2001 Fiscal Year Final Research Report Summary
Molecular genetical analysis of functions of integrins and D4GDI during intravasation of cancer dells.
| Project/Area Number |
12671182
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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 |
General surgery
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| Research Institution | Kanazawa Medical University |
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Principal Investigator |
OTA Takahide Medical Research Institute, Kanazawa Medical University, Assistant professor, 総合医学研究所, 助教授 (10152141)
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| Co-Investigator(Kenkyū-buntansha) |
MAEDA Masayo Dept. Pathology, Kanazawa Medical University, Assistant, 医学部, 助手 (30199632)
TATSUKA Masaaki RIRBM, Hiroshima University, Asisistant professor, 原爆放射能医学研究所, 助教授 (50216991)
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| Project Period (FY) |
2000 – 2001
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| Keywords | 3LL (Lewis lung carcinoma) / metastasis / intravasation of cancer cells / integrin β4 / metastasis model / adhesion molecules / LyGDI / Lewis lung carcinoma(3LL) |
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| Research Abstract |
The release of cancer cells from the primary site and penetration into blood vessels are obligatory preliminary steps for metastasis. To investigate the mechanism of such steps we isolated variant cells (designated as Int-3LL) possessing enhanced intravasating ability from Lewis lung carcinoma (3LL) cells by in vivo selection. We found that Int-3LL cells showed a highly penetrating abiility in vitro as well as an augmented intravasating potential in vivo. In three-dimensional collagen-gel, Int-3LL cells formed diffusive colonies with less plating efficiency than their parental cells. Despite these properties, Int-3LL cells showed an ability of invasive migration in vitro similar to parental cells. On the other hand, a reduced adhesiveness and less spreading on extracellular matrices, such as fibronectin and laminin, were revealed in Int-3LL cells. Analyses using anti-integrin antibodies indicated that the dysadhesion phtenotype in Int-3LL cells was associated with integrin β4 dysfuncti
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on, which is known to produce epithelial detachment. Also, the types and the levels of integrins were not indistinguishable between Int-3LL and parental 3LL cells. Thus, the impaired function of integrin β4-mediated adhesion is considered to be an important factor in intravasation during metastasis. In spite of enhanced intravasating ability of Int-3LL cells, both spontaneous and experimental metastatic abilities clearly decreased. The suppression of integrin β4-mediated adhesion may also contribute to the decreased metastatic ability of Int-3LL cells.
On the other hand, we found that the expression level of D4GDI, which is a member of RhoGDI proteins, increased in Int-3LL cells compared with parent cells. When N-terminus deleted D4GDI (Δ1-55) was introduced into Int-3LL cells, their intravasating ability was suppressed This suggests that D4GDI is involves in the process of cancer cell intravasation. We are now investigating whether D4GDI regulates the function of integrin β4 or other adhesion molecules. Less
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