Drosophila screening model for metastasis: Semaphorin 5c is required for l(2)gl cancer phenotype

Proceedings of the National Academy of Sciences of the United States of America - Tập 100 Số 20 - Trang 11463-11468 - 2003
Elisa C. Woodhouse1, A. P. Fisher1, Russell Bandle1, Bianca Bryant-Greenwood1, Lula Charboneau1, Emanuel F. Petricoin1, Lance A. Liotta1
1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and Office of the Director, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD 20892

Tóm tắt

Cancer metastasis is a complex process involving many genes and pathways. This complexity hinders the identification of molecules functionally required for this process. We have developed and used a Drosophila screening system to identify genes that are functionally important for tumorigenicity and metastasis. Deletion of Drosophila lethal giant larvae ( l(2)gl ) leads to highly invasive and widely metastatic tumors on transplantation into adult flies. Random homozygous P element insertions were screened for the ability to modulate the l(2)gl phenotype. Analysis of metastasis patterns of the lines containing P element insertions and lacking wild-type l(2)gl expression identified three homozygous mutations that dramatically alter tumorigenesis and/or metastasis. Semaphorin 5c ( Sema 5c ) is required for tumorigenicity, apontic overexpression suppresses metastasis but not tumorigenicity, and pointed up-regulation accelerates lethality of l(2)gl tumors. Furthermore, class 5 semaphorins are shown to be expressed in cancer cells and localized to the membrane. Drosophila Sema-5c and the mammalian homologs are transmembrane proteins with extracellular thrombospondin type I (TspI) repeats. TspI repeats are known in some proteins to bind and activate transforming growth factor (TGF)-β ligand. Phospho-Mad and the downstream target gene vestigial were elevated in l(2)gl tumors, thus linking Drosophila neoplasia to the Dpp (TGF-β-like) signal pathway. The activation of the Dpp pathway in l(2)gl tumors occurred only in the presence of Sema-5c. This study demonstrates that the power of Drosophila genetics can be applied to screen, identify, and characterize molecules that are functionally required for invasion and metastasis.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 100 Số 20

11463-11468

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