Aerogenous spread of primary lung adenocarcinoma induces ultrastructural remodeling of the alveolar capillary endothelium

Abstract

To determine whether pulmonary alveolar capillaries manifest ultrastructural remodeling at areas of neoplastic invasion of primary lung adenocarcinomas, we examined 17 well-differentiated adenocarcinomas of lung (2 bronchioloalveolar and 15 papillary adenocarcinomas) by electron microscopy. The expression of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) was demonstrated by immunohistochemical stainings. VEGF messenger RNA (mRNA) isoforms were detected by reverse-transcription polymerase chain reaction (RT-PCR) in alveolar walls microdissected from normal and tumor-associated tissues. Cytoplasm of neoplastic cells expressed VEGF protein in all patients. Endothelial cell nuclei of alveolar capillaries showed positive reaction for PCNA. Alveolar capillary lumina were distended like venules, and some intercellular junctions remained open. The cytoplasm of the capillary endothelial cells was enlarged and developed numerous organelles such as Weibel-Palade bodies and vesiculovacuolar organelles, in contrast to marked attenuation in their normal counterpart. Capillary sprouting occurred from proper alveolar capillaries in 2 patients. Cytoplasmic segments became extremely attenuated and developed diaphragm-like fenestrae in 65% of the patients. A relatively higher expression of diffusable isoforms of VEGF mRNA was seen in the tumor-bearing alveolar walls than in normal walls. Expression of KDR (one of the VEGF receptors) mRNA in tumor exceeded that in normal tissues. These results suggest that diffusable isoforms of VEGF mRNA released from the neoplastic cells are deeply involved in the induction of growth activity of alveolar capillary endothelial cells as much as in the characterization of tumor-associated microvessels in primary lung adenocarcinomas.