References

Notes: Department of Biochemistry, National Kyushu Cancer Center, FukuokaFAU - Iguchi, H
Abstract: A 57-year-old man with lung squamous cell carcinoma revealed hypercalcemia, hypophosphoremia, elevation of nephrogenous cAMP and metabolic alkalosis. Serum parathyroid hormone (PTH) and 1,25(OH)2D3 concentrations were not elevated. These findings were consistent with those in humoral hypercalcemia of malignancy (HHM). PTH-related peptide (PTHrP) concentrations were determined using N- and C-terminal specific radioimmunoassays (PTHrP-N, PTHrP-C), and elevation of both PTHrP-N and PTHrP-C concentrations in the serum was noted (PTHrP-N, 27 pmol/liter (normal < 5); PTHrP-C, 1408 pmol/liter (normal < 50)). High concentration of PTHrP (946 pmol/liter for PTHrP-N and 5983 pmol/liter for PTHrP-C) was also found in the pleural fluid obtained at autopsy. Immunohistochemical study, using paraffin-embedded sections of the tumor tissue obtained at autopsy, revealed numerous PTHrP-positive cells and expression of PTHrP gene was confirmed by Northern blot analysis. These findings indicate that PTHrP, produced in the tumor tissue, was secreted into the blood stream, which caused HHM in the patient. Gel permeation chromatography of the serum and pleural fluid revealed several peaks of both PTHrP-N and PTHrP-C. Molecular forms of PTHrP-N were larger than those of PTHrP-C in the serum as well as pleural fluid. These findings indicate that multiple forms of PTHrP molecules are present in the serum and pleural fluid. Granulocytosis was also noted in the patient. However, granulocyte- and granulocyte macrophage-colony stimulating factor were not detected in the serum, and the mechanism of the granulocytosis in the patient was unclear
Reference ID: 5514

Notes: Paratyroid hormone-related protein (PTHrP) producing cell line (KCC-C1) was established from malignant pleural effusion of a patient with squamous cell lung carcinoma. Hypercalcerima and granulocytosis were noted in the patient. The serum level of PTHrP, measured by N-terminal specific radioimmunoassay, was 110 pg/ml (normal < 20pg/ml). The established KCC-C1 tumor cells proved to have PTHrP RNA transcripts and produce a large amount of PTHrP. Besides the production of PTHrP, the culture medium contained a singificant level of interleukin (IL-1). However, tumor necrosis factor or colony stimulating factor was not defected. Transplantation of the KCC-C1 tumor cells into nude mice resulted in tumor fomation with hypercalcemia. As IL-1 is also known to have bone-resorbing activity, KCC-C1 which may prove valuable in the study of the interaction between PTHrP and IL-1 for induction of hypercalcemia.
Reference ID: 3913

Notes: Department of Biochemistry, National Kyushu Cancer Center, Fukuoka, JapanFAU - Iguchi, H
Abstract: In the formation of bone metastasis, osteoclastic bone resorption is necessary before the expansion of tumor cells from bone marrow to bone, and several cytokines, which possess osteoclast-stimulating activity, could be involved in this step. In this paper, we describe a bone metastasis model in nude mice using human lung squamous cell carcinoma-derived cells (HARA), in which the parathyroid hormone-related protein (PTHrP) gene, one of the most potent osteoclast-activating factors, is strongly expressed. The injection of HARA cells (1 x 10(5)) into the left cardiac ventricle resulted in tumor colonies exclusively in the skeletal system at 4 and/or 8 weeks after inoculation. An anti-PTHrP antibody injected via a tail vein reduced the incidence of bone metastases, number of tumor colonies, and tumor volume after the inoculation of HARA cells. The injection of another line of human lung squamous cell carcinoma-derived cells (QG-56), in which the PTHrP gene is not expressed, resulted in no bone metastasis. These findings suggest that PTHrP plays an important role in the formation of bone metastasis
Reference ID: 5515

Notes: National Kyushu Cancer Center Research Institute, Notame 3-1-1, Minami-ku, Fukuoka 811-1395, Japan higuchi@nk-ccgojpFAU - Iguchi, H
Abstract: Cachexia often causes deterioration in the quality of life in cancer patients; however, its mechanism remains poorly understood. Cachexia has often been observed in experimental animals with bone metastases, and parathyroid hormone-related protein (PTHrP) plays an important role in the formation of such metastases. We therefore investigated the possible involvement of PTHrP in an experimental cachexia model using human lung-cancer cells (HARA-B). HARA-B cells produce a high amount of PTHrP but no TNF-alpha, IL-6 or leukemia inhibitory factor. The s.c. inoculation of HARA-B cells into nude mice caused reductions in body weight, adipose tissue weight, muscle weight and serum glucose levels. Serum levels of calcium and PTHrP increased. Neutralization of PTHrP with antibody caused rapid weight gain along with a rapid decrease in serum calcium levels. Our findings suggest that PTHrP plays an important role in the development of cancer cachexia. PTHrP therefore is a possible target molecule for the treatment of cancer cachexia
Reference ID: 5516