Human skin fibroblasts induce anchorage‐independent growth of HPV‐16‐DNA‐immortalized cervical epithelial cells

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Abstract
Immortalized non‐malignant cells do not grow in soft agarose. We found, however, that HPV‐16‐DNA‐immortalized human uterine exocervical epithelial cells (HCE 16/3 cell line) formed colonies when co‐cultured with human embryonic skin fibroblasts. This appeared to be mediated by diffusible growth factors, and direct cell‐cell contacts were not required. HCE 16/3 cells from colonies remained unable to grow alone in soft agarose like the parental HCE 16/3 cells, indicating that only transient phenotypic changes without genetic alterations had occurred in the co‐cultures. In a modified soft‐agarose assay, HCE 16/3 cells grown as an underlying monolayer did not produce enough (transforming) growth factors which could confer an anchorage‐independent phenotype to non‐transformed fibroblasts. Lethally irradiated fibroblasts were able to stimulate DNA synthesis and proliferation of HCE 16/3 cells. Northern‐blot analysis showed that HPV‐16‐DNA expression of the immortalized cells was not altered in the presence of fibroblasts. The expression of the IL‐I gene in the immortalized cells, however, was augmented by the co‐cultured fibroblasts compared with immortalized cells alone. In organotypic collagen raft co‐cultures, in which epithelial cells were grown on top of a collagen gel containing fibroblasts, HCE 16/3 cells appeared to be chemotactic to fibroblasts and fibroblasts stimulated the growth of the immortalized epithelial cells. Our results suggest that fibroblasts may contribute to human epithelial carcinogenesis in vivo. © 1995 Wiley‐Liss, Inc.

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