Laminin molecular domains which alter metastasis in a murine model.

Abstract

Abstract. Human and murine tumor cells contain cell surface receptors for the basement membrane glycoprotein laminin. Since a biologic role for the receptor had not previously been demonstrated, we explored the possibility that the laminin receptor may be involved in hematogenous metastases formation.Preincubation of metastatic murine melanoma cells with syngeneic whole laminin followed by tail vein injection increased tumor cell retention in the lung and strongly stimulated metastases formation. The domain of the laminin molecule responsible for stimulating metastases was identified. Laminin is a cross-shaped molecule with three short arms and one long arm. All arms have globular end regions. Purified protease-derived fragments of laminin were prepared which (a) lacked only the long arm of the molecule (alpha fragment) or, (b) lacked both the long arm and the globular end regions of the short arms (C, fragment). Both types of fragments contained the laminin receptor binding region. The fragments had opposite effects on metastases. The alpha fragment stimulated metastases formation to the same extent as whole laminin. In contrast, the C, fragment greatly reduced or abolished metastases formation in a dose-dependent manner. The C, fragment also inhibited tumor cell attachment to whole amnion basement membrane in vitro. We conclude that intact globular end regions on the short arms (but not the long arm) of the cell surface receptor-bound laminin molecule are necessary for stimulating metastases by the intravenous route.

Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg-Gly-Asp (RGD) and Tyr-Ile-Gly-Ser-Arg (YIGSR) sequences

“…In a previous report (Barsky et al, 1984), the co-injection of tumour cells with purified laminin followed by i.v. injection enhanced pulmonary metastasis, whereas an enzymatic fragment of laminin inhibited the metastasis.…”

Involvement of extracellular matrix constituents in breast cancer

“…[97][98][99][100] However, tumor metastases were increased when cells were co-injected with laminin into blood vessels. [101][102][103] Interestingly, the active site responsible for the increase in metastatic potential is located in a region of the laminin molecule different from the inhibition site YIGSR. 102 …”

Effects of inoculation site and Matrigel on growth and metastasis of human breast cancer cells

“…Laminin, the major constituent of Matrigel, has been shown to accelerate the attachment, activation and growth of tumour cells (Fridman et al, 1990(Fridman et al, , 1991, and to increase tumour metastases when injected intravenously with B16F1O melanoma cells (Barsky et al, 1984;Terranova et al, 1984). However, I in in alone does not promote tumour growth as effectively as Matrigel in the s.c. site (Fridman et al, 1990).…”