Ayako Yokoyama1,2, Tomoka Hasegawa3, Toru Hiraga4, Tamaki Yamada5, Hiromi Hongo1, Tomomaya Yamamoto1,6, Miki Abe1, Taiji Yoshida1, Yasuo Imanishi7, Shinichiro Kuroshima8, Muneteru Sasaki8, Paulo Henrique Luiz de Fraitas9, Minqi Li10, Norio Amizuka1, Yutaka Yamazaki2. 1. Developmental Biology of Hard Tissue, Graduate School of Dental Medicine and Faculty of Dental Medicine, Hokkaido University, Kita-13, Nishi-7, Kita-Ku, Sapporo, Japan. 2. Gerodontology, Graduate School of Dental Medicine and Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan. 3. Developmental Biology of Hard Tissue, Graduate School of Dental Medicine and Faculty of Dental Medicine, Hokkaido University, Kita-13, Nishi-7, Kita-Ku, Sapporo, Japan. hasegawa@den.hokudai.ac.jp. 4. Department of Oral Anatomy, Matsumoto Dental University, Shiojiri, Japan. 5. Oral and Maxillofacial Surgery, Graduate School of Dental Medicine and Faculty of Dental Medicine, Hokkaido University, Sapporo, Japan. 6. Northern Army Medical Unit, Camp Makomanai, Japan Ground Self-Defense Forces,, Sapporo, Japan. 7. Department of Nephrology, Graduate School of Medicine, Osaka City University, Osaka, Japan. 8. Department of Applied Prosthodontics, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. 9. Department of Dentistry, Federal University of Sergipe at Lagarto, Sergipe, Brazil. 10. Division of Basic Science of Stomatology, The School of Stomatology, Shandong University, Jinan, China.
Abstract
INTRODUCTION: After the onset of bone metastasis, tumor cells appear to modify surrounding microenvironments for their benefit, and particularly, the levels of circulating fibroblast growth factor (FGF) 23 in patients with tumors have been highlighted. MATERIALS AND METHODS: We have attempted to verify if human breast carcinoma MDA-MB-231 cells metastasized in the long bone of nu/nu mice would synthesize FGF23. Serum concentrations of calcium, phosphate (Pi) and FGF23 were measured in control nu/nu mice, bone-metastasized mice, and mice with mammary gland injected with MDA-MB-231 cells mimicking primary mammary tumors. RESULTS AND CONCLUSIONS: MDA-MB-231 cells revealed intense FGF23 reactivity in metastasized lesions, whereas MDA-MB-231 cells cultured in vitro or when injected into the mammary glands (without bone metastasis) showed weak FGF23 immunoreactivity. Although the bone-metastasized MDA-MB-231 cells abundantly synthesized FGF23, osteocytes adjacent to the FGF23-immunopositive tumors, unlike intact osteocytes, showed no FGF23. Despite significantly elevated serum FGF23 levels in bone-metastasized mice, there was no significant decrease in the serum Pi concentration when compared with the intact mice and mice with a mass of MDA-MB-231 cells in mammary glands. The metastasized femora showed increased expression and FGFR1 immunoreactivity in fibroblastic stromal cells, whereas femora of control mice showed no obvious FGFR1 immunoreactivity. Taken together, it seems likely that MDA-MB-231 cells synthesize FGF23 when metastasized to a bone, and thus affect FGFR1-positive stromal cells in the metastasized tumor nest in a paracrine manner.
INTRODUCTION: After the onset of bone metastasis, tumor cells appear to modify surrounding microenvironments for their benefit, and particularly, the levels of circulating fibroblast growth factor (FGF) 23 in patients with tumors have been highlighted. MATERIALS AND METHODS: We have attempted to verify if humanbreast carcinomaMDA-MB-231 cells metastasized in the long bone of nu/nu mice would synthesize FGF23. Serum concentrations of calcium, phosphate (Pi) and FGF23 were measured in control nu/nu mice, bone-metastasized mice, and mice with mammary gland injected with MDA-MB-231 cells mimicking primary mammary tumors. RESULTS AND CONCLUSIONS:MDA-MB-231 cells revealed intense FGF23 reactivity in metastasized lesions, whereas MDA-MB-231 cells cultured in vitro or when injected into the mammary glands (without bone metastasis) showed weak FGF23 immunoreactivity. Although the bone-metastasized MDA-MB-231 cells abundantly synthesized FGF23, osteocytes adjacent to the FGF23-immunopositive tumors, unlike intact osteocytes, showed no FGF23. Despite significantly elevated serum FGF23 levels in bone-metastasized mice, there was no significant decrease in the serum Pi concentration when compared with the intact mice and mice with a mass of MDA-MB-231 cells in mammary glands. The metastasized femora showed increased expression and FGFR1 immunoreactivity in fibroblastic stromal cells, whereas femora of control mice showed no obvious FGFR1 immunoreactivity. Taken together, it seems likely that MDA-MB-231 cells synthesize FGF23 when metastasized to a bone, and thus affect FGFR1-positive stromal cells in the metastasized tumor nest in a paracrine manner.
Entities:
Keywords:
Bone metastasis; Fibroblast growth factor 23; Immunohistochemistry; MDA-MB-231; Osteocyte