title: Production of parathyroid hormone-related protein in tumour xenografts in nude mice presenting with hypercalcaemia.
abstract: This study examined the pathophysiological role of parathyroid hormone-related protein (PTHrP) in humoral hypercalcaemia of malignancy (HHM). Seven human tumour xenografts were analysed in nude mice; five tumours (KEsC-2, oesophageal carcinoma; FA-6, pancreatic carcinoma; SEKI, melanoma; Lu-65A and Lu-61, lung carcinomas) were associated with hypercalcaemia and two tumours (MIA PaCa-2, pancreatic carcinoma; PLC/PRF/5, hepatocellular carcinoma) with normocalcaemia. Northern blot analyses, radioimmunoassay and bioassay confirmed the synthesis of PTHrP-like peptides by all five tumours associated with hypercalcaemia, but not by the two associated with normocalcaemia. These observations indicated a very close relationship between the production of PTHrP and the development of HHM. Gel filtration studies of three tumour tissue extracts revealed at least two different molecules with both PTHrP-like immunological and biological activities. One peak eluted at a position between PTHrP (1-141) and cytochrome C and the other at a position identical to cytochrome C. These results suggest that PTHrP molecules with a molecular size equal to or greater than cytochrome C participate as causative agents of HHM. All five tumour xenografts caused hypercalcaemia when grown to a size of 1.5 g in nude mice. Under cell culture conditions, four original cell lines, KEsC-2, FA-6, SEKI and Lu-65A secreted 450.0, 45.0, 3.6 and 3.0 pmol of immunoreactive PTHrP/1.5 x 10(9) cells (approximately equivalent to 1.5 g wet weight) 24 h-1 into their respective culture media. Since a subcutaneous infusion of 100 pmol 24 h-1 of PTHrP (1-34) into nude mice was sufficient to induce significant hypercalcaemia, we speculate that PTHrP alone released from tumour cells could induce hypercalcaemia at least in the case of KEsC-2, and possibly in FA-6. With regard to other tumours associated with hypercalcaemia, further examination of PTHrP and other compounds with bone-resorbing activity in these transplantable tumours is required to obtain a better understanding of this morbidity.
authors.affiliation: Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Nagasaki
authors.forename: T
authors.initials: T
authors.lastname: Tsuchihashi
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000209:etiology; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000096:biosynthesis*; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D014183:Transplantation, Heterologous
chemical_list: D009363:Neoplasm Proteins; C470121:PTHLH protein, human; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger