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Tumor Invasion-inhibiting Factor 2: Primary Structure and Inhibitory Effect on Invasion in Vitro and Pulmonary Metastasis of Tumor Cells¹

Research Center, Asahi Glass Co., Ltd., 1150 Hazawa-cho, Kanagawa-ku, Yokohama 221 [A. I., Y. G-H., H. K], and Department of Tumor Biochemistry, Research Institute, The Center for Adult Diseases, Osaka, Higashinari-ku, Osaka 537 [K. S., M. M., H. A.], Japan

The primary structure of tumor invasion-inhibiting factor 2 (IIF-2) purified from bovine liver (A. Isoai et al., Jpn. J. Cancer Res., 81: 909–914, 1990) was determined. A computer homology search of the National Biomedical Research Foundation data bank revealed that IIF-2 is identical to the carboxyl-terminal region, residue number [69–89], of high mobility group 17 which is a DNA-binding non-histone protein. IIF-2 synthesized by an automated peptide synthesizer showed similar invasion-inhibitory activity as compared with the purified factor, when tested with the monolayer invasion assay system using highly invasive rat ascites tumor cells. When examined with the other in vitro assay systems using a modified Boyden chamber, the synthetic IIF-2 suppressed the chemotactic migration of highly metastatic B16 melanoma (B16FE7) cells to fibronectin or laminin and invasion through Matrigel. The IIF-2 inhibited neither the cell proliferation nor the binding of cells to fibronectin or Matrigel and also showed no significant inhibition of M_r 90,000 type IV collagenase (gelatinase) obtained from human schwannoma (YST-3) cells. The formation of lung colonies in mice given injections of B16FE7 and Lewis lung carcinoma cells was significantly reduced by the coinjection of the IIF-2. These results suggest that IIF-2 suppresses tumor invasion by impairing cell motility and inhibits the migration of metastasizing cells through extracellular matrix (extravasation steps) following their arrest in the capillary bed of the lung in vivo.

¹ This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare for a Comprehensive 10-Year Strategy of Cancer Control.

² To whom requests for reprints should be addressed.

Received 12/17/90. Accepted 1/ 2/92.