Summary
Tumor tissue from a patient with squamous cell carcinoma of the lung and hypercalcemia has been serially implanted into athymic mice. Tumor-bearing mice develop cachexia, hypercalcemia without bone metastases, hypophosphatemia, increased urinary cyclic adenosine monophosphate (cAMP) to creatinine ratio, and undetectable human immunoreactive parathyroid hormone levels. Radiographs of spines in the tumor-bearing mice demonstrate demineralization, suggesting skeletal resorption as the source of the hypercalcemia. Within 4–8 hours following tumor removal, hypercalcemia is reversed, suggesting that a relatively short-acting humoral substance is responsible for the hypercalcemia. The animals gain weight and become essentially normal within 4 days following tumor removal. The studies demonstrate that this animal model is similar in many aspects to human malignancy-associated humoral hypercalcemia (MAHH) and can provide a useful tool for further investigation of the pathogenesis and treatment of this syndrome.
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Kukreja SC, Shemerdiak WP, Lad TE, Johnson PA (1980) Elevated nephrogenous cyclic AMP with normal serum parathyroid hormone levels in patients with lung cancer. JCEM 51:167–169
Singer FR, Sharp CF, Rude RK (1979) Pathogenesis of hypercalcemia of malignancy. Mineral Electroyte Metab 2:161–178
Caro JF, Besarab A, Flynn JT (1979) Prostaglandin E and hypercalcemia in breast carcinoma: only a tumor marker? A need for perspective. Am J Med 66:337–341
Simpson EL, Mundy GR, D'Souza SM, et al (1983) Absence of parathyroid hormone messenger RNA in nonparathyroid tumors associated with hypercalcemia. N Engl J Med 309:325–330
Durie BGM, Salmon SE, Mundy GR (1981) Relation of osteoclast activating factor (OAF) production to the extent of bone disease in multiple myeloma. Br J Haematol 47:21–30
Seyberth HW, Hubbard WC, Oelz O, Sweetmen BJ, Watson JT, Oates JA (1977) Prostaglandin-mediated hypercalcemia in the VX2 carcinoma-bearing rabbit. Prostaglandins 14:319–331
Tashjian AH, Voelkel EF, Goldhaber P, Levine L (1974) Prostaglandins, calcium metabolism and cancer. Fed Proc 33:81–86
Minne M, Raul F, Bellwinkel S, Ziegler R (1975) The hypercalcemic syndrome in rats bearing the Walker Carcinosarcoma 256. Acta Endocrinologica 78:613–624
Troyer H, Sowers JR, Babich E (1982) Leydig cell tumor-induced hypercalcemia in the Fischer Rat: morphometric and histochemical evidence for a humoral factor that activates osteoclasts. Am J Pathol 108:284–290
Fogh J, Bean MA, Bruggen J, Fogh H, Fogh JM, Hammar SP, Kodera Y, Loveless JD, Sorg C, Wright WC (1978) Comparison of a human tumor cell line before and after growth in the nude mouse. In: Fogh J, Giovannella BC (eds) The nude mouse in experimental and clinical research. Academic Press, New York, p 215
Giovannella BC, Stehlin JS, Williams LJ, Jr, Lee S, Shepard R (1978) Heterotransplantation of human cancers into nude mice: a model system for human cancer chemotherapy. Cancer 42:2269–2281
Oshawa N, Ueyama Y, Morita K, Kondo Y (1977) Heterotransplantation of human functioning tumors to nude mice. In: Nomura T, Oshawa N, Tamaoki N, Fujiwara F (eds) Proceedings of the Second International Workshop on Nude Mice. University of Tokyo Press, Tokyo, pp 395–405.
Kondo Y, Sato K, Ohkawa H, Ueyama Y, Okabe T, Sato N, Asano S, Mori M, Ohsawa N, Kosaka K (1983) Association of hypercalcemia with tumors producing colony stimulating factor(s). Cancer Research 43:2368–2374
Takeuchi T, Takeuchi H, Hoshino R, Ohmi K (1982) Rhabdomyosarcoma-induced hypercalcemia in a nude mouse. Cancer 50:94–96
Rousseau-Merck MF, Baccon-Gibod L, Nogues C, Lesec G, Lenoir G, Chatelet F, Avril S, Nezelof C (1982) An original hypercalcemic infantile renal tumor without bone metastasis: heterotransplantation to nude mouse. Cancer 50:85–93
Strewler GH, Williams RD, Nissenson RA (1983) Human renal carcinoma cells produce hypercalcemia in the nude mouse and a novel protein recognized by parathyroid hormone receptors. J Clin Invest 71:769–774
Alexander RL (1971) Evaluation of an automatic calcium titrator. Clin Chem 17:1171
Hargis GK, Williams GA, Reynolds WA, Kawahara W, Jackson B, Bowser EN, Pitkin RM (1977) Radioimmunoassay of parathyroid hormone (parathyrin) in monkey and man. Clin Chem 23:1989–1994
Stewart AF, Horst R, Deftos LJ, Cadman EC, Lang R, Broadus AE (1980) Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and nonhumoral groups. N Engl J Med 303:1377–1383
Rude RK, Sharp CF, Fredericks RS, Oldham SB, Elbaum N, Link J, Irwin L, Singer FR (1981) Urinary and nephrogenous 3′, 5′-monophosphate in the hypercalcemia of malignancy. JCEM 52:765–771
Abramson EC, Kukreja SC, Lad TE, Shemerdiak WP, York PAJ (1984) Nephrogenous cyclic AMP levels in normocalcemic cancer patients: its significance. Horm Metab Res 16:153–156
Tanaka Y, Deluca HF (1973) The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys 154:566
Coburn JW, Brickman AS, Sherrard DJ, Singer FR, Baylink DJ, Wong EGC, Massry SG, Norman AW (1977) Clinical efficacy of 1,25-dihydroxy-vitamin D3 in renal osteodystrophy. In: Norman AW, Schaefer D, Coburn JW, Deluca HF, Fraser D, Grigoleit HG, Herrath DV (eds) Vitamin D biochemical, chemical and clinical aspects related calcium metabolism. Walter de Gruyter, p 662
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Abramson, E.C., Kukla, L.J., Shevrin, D.H. et al. A model for malignancy-associated humoral hypercalcemia. Calcif Tissue Int 36, 563–567 (1984). https://doi.org/10.1007/BF02405367
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DOI: https://doi.org/10.1007/BF02405367