Hypercalcemia in association with a Leydig cell tumor in the rat: A model for tumor-induced hypercalcemia in man

Berger, Morris E.; Golub, Michael S.; Sowers, James R.; Brickman, Arnold S.; Nyby, Michael D.; Troyer, Henry; Rude, Robert K.; Singer, Frederick R.; Horst, Ronald L.; Deftos, Leonard J.

doi:10.1016/0024-3205(82)90237-5

Cited by 16 publications

(5 citation statements)

References 25 publications

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“…When transplanted subcutaneously, the non-metastasizing Leydig tumor cell line has been shown to stimulate bone resorption in rats. The effects of 13-19 days of tumor burden have been reported to include increased osteoclast number or activity [15][16][17][18], decreased formation surface [15,16,18], decreased trabecular bone content [15,17,18], and hypercalcemia [15,16,18,19]. These effects on the skeleton have recently been attributed to the production and secretion by Leydig tumor cells of parathyroid hormone-related protein (PTHrP) [20,21], a polypeptide which has been shown to cause similar systemic skeletal responses when directly injected into rats [22,23].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone

et al. 1992

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To test the hypothesis that bone metastasis is related to the rate of bone remodeling, we have examined the effect of enhanced bone resorption on the growth of spontaneously metastatic Walker 256 (W256) cancer cells. Bone resorption was stimulated in male Fischer rats by injecting Rice H-500 Leydig tumor cells subcutaneously. The resorptive response of the skeleton was confirmed in a pilot study by evaluating parameters of bone morphometry after 4, 7 and 10 days of tumor burden. The distal femoral epiphyses had 35 +/- 10% more osteoclast surface, 83 +/- 11% less osteoblast surface, and 46 +/- 5% less trabecular bone after 10 days of tumor burden, compared to non-tumor-bearing controls. To evaluate the effect of Leydig tumor-induced bone resorption on the growth response of W256 cells, 20 rats were injected intramuscularly with 2 x 10(7) W256 cells, and 20 rats were vehicle-injected. Two days later, 10 rats from each group were injected subcutaneously with Leydig tumor cells. Twelve days after W256/vehicle injection, rats were injected with [3H]thymidine, killed 2 h later, and their femurs, liver, lungs and kidneys were processed for histology. In rats injected with Leydig tumor cells only, enhanced bone resorption was confirmed by a 40 +/- 4% increase in serum calcium concentration, a 48 +/- 8% decrease in trabecular bone content, and a 72 +/- 15% decrease in osteoblast surface, compared with non-tumor-bearing rats. Metastatic W256 cells adjacent to trabecular bone in Leydig tumor-bearing rats had a 56 +/- 18% greater relative [3H]thymidine labeling index (TdR) than did W256 cells in the bones of non-Leydig tumor-bearing rats. The TdRs of W256 cells in the liver, lungs, and kidneys were not affected by Leydig tumor burden. In this model, enhanced bone resorption was associated with the selective growth promotion of metastatic W256 cells in bone, suggesting the existence of a bone-derived factor which is mitogenic to W256 cells.

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Section: Introductionmentioning

confidence: 99%

Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone

et al. 1992

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“…Allogenic models: Two spontaneously-derived, transplantable rat tumors, Rice H-500 and the Walker rat carcinosarcoma 256, have been developed as models of CAH [ 169 , 170 , 171 , 172 , 173 ]. The testicular tumor of Fischer rats (Rice H-500) does not metastasize following subcutaneous injection, and rats develop progressive hypercalcemia within 8–10 days with increased circulating PTHrP concentrations [ 174 ].…”

Section: Mouse Models Of Cahmentioning

confidence: 99%

“…The testicular tumor of Fischer rats (Rice H-500) does not metastasize following subcutaneous injection, and rats develop progressive hypercalcemia within 8–10 days with increased circulating PTHrP concentrations [ 174 ]. Additional clinicopathologic changes include hypophosphatemia, hypercalciuria, hyperphosphaturia and increased urine cyclic adenosine monophosphate (cAMP) excretion [ 169 , 173 ]. Osteoclastic bone resorption was increased, and bone formation was decreased.…”

Section: Mouse Models Of Cahmentioning

confidence: 99%

“…Furthermore, renal phosphate uptake was specifically and persistently inhibited, which contributed to the hypophosphatemia [ 176 ]. While serum PGE has been shown to parallel the increase in serum calcium in the Rice model, inhibition of PGE did not affect the degree of hypercalcemia [ 169 ].…”

Section: Mouse Models Of Cahmentioning

confidence: 99%

“…Immunoreactive serum PTH levels were decreased, and PTHrP and calcitriol concentrations were increased in rats with H-500 tumors [ 169 ]. The Rice H-500 model was useful in the identification and purification of PTHrP and in the development of an immunoradiometric assay [ 177 , 178 , 179 ].…”

Section: Mouse Models Of Cahmentioning

confidence: 99%

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Animal Models of Cancer-Associated Hypercalcemia

Kohart

Elshafae

Breitbach

et al. 2017

Veterinary Sciences

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Cancer-associated hypercalcemia (CAH) is a frequently-occurring paraneoplastic syndrome that contributes to substantial patient morbidity and occurs in both humans and animals. Patients with CAH are often characterized by markedly elevated serum calcium concentrations that result in a range of clinical symptoms involving the nervous, gastrointestinal and urinary systems. CAH is caused by two principle mechanisms; humorally-mediated and/or through local osteolytic bone metastasis resulting in excessive calcium release from resorbed bone. Humoral hypercalcemia of malignancy (HHM) is the most common mechanism and is due to the production and release of tumor-associated cytokines and humoral factors, such as parathyroid hormone-related protein (PTHrP), that act at distant sites to increase serum calcium concentrations. Local osteolytic hypercalcemia (LOH) occurs when primary or metastatic bone tumors act locally by releasing factors that stimulate osteoclast activity and bone resorption. LOH is a less frequent cause of CAH and in some cases can induce hypercalcemia in concert with HHM. Rarely, ectopic production of parathyroid hormone has been described. PTHrP-mediated hypercalcemia is the most common mechanism of CAH in human and canine malignancies and is recognized in other domestic species. Spontaneous and experimentally-induced animal models have been developed to study the mechanisms of CAH. These models have been essential for the evaluation of novel approaches and adjuvant therapies to manage CAH. This review will highlight the comparative aspects of CAH in humans and animals with a discussion of the available animal models used to study the pathogenesis of this important clinical syndrome.

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In Vivo Models of Hypercalcemia of Malignancy

Schilling

1994

Hypercalcemia of Malignancy

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Hypercalcemia in association with a Leydig cell tumor in the rat: A model for tumor-induced hypercalcemia in man

Cited by 16 publications

References 25 publications

Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone

Stimulation of bone resorption results in a selective increase in the growth rate of spontaneously metastatic Walker 256 cancer cells in bone

Animal Models of Cancer-Associated Hypercalcemia

In Vivo Models of Hypercalcemia of Malignancy

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