Bone Resorption and Humoral Hypercalcemia of Malignancy: Stimulation of Bone Resorption<i>in Vitro</i>by Tumor Extracts is Inhibited by Prostaglandin Synthesis Inhibitors*

Minkin, Cedric; Fredericks, Robert; Pokress, Selma; Rude, Robert K.; Sharp, Charles F.; Tong, Myron J.; Singer, Frederick R.

doi:10.1210/jcem-53-5-941

Cited by 30 publications

(9 citation statements)

References 22 publications

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“…When nonconditioned medium (60 ml) containing 5% FCS was concentrated [44][45][46][47][48] with an apparent molecular weight of 14,000, which exactly corresponds to the BRA ofpeak III in the cystic fluid (Figs. 1 and 3).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we assume that it stimulates bone resorption through the local stimulation of prostaglandins of the E series or other metabolites of arachidonic acid in bone as reported in EGF, PDGF, TGF and some osteolytic factors derived from solid tumors (34,36,40,44).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the amount of PGE produced in the fetal bones and released into the culture medium, fetal mouse bones that had not been labeled with 4'Ca were cultured in the control (tubes 1-5), fractions with BRA (tubes [43][44][45][46][47][48] and the same fractions containing 10-6 M indomethacin. After 3 d of culture, spent culture medium (0.5 ml/well) from four fetal bones was combined and stored at -20°C.…”

Section: Methodsmentioning

confidence: 99%

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Production of bone-resorbing activity and colony-stimulating activity in vivo and in vitro by a human squamous cell carcinoma associated with hypercalcemia and leukocytosis.

Sato¹,

Mimura²,

Han³

et al. 1986

J. Clin. Invest.

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A squamous cell carcinoma of 33-yr-old patient who developed marked leukocytosis and hypercalcemia was transplanted into nude mice in which more marked leukocytosis and hypercalcemia also developed. This tumor (LJC-1-JCK) produced a colonystimulating factor (CSF) and formed a cyst in the tumor from which a CSF-producing cell line (T3M-1) was established. The CSF causes predominantly formation of granulocytic colonies in addition to macrophage colonies.Bone-resorbing activity (BRA) was detected in the cystic fluid and was eluted as two separate peaks with proteins of an apparent molecular weight of 30,000-50,000 and 10,000-20,000. Colonystimulating activity (CSA) was eluted at an apparent 30,000 mol wt. The conditioned medium of the T3M-1 cells also contained a BRA with an apparent 14,000 mol wt, whereas CSA eluted at an apparent 30,000 mol wt. PT1H, epidermal growth factor, transforming growth factor-alpha, prostaglandin Es, and vitamin D could not account for the powerful BRA. In contrast to CSA, BRA was not inactivated by trypsin and more stable at 70°C. When T3M-1 cells were transplanted into nude mice, marked hypercalcemia developed in addition to granulocytosis.Our findings suggest that the tumor produces and secretes a powerful BRA in vivo and in vitro, which is different from CSA in terms of molecular weight, heat stability, and trypsin treatment. We speculate that the synergistic action of CSF that stimulates macrophage colony formation and recruits osteoclast precursors, and BRA, which stimulates mononuclear phagocytes and/or osteoclasts were responsible for a marked increase in osteoclastic bone resorption and humoral hypercalcemia in the patient.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Production of bone-resorbing activity and colony-stimulating activity in vivo and in vitro by a human squamous cell carcinoma associated with hypercalcemia and leukocytosis.

Sato¹,

Mimura²,

Han³

et al. 1986

J. Clin. Invest.

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“…They displayed hypercalcemia in addition to high levels of PTHrP, vitamin D and/or PGE2 and/or IL-1. In this subgroup of patients, bone resorption might occur through the release of humoral factors: PTH, PTHrP, PGE2; tumor-derived osteolytic factors; lymphokines such as IL-1 and tumor necrosis factor (TNF); or transforming growth factors (TGFs) [13,21,[34][35][36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

“…The nature of these humoral factors has yet to be fully defined, but recent evidence suggests that parathyroid hormone-related protein (PTHrP), prostaglandin E 2 (PGE2) , interleukin-1 (IL-1) and growth factors (GFs) may be involved. These factors may be secreted by remote tumor tissue or released locally by metastatic cells [13][14][15][16][17][18][19][20][21]. Another possible mechanism of hypercalcemia could be that tumoral cells are able to resorb bone directly, independently of osteoclast stimulation and release of humoral factors [3,6,22].…”

mentioning

confidence: 99%

Hypercalcemia in breast cancer

et al. 1993

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Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.

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Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria

Lerner

Ljungberg

1989

Journal of Bone and Mineral Research

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The bone-resorbing capacity of human renal cell carcinomas in vitro has been examined. Bone resorption in cultures of mouse calvarial bones was assessed by the release of 45Ca from bones prelabeled in vivo and the mobilization of stable calcium and inorganic phosphate from nonlabeled bones. In addition, bone organic matrix degradation was determined either by the release of 3H from [3H]proline-labeled bones or by the loss of hydroxyproline from bone explants during culture. Tumor tissue-conditioned media (TCM) from 13 of 13 renal cell carcinomas stimulated bone resorption in a dose-dependent manner. From 5 of 13 kidneys with renal cell carcinoma, normal kidney cortex tissue was cultured and 4 of these 5 also produced bone-resorbing activity, but the amount was much less compared with the tumor tissue. The stimulatory effect of TCM on 45Ca release could be observed first after 12-24 h of culture. The effect could be inhibited by calcitonin but not by inhibitors of prostaglandin synthesis. The production of bone-resorbing activity by tumor cells could be inhibited by indomethacin and meclofenamic acid. In some tumors, the inhibition by indomethacin was total, whereas in other tumors only partial inhibition could be obtained. In 3 of 4, TCM bone-resorbing activity could be found in the retentate after dialysis. The results show that fresh human renal cell carcinoma tissue can elaborate prostanoid as well as nonprostanoid products that can stimulate bone resorption.

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Bone Resorption and Humoral Hypercalcemia of Malignancy: Stimulation of Bone Resorptionin Vitroby Tumor Extracts is Inhibited by Prostaglandin Synthesis Inhibitors*

Cited by 30 publications

References 22 publications

Production of bone-resorbing activity and colony-stimulating activity in vivo and in vitro by a human squamous cell carcinoma associated with hypercalcemia and leukocytosis.

Production of bone-resorbing activity and colony-stimulating activity in vivo and in vitro by a human squamous cell carcinoma associated with hypercalcemia and leukocytosis.

Hypercalcemia in breast cancer

Renal cell carcinoma in tissue culture secretes nondialyzable product that stimulates bone resorption in organ-cultured mouse calvaria

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