2003 Fiscal Year Final Research Report Summary
Comprehensive analysis of pathogenesis in lymphangioleiomyomatosis
| Project/Area Number |
14570563
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
SEYAMA Kuniaki Juntendo University, Respiratory Medicine, Lecturer, 医学部, 講師 (10226681)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Teruhiko Juntendo University, Respiratory Medicine, Assistant, 医学部, 助手 (10348964)
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| Project Period (FY) |
2002 – 2003
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| Keywords | lymphangioleiomyomatosis / The TSC genes / germline mutation / tumor suppressor gene / LOH / Tuberous sclerosis complex / Fractal / lymphangiogenesis |
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| Research Abstract |
Lymphangiolejomyomatosis (LAM) is characterized by proliferation of LAM cells, transformed smooth muscle-like cells (LAM cells) by mutations of the TSC genes, and occurs exclusively women of reproductive ages. Utilizing Juntendo LAM registry that has compiled about 90 patients with LAM, we performed mutation analysis of the TSC genes and LOH analysis in LAM cells, fractal analysis of low attenuation area (LAA) cluster on high resolution CT of the chest (HRCT), frequency of extrapulmonary LAM lesion by abdominopelvic CT and ultrasonograpy of the abdomen, and retrospective analysis of clinical data including pulmonary function tests, LAA% on HRCT and the results of hormone therapy to identify the factors that are important for deciding the treatment option. We identified a LAM patient who has TSC1 geimline mutation but her phenotype was sporadic LAM, then indicating the occurrence of LAM as a forme fruste of tuberous sclerosis complex. The frequency of extrapulmonary LAM lesion was as follows; renal angiomyolipoma in 26.4% and lymphangioleiomyoma in 20.6%. HRCT analysis demonstrates the lack of fractal properties in LAA clusters of LAIVI while LAA clusters in COPD demonstrated to have fractal properties, indicating that LAM is likely to progress due to the metastatic process rather than the progress based on the bronchopulmonary structures inherently possessing fractal properties. Immunohistochemical analysis of LAM lesions, using anti-Flt-4 (VEGFR-3) antibody, demonstrated the marked lymphangiogenesis rather than angiogenesis. LAM cells appears to produce VEGF-C, one of potent growth factors for lymphangiogensis, and induce lymphangiogenesis. Since fragmented LAM cell nests covered by a layer of lymphatic endothelial cells were identified in dilated neolymphatics, lymphangiogenesis followed by lymphatic spreads are postulated to be a n important mechanism in the progression of LAM.
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