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ABSTRACT: The expression of vascular endothelial growth factors (VEGFs) in tumors including lung cancer is considered to be associated with tumor development via capillary and lymph vessel neogenesis. Dissemination of the tumor cells to the pleura or regional lymph nodes is a critical poor prognostic factor for lung cancer patients. To investigate how VEGFs expressed in the intrathoracic infiltrating lung cancer cells participate in disease progression, we established stably VEGF-A-, VEGF-C-, VEGF-D-, VEGF-A and VEGF-C-, and VEGF-A and VEGF-D-expressing large cell lung cancer clones (TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, TKB5/VEGF-A/C, and TKB5/VEGF-A/D), orthotopically inoculated these into the right thoracic cavity (i.t.) of nude mice, and evaluated the subsequent development of lung lesion, pleural effusion, pleural dissemination, and lymph node metastasis. While there were no significant differences either in culture or in subcutaneous tumor cell growth between the empty vector-transfected group (TKB5/empty) and each transfectant, the i.t. model demonstrated significantly different biological properties between the transfectants. TKB5/empty-inoculated mice frequently developed a large tumor on the pleura without pleural effusion, dissemination, or lymph node (LN) metastasis. In contrast, VEGF-A promoted a bloody pleural effusion (6/14), and VEGF-A and VEGF-D frequently generated pleural dissemination (11/14 and 9/11, respectively). Although both VEGF-C and VEGF-D generated LN metastasis (6/10 and 8/11, respectively), the locations of the metastasized LNs were quite different. TKB5/VEGF-C metastasized on the same side of axillary LNs as i.t. (right axillary LNs), whereas TKB5/VEGF-D metastasized to the mediastinal and left axillary and/or cervical LNs. Since the TKB5/VEGF-A/C or TKB5/VEGF-A/D co-transfectants revealed overlapping tumor progression patterns of VEGF-A and VEGF-C or VEGF-D, the metastatic LNs had abundant new capillaries and were larger than those of TKB5/VEGF-C or TKB5/VEGF-D-inoculated mice. Our results clearly demonstrate that VEGF-A secreted from intrathoracic lung cancer cells plays important roles in producing pleural effusion, dissemination, and capillary neogenesis, that VEGF-C is involved in LN metastasis, and VEGF-D in pleural dissemination and LN metastasis. It is most likely, however, that the mechanisms by which VEGF-C promotes LN metastasis are different from those of VEGF-D. The regulation of the expression of VEGFs in intrathoracic lung cancer cells might be a useful therapeutic approach to inhibiting tumor development and improving patient prognosis.
Lung Cancer 10/2004; 45(3):325-37. · 3.43 Impact Factor
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ABSTRACT: The validity of limited surgery for lung carcinomas have not been clearly established. Several reports suggest that not only tumor size but also the histological findings may be of importance in this role. By conducting immunohistochemical examinations of lymph node micrometastases from small lung adenocarcinomas, we considered the suitability of limited surgery for especially localized bronchioloalveolar carcinoma (LBAC) without active fibroblastic proliferation (Noguchi's histologic classification types A and B). In this study, we enrolled 54 patients with lung adenocarcinoma smaller than 2 cm in diameter. Lymph node involvement was demonstrated in 11 (20.4%) patients. Lymph node micrometastasis was present in 11 (25.6%) of the 43 patients at pN0 disease. However, 13 patients with LBAC without active fibroblastic proliferation (types A and B) had neither lymph node involvement nor micrometastasis. Our results indicate that limited pulmonary resection may be acceptable procedure for LBAC without active fibroblastic proliferation.
Lung Cancer 03/2003; 39(2):159-64. · 3.43 Impact Factor
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ABSTRACT: We have experienced a very rare case of hepatoid adenocarcinoma in the lung. A 55-year-old male with a history of smoking was diagnosed as adenocarcinoma of the right S2, and underwent resection of the right upper lobe and dissection of the hilum and mediastinal lymph nodes (complete resection). Pathological examination revealed cuboid atypical cells arranged in a papillary or trabecular fashion, and a proliferating pattern in most part of the tumor resembling that of hepatocellular carcinoma. Immunohistochemistry study showed alpha-fetoprotein (AFP)-positive tumor cells, hence the diagnosis of hepatoid adenocarcinoma was confirmed. Postoperative pathological staging classified the patient as having as p-T2NOMO, p-stage I B disease. The serum AFP level was not determined before surgery, but the value decreased gradually after surgery and has since remained within the normal range. At present, 32 months after the operation, no signs of recurrence have been observed. Hepatoid adenocarcinoma in the lung has been reported in eight patients with the present one being the ninth case. All were males, the tumor diameter was large and the patient prognoses were mostly poor, but at early stage two cases of long-term survival have been reported indicating that the stage is the most important prognostic factor also for rare tumor.
Lung Cancer 12/2002; 38(2):211-4. · 3.43 Impact Factor
