Hepatocyte growth factor induces proliferation, motility and differentiation of epithelial cells through the tyrosine kinase receptor encoded by the MET proto‐oncogene. The cytoplasmic portion of Met (referred to as cyto‐Met) is activated but only weakly transforming. In order to determine the effect of activated Met on hepatocytes, we have targeted truncated Met expression to the liver by incorporating the cDNA into a vector carrying the entire human a‐1‐antitrypsin transcriptional unit. Transgenic expression in the liver of truncated human Met, containing the regulatory and the catalytic cytoplasmic domains, renders hepatocytes constitutively resistant to apoptosis and reproducibly permits immortalization. The emerging stable cell lines are not transformed and maintain a highly differentiated phenotype judged by the retention of epithelial cell polarity and the expression of hepatocyte‐enriched transcription factors as well as hepatic products.

Studies with tumor necrosis factor p55 receptor‐ and interleukin‐6 (IL‐6)‐deficient mice have shown that IL‐6 is required for hepatocyte proliferation and reconstitution of the liver mass after partial hepatectomy. The biological activities of IL‐6 are potentiated when this cytokine binds soluble forms of its specific receptor subunit (sIL‐6R) and the resulting complex interacts with the transmembrane signaling chain gp130. We show here that double transgenic mice expressing high levels of both human IL‐6 and sIL‐6R under the control of liver‐specific promoters spontaneously develop nodules of hepatocellular hyperplasia around periportal spaces and present signs of sustained hepatocyte proliferation. The resulting picture is identical to that of human nodular regenerative hyperplasia, a condition frequently associated with immunological and myeloproliferative disorders. In high expressors, hyperplastic lesions progress with time into discrete liver adenomas. These data strongly suggest that the IL‐6/sIL‐6R complex is both a primary stimulus to hepatocyte proliferation and a pathogenic factor of hepatocellular transformation.

The presence of epithelioid osteoblasts, lace- or sheetlike osteoid production, and a permeative pattern of tumor growth in osteoblastomas is thought to be associated with an aggressive clinical behavior. This study assessed the prognostic significance of these and other histologic parameters by analyzing a large group of cases. Histologic material obtained from 55 patients who had osteoblastoma diagnosed and treated at Memorial Sloan-Kettering Cancer Center was analyzed. Additionally, the radiographic images were studied and the lesions were radiologically staged as stage 1 (quiescent), stage 2 (active), or stage 3 (aggressive). Epithelioid osteoblasts were detected in 14% of the cases without any mitotic activity. Lace- or sheet-like osteoid was present in 36% of the cases studied. A permeative pattern of tumor growth was present in 15% of lesions in all but one arising in the short tubular or large flat bones. Thirty-four percent of the lesion were in stage 1, 48% in stage 2, and 17% in stage 3. All stage 1 tumors involved long tubular bones, whereas all stage 3 tumors arose in the short tubular or flat bones. Local recurrence was noted in 16% of patients, all of whom had stage 2 lesions. One patient with a vertebral tumor eventually died with persistent disease. No association between the histologic features and disease outcome was demonstrated. The clinically aggressive behavior of osteoblastoma is not related to particular histologic features, but rather to the skeletal location. Mitotic activity is not present in osteoblasts in the osteoblastoma.