RELATIONSHIP BETWEEN BONE RESORBING ACTIVITY & COLONY

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Solid tumors are frequently associated with increased bone resorption and hypercalcenia. The mechanism for increased bone resorption is production by the tumor cells of a humoral factor or factors which stimulate osteoclastic bone resorption. Recently, we and others have noted that tumors of the oral cavity which cause hypercalcenia are often associated with leukocytosis, concomitantly with the production of colony stimulating activity. In order to identify the factors responsible for hypercalcemia in these tumors, our approach will be to use an in vitro bioassay for bone resorption based on the release of previously incorporated 45Ca in organ culture to characterize the bone resorbing factors present in the tumor cell culture media, and determine the relationship between these factors and the tumor products responsible for leukocytosis which stimulate colony formation in cultures of mouse bone marrow mononuclear cells in methyl cellulose. We plan to evaluate the relationships between bone resorbing activity and colony stimulating activity by examining culture media from tumor cells derived from a patient with squamous cell carcinoma of the maxilla who manifested only leukocytosis, from a patient with squamous cell carcinoma of the maxilla who manifested only hypercalcemia, and from a patient with squamous cell carcinoma of the tongue who manifested both hypercalcemia and leukocytosis. These tumors have been carried in nude mice and preliminary results show that only those associated with colony stimulating activity production cause leukocytosis, and only those associated with bone resorbing activity production cause hypercalcemia. Since cells derived from these tumors are now maintained in culture, we plan to purify further the bone resorbing activity and the colony stimulating activity produced by these tumors, and determine the relationship of the colony stimulating activity to known colony stimulating factors (CSFs). Our hope is that these studies will clarify the mechanisms by which tumor cells increase osteoclastic bone resorption and cause leukocytosis, and may lead to identification of normal factors which influence both osteoclastic bone resorption and leukocyte differentiation.