Similar epithelial-stromal interactions in the regulation of hyaluronate production during limb morphogenesis and tumor invasion.

Changes in extracellular hyaluronate occur during the onset of cell migratory stages of development, wound healing, regeneration, and tumor invasion. During development, the production of hyaluronate, which is spatially and temporarily patterned, is regulated, in part, by epithelial-mesenchymal interactions, as demonstrated in the developing limb (Knudson, and Toole (1988) Biochem, Int., 17, 735). Analogous regulatory interactions occur during tumor invasion. One of us (Knudson, W. et al. (1984) Proc. Natl. Acad. Sci. USA, 81, 6767) has shown that several human carcinoma cells interact with normal human fibroblasts in co-culture to effect the stimulation of hyaluronate production. This type of interaction in vivo may account for the large accumulations of hyaluronate often associated with invasive tumors. Heterologous coculture experiments were performed to determine whether carcinoma cells and embryonic epithelial cells express a common regulatory mechanism to effect the stimulation of hyaluronate production by stromal cells. Human LX-1 lung carcinoma cells or human HCV-29T bladder carcinoma cells cultured together with chick embryo limb bud mesoderm synthesized 2- to 4-fold more hyaluronate than the sum of that produced by carcinoma and mesoderm cultures grown separately. Co-cultures of chick embryo limb bud epithelial cells with adult human skin fibroblasts also synthesized 1.5- to 2.5-fold more hyaluronate. The increase in hyaluronate in these co-cultures was not due to a stimulation of cell proliferation and was additive to the effect of fetal bovine serum. The results suggest a common mechanism of epithelial-stromal interaction in the regulation of hyaluronate production during embryonic development and tumor invasion.