Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis.
Early lymph node metastasis is common in pancreatic ductal adenocarcinoma (PDAC). The present study has examined the relationship of lymphatic spread to lymph vessel development and the expression of lymphangiogenic cytokines in a series of well-characterized PDACs. The hot spot method revealed the intratumoural and peritumoural lymphatic vessel density (LVD) to be slightly higher in PDACs than in the normal pancreas. The average intratumoural LVD, however, was strikingly decreased. There was no overexpression of vascular endothelial growth factor (VEGF)-C and VEGF-D in PDACs compared with the normal pancreas. LVD and expression of lymphangiogenic cytokines were not related to any of the biological tumour features or to patient survival. Three orthotopic nude mouse PDAC models did not reveal any increase in tumour-associated LVD, despite a high rate of lymph node metastasis. Lymph vessel proliferation was comparable in PDAC and chronic pancreatitis, in both humans and mice. In conclusion, increased lymphangiogenic activity is not required for and does not significantly affect the lymphatic spread of PDAC. The reduced number of human and murine intratumoural lymph vessels indicates that lymphatic metastasis takes place predominantly via peritumoural lymphatic vessels. The weak expression of lymphangiogenic cytokines in neoplastic cells and lymphatic vessel proliferation in peritumoural regions and chronic pancreatitis indicate that inflammation may be the reason for the low rate of lymphangiogenesis.
Sipos
Bence
B
Department of Pathology, University of Kiel, Germany. s.bence@path.uni-kiel.de
Kojima
Motohiro
M
Tiemann
Katharina
K
Klapper
Wolfram
W
Kruse
Marie-Luise
ML
Kalthoff
Holger
H
Schniewind
Bodo
B
Tepel
Jürgen
J
Weich
Herbert
H
Kerjaschki
Dontscho
D
Klöppel
Günter
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D044584:Carcinoma, Ductal / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D042583:Lymphangiogenesis / Q000502:physiology*; D008207:Lymphatic Metastasis / Q000473:pathology* / Q000503:physiopathology; D042601:Lymphatic Vessels / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis
D016207:Cytokines; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D