Background: Transforming growth factor-βpl (TGF-β1), a potent growth modulator produced by a variety of tumor cells, as well as by platelets, has pleiotropic effects on cell-extracellular matrix interactions and may influence tumor cell invasion and metastasis. Purpose: Our purpose was to characterize the effects of TGF-β1 on the adhesion, motility, and invasiveness of a metastatic human pulmonary carcinoma (A549 cell line) in vitro. Methods: A549 cells were seeded onto type I collagen gels, and invasion over a 9-day period was measured in the presence or absence of TGF-β1 (0.1-10 ng/mL). In addition, cell adhesion to substrata coated with type I collagen (1-100 nM) as well as haptotactic migration through filters coated with type I collagen (100 μg/mL) were measured following a 24-hour treatment with TGF-β1 (1-10 ng/mL). Results: TGF-β1 stimulated the invasion of A549 cells into type I collagen gels in a dose-dependent manner. Both the number of cells entering the gel and the depth of invasion into the gel were increased. In addition, the effects,of TGF-β1 were blocked in a dose-dependent manner by a purified polyclonal IgG against TGF-β1 but not by normal rabbit IgG. A549 cell invasion was accompanied by dramatic changes in A549 cell morphology that included the appearance of numerous long pseudo-podia, consistent with a change in the motile behavior of these cells. TGF-β1 stimulated by approximately fourfold the haptotactic migration of A549 cells on haptotactic migration of A549 cells on polycarbonate filters coated with type I collagen. The TGF-β1-mediated increase in invasion and motility was accompanied by a fourfold increase in A549 cell adhesion to type I collagen. Conclusions: The results suggest that TGF-β1 can influence cellular recognition of extracellular matrix components and can modulate cellular adhesion and migration on these components, leading to increased invasive potential. Implications: Given the widespread tissue distribution of TGF-β1 and its secretion by a variety of tumor cells as well as by platelets, TGF-β1 may be an important autocrineparacrine regulator of the invasive phenotype in vivo. (J Natl Cancer Inst 84: 523-527, 1992)
Bibliographical noteFunding Information:
Received June 5, 1991; revised December 4, 199T; accepted January 2, 1992. Supported in part by an American Heart Association—Minnesota Affiliate—Postdoctoral Fellowship (D. L. Mooradian); and by Public Health Service grants CA-29995, CA-21463 (L. T. Furcht), and CA-43924 (J. B. McCarthy) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Department of Laboratory Medicine and Pathology and the Biomedical Engineering Center, University of Minnesota, Minneapolis. We thank Denice Malone, Mary Chelberg, and Stacy Douglas for outstanding technical assistance during various phases of this work. *Correspondence to: Daniel L. Mooradian, Ph.D., Department of Laboratory Medicine and Pathology, Box 609 Mayo Memorial Building, University of Minnesota, 420 Delaware St., S.E., Minneapolis, MN 55455.