Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells.
BACKGROUND
Previous studies demonstrated that excess IL-6 production correlated with the metastatic potential of rat hepatocellular carcinoma cells. In the work reported here a retroviral construct containing the gene for murine IL-6 was introduced into otherwise nonmetastatic tumor cells to directly determine the effect of IL-6 overexpression on tumor metastatic potential.


METHODS
The clonal cell lines 1682.C.2.9.L0 (L0, poorly metastatic) and 1682.C.2.9.L10 (L10, highly metastatic) were selected from a parental hepatocellular carcinoma induced in ACI rats by feeding an ethionine-containing diet. Viral supernatant was used to infect the PA317 amphotropic cell line, and retrovirus produced from these cells infected the poorly metastatic L0 hepatocellular carcinoma cell line. Neomycin-resistant cells were selected in G418 and designated L0-IL-6.


RESULTS
As determined by bioassay, L0 cells produce 10 +/- 1.2 U/mL IL-6 in culture, whereas L10 cells release 95 +/- 11 U/mL (P < 0.01, Student's t-test). Retroviral-mediated IL-6 gene transfer resulted in the production of 1266 +/- 48 U/mL IL-6 by L0-IL-6 cells under identical culture conditions. When an inoculum of 5 x 10(6) cells is injected subcutaneously, both L0 and L10 cell lines result in primary tumors with equivalent rates of growth; only L10 cells metastasize to the lung, however. A similar inoculation of L0-IL-6 cells produced local tumors in all 24 animals tested. Interestingly, 15 of 24 (62%) animals presented with metastatic nodules in the abdominal cavity, whereas no such tumors were found in animals receiving L10 cells.


CONCLUSIONS
Overexpression of IL-6 increases metastatic potential of tumor cells, with preferential metastases to the abdominal cavity when compared with tumor cells elaborating endogenous IL-6.
Reichner
J S
JS
Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence 02903, USA.
Mulligan
J A
JA
Spisni
R
R
Sotomayor
E A
EA
Albina
J E
JE
Bland
K I
KI
D000008:Abdominal Neoplasms / Q000556:secondary; D000818:Animals; D002273:Carcinogens; D004195:Disease Models, Animal; D005001:Ethionine; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000276:immunology*; D051381:Rats; D011912:Rats, Inbred ACI; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D015850:Interleukin-6; D005001:Ethionine