CYTOKINE PRODUCTION IN 5 TUMOR-CELL LINES WITH ACTIVITY TO INDUCE CANCER CACHEXIA SYNDROME IN NUDE-MICE

To identify the so-called toxohormone, which is a tumor-derived factor with activity to induce cancer cachexia syndrome in tumor-bearing animals, 5 human cancer cell lines with this activity were studied for cytokine production. Tumor cell products with activity to inhibit lipoprotein lipase (LPL) were shown to play an important role in the development of the cancer cachexia syndrome. All culture media conditioned by the 5 cell lines possessed LPL-inhibitory activity. However, the activity differed with the cell line. In order to characterize the activity, we examined whether the cultured cells produced cytokines with activity to inhibit LPL. A melanoma cell line, SEKI, and a neuoepithelioma cell Line, NAGAI, were found to express a large amount of leukemia inhibitory factor (LIF) mRNA. Furthermore, both of these cell lines were demonstrated to produce a large amount of LIF protein, and plasma levels of LIF were extremely elevated in SEKI- and NAGAI-bearing nude mice, indicating that LIF produced by the tumor cells induced cancer cachexia syndrome in the animals. Thus, LIF fulfills the requirements for a toxohormone, except for suppressive activity on liver catalase. In contrast, the mechanisms responsible for cachexia in the MKN-1-, LX-1- and LS180-bearing mice remain unknown. These findings suggest that various types of bioactive substances produced by cancer cells could be toxohormones.