Angiogenesis and phenotypic alteration of alveolar capillary endothelium in areas of neoplastic cell spread in primary lung adenocarcinoma.
Normal alveolar capillary endothelium is quiescent in nature and displays anticoagulant thrombomodulin (TM) on its surface. The cytoplasms of these endothelial cells are ultrastructurally non-fenestrated type, and they barely express von Willebrand factor (vWf). Alveolar fibrosis is accompanied by a capillary endothelium reactive for vWf, and a loss of TM expression. In primary lung adenocarcinoma, neovascularization occurs in association with alveolar fibrosis. In order to study basic factors related to angiogenesis and phenotypic changes of the capillaries located in tumor-bearing alveolar walls, we examined 37 primary lung adenocarcinomas with electron microscopy and confocal laser scanning microscopy with antibodies for TM, vWf, vascular endothelial growth factor (VEGF), and its receptors (KDR and Flt-1), and proliferating markers (Ki-67/proliferating cell nuclear antigen). Tissues microdissected specifically from alveolar walls were used for reverse transcription-polymerase chain reaction (RT-PCR) to assess expressions of mRNA isoforms of VEGF and its receptors. New capillary branching was found by ultrastructural study in the alveolar walls in 12% of the patients. Nuclei of the capillary endothelial cells were reactive for proliferating cell markers. Endothelial fenestrae were developed in 65% of the patients, TM reactivity was lost in the alveolar capillaries, and their cell cytoplasms obtained a reactivity for vWf through a transitional mosaic-like distribution pattern of both antigens. Besides cytoplasmic VEGF expression in neoplastic cells, tumor-bearing alveolar walls showed significant expression of mRNA of VEGF165 and KDR. These findings imply that angiogenesis and phenotypic changes of the alveolar capillaries are closely related to a higher expression of tumor-associated VEGF165 and of KDR in the alveolar walls in primary lung adenocarcinoma.
Jin
E
E
Department of Molecular Pathology, Institute of Gerontology, Nippon Medical School, Kawasaki, Japan.
Ghazizadeh
M
M
Fujiwara
M
M
Nagashima
M
M
Shimizu
H
H
Ohaki
Y
Y
Arai
S
S
Gomibuchi
M
M
Takemura
T
T
Kawanami
O
O
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D002196:Capillaries / Q000473:pathology*; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008222:Lymphokines / Q000032:analysis / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics; D017978:Receptors, Growth Factor / Q000032:analysis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000032:analysis
D016228:Endothelial Growth Factors; D019394:Ki-67 Antigen; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D018180:Thrombomodulin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor