Mediators of vascular remodelling co-opted for sequential steps in lung metastasis (Nature, 2007, 446:765-770)

報告日期: 2007/10/19
報告時間: 15:10/16:00
報告學生: 陳家揚
講評老師: 吳梨華

Mediators of vascular remodeling co-opted for sequential steps in lung metastasis

Gaorav P. Gupta, Don X. Nguyen, Anne C. Chiang, Paula D. Bos, Juliet Y. Kim, Cristina Nadal, Roger R. Gomis, Katia Manova-Todorova, and Joan Massague

Nature, 2007, 446:765-770

Speaker: 陳家揚

Commentator: 吳梨華博士

Time/Date: 15:10-16:00, Oct. 19, 2007

Room: 602


Tumor metastasis is the main reason that causes poor prognosis in cancer patients. It includes multiple processes to colonize at distant site, such as tumorigenesis, angiogenesis, intravasation, extravasation, and distant colonization. Many genes are identified to responsible for tumor metastasis including epidermal growth factor receptor ligand epiregulin (EREG), cyclooxygenase2 (COX2), and matrix-remodeling metalloproteinases MMP1 and MMP2. These four genes were previous known as some of lung metastasis signature genes. In this study, authors use short hairpin RNA interference (shRNA) to stably reduce the highly expression of EREG, COX2, MMP1, and MMP2 in LM2 breast cancer cell line. The results showed that combination knockdown of these four genes could significantly inhibit the tumor growth compare to mono-knockdown tumors. And combination knockdown of these four genes could also significantly inhibit tumor angiogenesis by reducing the length and the number of lumen, the number of branch points, and the permeability of the newly formed vascular around the tumor nodule, which could finally induce apoptosis through reactive oxidative species induction to reach the goal of tumor shrinkage. In addition, tail-vein injection of LM2 cells with combination knockdown and all four shRNAs knockdown could apparently inhibit the in-vitro invasion and in-vivo extravasation abilities to avoid cancer cell from distant colonization. These results could also be proven by pharmacological targeting using anti-EGFR antibody cetuximab, broad-spectrum MMP inhibitor GM6001, and COX2 inhibitor celecoxib as orthotopic model for combination treatment in-vivo and other potential lung metastasis cells. This study demonstrates the lung metastasis signature genes EREG, COX2, MMP1, and MMP2 could collectively facilitate angiogenesis and invasion in lung colonization of breast cancer cells. It links the aggressive primary tumor ability to its greater metastatic potentials and how these potentials may be pharmacological targeted.



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