Characterization of hypercalcemia-producing factor produced by carcinomas by Northern blot hybridization.

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Malignancy-associatied hypercalcemia is elicited by bone-resorbing factors produced by malignant tumors. We reported that squamous carcinoma cells established from patients with hypercalcemia produced a potent bone resorbing factor which has no PTH-like activity. The bone resorbing activity comigrated with thymocyte proliferation-stimulating activity and completely inhibited by anti-IL-1 alpha antibody but not by anti-IL-1 beta antibody.To investigate whether this IL-1-like activity is an authentic IL-1-alpha, mRNA was extracted from tumor cells (T3M-1, EC-GI) and subjected to Northern blot hybridization analysis. We have found that both cells produced constitutively IL-1 alpha mRNA but no IL-1beta mRNA.Furthermore, we identified that both cells produced mRNA for PTH-related protein (PTH-RP), a recently characterized bone-resorbing factor, which has PTH-like properties.We have found that IL-1 and PTH rP synergistically stimulate bone resorption in vitro and also synergistically increase serum calcium concentration in mice in vivo.Therefore, we demonstrated that some solid tumors produced more than two bone resorbing factors and that both factors are synergistically responsible for humoral hypercalcemia of malignancy.