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Autotaxin (NPP-2), a Metastasis-enhancing Motogen, Is an Angiogenic Factor

Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 20892

Autotaxin [ATX (NPP-2)], originally isolated as a tumor motility-stimulating protein, has recently been shown to augment tumor aggressiveness. Specifically, atx-transfected, ras-transformed NIH3T3 cell lines have been shown to be more invasive, tumorigenic, and metastatic than mock-transfected ras-transformed control cells. In addition, the atx-transfected ras-transformed cell lines appeared to produce tumors that were much more hyperemic than those formed by appropriate control cells. This observation led to the present study, in which we demonstrate that ATX modulates angiogenesis both directly and indirectly. We have used a murine in vivo angiogenesis model in which treated Matrigel plugs are injected s.c. into athymic nude BALB/c mice. Using the same transfected cell lines as before, we found that mixing atx-transfected ras-transformed NIH3T3 cells into the Matrigel resulted in greater new blood vessel formation than control cells. Similarly, mixing purified ATX into the Matrigel resulted in new blood vessel formation within the plug, similar to that produced by vascular endothelial growth factor. Mechanistically, ATX is not a strong chemoattractant for human endothelial cells (HUVECs); however, it strongly stimulates motility in human coronary artery smooth muscle cells. In addition, ATX stimulates HUVECs grown on Matrigel to form tubules, much like vascular endothelial growth factor. Both of these normal cell types are shown to express and secrete ATX. In HUVECs, ATX expression is up-regulated by basic fibroblast growth factor in a time-dependent manner. This up-regulation also extends to secretion of enzymatically active protein, as demonstrated by Western blot analysis and quantification of type-1 phosphodiesterase activity. These results establish the presence of ATX in HUVECs and coronary artery smooth muscle cells and specify ATX as a novel angiogenic factor, suggesting that ATX could contribute to the metastatic cascade through multiple mechanisms, perhaps by supporting an invasive microenvironment for both normal and tumor cells.

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