and -D are expressed in endocrine cells, we investigated their expression in pancreatic endocrine tumors (PETs) and correlated these data and intratumoral lymph vessel density (iLVD) with clinicopathological features. Lymph vessels were identified with anti-podoplanin antiserum and with podoplanin/proliferating cell nuclear antigen double labeling. PETs (n = 104) were investigated by immunohistochemical staining for VEGF, basic fibroblast growth factor, and VEGF-C expression. VEGF-C and VEGF-D mRNA were quantified by real-time reverse transcriptase-polymerase chain reaction. PETs showed higher iLVD than normal pancreata, but iLVD did not discriminate between benign and malignant PETs. In PETs proliferating lymph vessels were identified. High iLVD was associated with lymph vessel invasion and it was more frequent in angioinvasive/metastatic tumors than in grossly invasive tumors. VEGF-C expression correlated with iLVD as well as with glucagon and pancreatic polypeptide expression. PETs show intratumoral lymphangiogenesis, which is associated with VEGF-C expression in tumor cells. The association between iLVD and lymph vessel invasion and angioinvasive/metastatic features in PETs suggests that lymphangiogenesis may promote malignant progression of PETs. PET is the first human tumor entity in which VEGF-C-related intratumoral lymphangiogenesis has been demonstrated.
Department of Pathology, University of Kiel, Michaelisstr. 11, 24105 Kiel, Germany. s.bence@path.uni-kiel.de.
Bence
B
Sipos
Wolfram
W
Klapper
Marie-Luise
ML
Kruse
Holger
H
Kalthoff
Dontscho
D
Kerjaschki
Günter
G
Klöppel
D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D042643:Vascular Endothelial Growth Factor D / Q000096:biosynthesis; D000098853:Podoplanin
D016222:Fibroblast Growth Factor 2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C117468:PDPN protein, human; D000098853:Podoplanin