INTERLEUKIN-6 PRODUCTION BY RAT HEPATOCELLULAR-CARCINOMA CELLS IS ASSOCIATED WITH METASTATIC POTENTIAL BUT NOT WITH TUMORIGENICITY

Background: The phenotypic characteristics that allow some tumor cells to metastasize have not been fully identified. The production and/or response of tumor cells to various growth factors have been shown to d istinguish cells of differing metastatic potentials. Objectives: To de termine (1) whether rat hepatocellular carcinoma cell lines produce in terleukin-6 (IL-6) and (2) whether production of IL-6 correlates with either metastatic potential or tumorigenicity. Methods: The clonal cel l lines 1682.C.2.9.L0 (poorly metastatic) and 1682.C.2.9.L10 (highly m etastatic) were selected from a parental hepatocellular carcinoma indu ced in ACI rats by feeding an ethionine-containing diet and adapted to growth in vitro. Results: Both cell lines resulted in primary tumors with equal frequency and developed a 40-mm nodule in a similar period of time, when an inoculum of 5 x 10(6) tells was injected subcutaneous ly; however, only L10 cells metastasized to the lung. These cell lines did not demonstrate differential expression of several antigens noted to correlate with metastatic potential, including CD44 variant glycop rotein, p53, transferrin receptor, and E-cadherin. In contrast, L0 cel ls produced less than 10 U of IL-6 per milliliter in culture (as deter mined by bioassay using 7TD1 cells), whereas L10 cells released more t han 95 U of this cytokine per milliliter under identical culture condi tions (P<.01, Student's t test). In addition, serum concentrations of IL-6 were elevated in animals bearing L10-induced primary tumors but n ot in those with L0-induced tumors of comparable mass. Exogenous addit ion of IL-6 to both tumor cell lines had no effect on the rate of grow th in vitro, supporting the similar tumorigenic potentials observed in vivo. Conclusion: Excess IL-6 production appears to identify cells wi th metastatic potential and does not appear to be essential to the est ablishment of a primary tumor.