Production of Interleukin 1 Alpha-like Factor and Colony-stimulating Factor by a Squamous Cell Carcinoma of the Thyroid (T3M-5) Derived from a Patient with Hypercalcemia and Leukocytosis

In order to elucidate the pathogenesis of humoral hypercalcemia and leukocytosis in a 71-year-old patient with squamous cell carcinoma of the thyroid, bone-resorbing activity (BRA) and colony-stimulating activity in the conditioned medium of T3M-5 cells, a clonal cell line established from the tumor, were studied. Gel chromatography of the concentrated conditioned medium revealed respective single peaks of colony-stimulating activity (Mr approximately 27,000) and BRA (Mr 15,000-20,000). BRA did not elicit parathyroid-hormone-like activity but greatly enhanced phytohemagglutinin-induced thymocyte proliferation. This interleukin 1 (IL-1)-like activity exactly coeluted with BRA upon gel chromatography, DEAE-Sepharose ion-exchange chromatography, and isoelectric focusing (pI, 4.7-5.2). BRA was partially inhibited by indomethacin and hydrocortisone, and completely inhibited by anti-IL-1 alpha antiserum, whereas anti-IL-1 beta antiserum had no effect. Furthermore, transplantation of T3M-5 cells into nude mice caused marked hypercalcemia as well as leukocytosis. These findings suggested that excessive production of colony-stimulating factor and IL-1 alpha-like factor by the squamous cell carcinoma was responsible for leukocytosis and hypercalcemia, respectively, in the tumor-bearing nude mice and in the patient. Since several similar cases have been reported in Japan, the syndrome of leukocytosis and hypercalcemia associated with certain solid tumors may constitute a new paraneoplastic syndrome.