-Original-

Angiogenic Switching in the Alveolar Capillaries in Primary Lung Adenocarcinoma and Squamous Cell Carcinoma

Chizuko Morishita¹, Enjing Jin¹, Mari Kikuchi¹, Seiko Egawa¹, Masakazu Fujiwara¹, Yoshiharu Ohaki², Mohammad Ghazizadeh¹, Tamiko Takemura³ and Oichi Kawanami¹

¹Department of Molecular Pathology, Institute of Gerontology, Field of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School
²Department of Surgical Pathology, Nippon Medical School Chiba Hokusoh Hospital
³Department of Surgical Pathology, Japan Red Cross Center Hospital

The status of angiogenic switching was examined in alveolar capillaries of primary lung adenocarcinoma (ADC) from 10 patients and primary squamous cell carcinoma (SCC) from 11 patients, using immunostaining for CD31, thrombomodulin, von Willebrand factor (vWF), collagen types IV and VII, and α-smooth muscle actin (α-SMA). We applied the TdT-mediated dUTP nick-end labeling assay and the reverse transcription-polymerase chain reaction for vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). In bronchioloalveolar and papillary subtypes of ADC, the neoplastic cells, replacing the normal alveolar epithelial cells, had spread over alveolar walls and adhered firmly to alveolar interstitium as shown by the development of type IV collagen. Neoplastic cells of SCC were characterized by local proliferation in alveolar sacs without firm attachment to alveolar walls. Tumor lesions of SCC had often developed necrotic foci of various size. In ADC and SCC, alveolar capillary endothelial cells newly obtained reactivity to vWF. Such segments of endothelial cells lost surface thrombomodulin expression. CD31 was consistently expressed in normal and ADC tissues, but each endothelial cell marker was often attenuated or even lost in SCC, suggesting degeneration or necrosis of the alveolar capillaries. The capillary pericytes and interstitial fibroblasts were often hypertrophic and developed α-SMA in the cytoplasm in ADC, but they became atrophic in SCC. In ADC, apoptosis occurred in cells of alveolar capillaries more frequently in the peripheral zone than in the deeper zone of the tumor, whereas the frequency was not consistent in SCC. In microdissected alveolar wall tissues, mRNA expression patterns of VEGF isoforms and VEGFRs were similar in both ADC and SCC. In ADC, de novo angiogenic switching took place in cytoplasm as a unit of cells segments in alveolar capillary endothelium. Suppression of angiogenic switching in SCC implies that factors other than VEGF-VEGFR interaction, such as physical contact and compression of tumor cells, might play a critical role in alveolar capillaries.

J Nippon Med Sch 2007; 74: 344-354

Keywords
angiogenesis, alveolar capillary endothelial cell, angiogenic switching, squamous cell carcinoma, adenocarcinoma

Correspondence to
Oichi Kawanami, MD, PhD, Director of the Institute of Gerontology, Department of Molecular Pathology, Field of Development of Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho Nakahara-ku, Kawasaki, Kanagawa 211-0063, Japan
kawanami@nms.ac.jp

Received, March 1, 2007
Accepted, July 4, 2007