Establishment of a transplantable tumor line (IP) derived from rat pulmonary carcinoma, developing humoral hypercalcemia of malignancy in IP-bearing rats.
A transplantable tumor line (IP) was established in syngeneic rats from a spontaneous pulmonary carcinoma found in a male F344 rat aged 25 months. A tissue fragment of IP grew into a nodule, 2-3 cm in diameter, 2-3 weeks after implant, and IP has been serially passed through 26 generations. Lined by cuboidal or columnar epithelial cells, the primary tumor consisted of completely alveolar architecture. However, IP tumors developed various growth patterns such as glandular, acinar, trabecular, cord, and solid, and consisting of epithelial cells showing cellular atypia. Ultrastructurally, neoplastic cells had microvilli, basement membranes, and desmosomes, and occasional cells possessed dense cytoplasmic granules. Interestingly, it was shown by the immunohistochemistry, the RT-PCR method, and immunoradiometric assay that IP tumor cells produce parathyroid hormone-related protein (PTHrP). During a 3-week observation period after implant, IP-bearing rats showed severe emaciation, hypercalcemia, and hypophosphatemia, as well as an increase in osteoclastic areas and a decrease in shaft thickness of the femurs. These were considered to be due to a marked elevation of plasma PTHrP levels. Furthermore, IP-bearing rats developed calcification in various organs including the kidneys, lungs, and heart. These findings in IP-bearing rats were similar to those of humoral hypercalcemia of malignancy (HHM) reported in human cancer patients. PTHrP plays a central role in the development of HHM, but the mechanisms of HHM remain poorly understood. IP may become a useful model for studying the pathogenesis of HHM and the pathophysiological role of PTHrP.
Nakanishi
Masako
M
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
Yamate
Jyoji
J
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
Nakatsuji
Shunji
S
Department of Pathology, Toxicology Research Laboratories, Fujisawa Pharmaceutical Co., LTD., Kashima 2-chome, Yodogawa-ku, Osaka, 532-8514, Japan, Japan.
Ide
Mika
M
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
Sawamoto
Osamu
O
Naruto Research Institute, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, 772-8601, Japan, Japan.
Kuwamura
Mitsuru
M
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
Kotani
Takao
T
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
Sakuma
Sadashige
S
Department of Veterinary Pathology, Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka, 599-8531, Japan, Japan.
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002277:Carcinoma / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D022082:Cellular Structures / Q000648:ultrastructure; D019963:Clinical Chemistry Tests; D004195:Disease Models, Animal; D006934:Hypercalcemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D008175:Lung Neoplasms / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009368:Neoplasm Transplantation; D010257:Paraneoplastic Syndromes / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000199:Actins; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm