The hypercalcemic rat leydig cell tumor-A model of the humoral hypercalcemia of malignancy

Domenic A. Sica, Raymond R. Martodam, Jessie Aronow, Gregory R. Mundy

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

A transplantable nonmetastasizing Leydig cell tumor, which occurs spontaneously in the aged Fischer rat, was examined both in vitro and in vivo. Animals carrying this tumor were found to have the syndrome recently called the humoral hypercalcemia of malignancy, characterized by hypercalcemia, hypercalciuria, hypophosphatemia, renal phosphate wasting, increased urinary 3′5′-cyclic monophosphate (cyclic AMP) excretion, and suppressed circulating parathyroid hormone (PTH) concentrations. The changes in urinary cyclic adenosine monophosphate (cAMP) excretion occurred simultaneously with hypercalcemia in most animals. In one animal, the primary tumor was excised and this was followed by an immediate fall in serum calcium and urine cAMP excretion. Hypercalcemia was due to increased bone resorption. This was shown by bone histology, which demonstrated an increase in osteoclast number and activity on trabecular bone surfaces associated with bone loss in tumor-bearing animals. No tumor cells were seen adjacent to the osteoclasts. There was no evidence of metastatic disease as assessed by bone-seeking isotopes. Urinary hydroxyproline excretion was increased in tumor-bearing hypercalcemic animals, indicating an increase in bone turnover. The tumor cells were established in culture and found to produce a bone-resorbing factor in vitro using a bioassay for bone resorption based on the release of previously incorporated45Ca from fetal rat long bones in culture. This model of the humoral hypercalcemia of malignancy should make it possible to determine the nature of the boneresorbing factor produced by the cultured tumor cells which is responsible for the hypercalcemia, and the relationship of hypercalcemia and the production of the bone-resorbing factor to the other parameters of the syndrome, namely, renal phosphate wasting and increased urinary cAMP excretion.

Original languageEnglish (US)
Pages (from-to)287-293
Number of pages7
JournalCalcified tissue international
Volume35
Issue number1
DOIs
StatePublished - Dec 1983

Keywords

  • Bone resorption
  • Humoral
  • Hypercalcemia
  • Tumor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Endocrinology

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