Two crucial requirements for successful penetration of host tissues by invading tumor cells are (i) destruction of connective tissue barriers and (ii) reconstruction of an appropriate extracellular environment for cellular proliferation and movement. One important aspect of the former requirement is likely to be production of collagenases and of the latter would be production of a hyaluronate-rich pericellular milieu. Recent studies have provided evidence that the elevated production of both type I collagenase and hyaluronate, which is characteristic of many tumors, is regulated by interactions between the tumor cells and host fibroblasts; that components of fibroblast-deposited matrix, most probably heparan sulfate-proteoglycan, promote production and/or secretion of a collagenase-stimulatory factor by tumor cells; and that heparan sulfatz binding sites are present on the tumor cell surface and on isolated tumor cell membranes. Based on these findings the following aims are proposed: (a) further characterize the effect of fibroblast-deposited matrix on production and release of the collagenase- and hyaluronate-stimulatory factors of human LX1 lung carcinoma cells; (b) to study in detail the heparan sulfate (-proteoglycan) receptor on the surface of the human LX1 carcinoma cells; (c) to produce monoclonal antibodies to the heparan sulfate receptor protein(s) and to use these antibodies for purification and further characterization of the receptor; (d) to use the monospecific antibodies to the heparan sulfate receptor to begin probing its role in regulation of tumor matrix composition and tumor cell behavior. Future studies will include immunoassay and immunolocalization of heparan sulfate receptors on benign and metastatic tumor cells in vitro and in vivo, and analysis of the mechanism of regulation of tumor cell production of the collagenase- and hyaluronate-stimulatory factors by heparan sulfate-receptor interactions. These studies will contribute to our understanding of the mechanisms of tumor cell invasiveness.
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| Biswas, C (1988) Heparin and heparan sulfate binding sites on B-16 melanoma cells. J Cell Physiol 136:147-53 |
| Kandel, R A; Dinarello, C A; Biswas, C (1987) The stimulation of collagenase production in rabbit articular chondrocytes by interleukin-1 is increased by collagens. Biochem Int 15:1021-31 |
