ROLE OF RANKL IN OSTEOLYTIC BONE METASTASIS OF MALIGNANT TUMOR

RANKL在恶性肿瘤溶骨骨转移中的作用

• 批准号: 13670217
• 负责人: KITAZAWA Sohei
• 金额: $ 1.98万
• 依托单位: KOBE UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670217/
• 关键词: cancer; osteolytic meastasis; osteoclast; RANKL; PTHrP; 高カルシウム血症; 溶骨性骨移植

Breast cancer is frequently associated with osteolytic bone metastasis, where osteoclasts play a major role in bone destruction. Recently, osteoclast differentiation factor (RANKL) has been identified as a prerequisite for the formation and maintenance of osteoclasts from haematopoietic precursors. To elucidate the mechanism of osteoclastogenesis and bone destruction in bone-residing breast cancer, human breast cancer cells (MCF-7) were injected into the forehead of nude mice. The expression of RANKL and PTHrP mRNA, and osteoclastogenesis were analysed by in situ hybridization and TRAP staining. At early stages, spindle-shaped stromal cells and osteoblasts on the bone surface expressed RANKL, then numerous osteoclasts were induced on the periosteal bone surface. Three weeks after the transplantation, cancer cells migrated onto the eroded bone surface, where they survived apoptosis. At all stages, RANKL expression was confined to the stromal/osteoblastic cells, whereas PTHrP was confined to the MCF-7 breast cancer cells. On the other hand, neither induction of osteoclasts nor infiltrative growth of cancer cells was observed in mice transplanted with PTHrP-non producing cancer cells. Moreover, in vitro treatment with PTHrP resulted in increased RANKL mRNA expression and transcription activity in the MC3T3-E1 mouse osteoblastic cell line. Thus PTHrP induces osteoclastic bone resorption through the transactivation of the RANKL gene on stromal/osteoblastic cells, affording a bone microenvironment conducive to the survival of PTHrP-producing cancer cells.We have presented our data at various international as well as domestic meeting, and published scientific papers for academic journals.

乳腺癌常伴有溶骨性骨转移，其中破骨细胞在骨破坏中起主要作用。最近，破骨细胞分化因子（RANKL）已被确定为从造血前体细胞的破骨细胞的形成和维持的先决条件。为了阐明破骨细胞生成和骨破坏在骨驻留型乳腺癌中的机制，将人乳腺癌细胞（MCF-7）注射到裸鼠前额。原位杂交和TRAP染色检测RANKL和PTHrP mRNA的表达及破骨细胞的生成。在早期，骨表面的梭形基质细胞和成骨细胞表达RANKL，然后在骨膜骨表面诱导大量破骨细胞。移植后三周，癌细胞迁移到侵蚀的骨表面，在那里它们通过凋亡存活下来。在所有阶段，RANKL表达仅限于基质/成骨细胞，而PTHrP仅限于MCF-7乳腺癌细胞。另一方面，在移植PTHrP非产生癌细胞的小鼠中既没有观察到破骨细胞的诱导，也没有观察到癌细胞的浸润性生长。此外，PTHrP体外处理导致MC 3 T3-E1小鼠成骨细胞系中RANKL mRNA表达和转录活性增加。因此，PTHrP通过基质/成骨细胞上的RANKL基因的反式激活来诱导骨细胞骨吸收，提供有利于产生PTHrP的癌细胞存活的骨微环境。我们在各种国际和国内会议上展示了我们的数据，并在学术期刊上发表了科学论文。

项目成果

Fujimoto M, Kitazawa S, Kondo T, Inoue H, Kajimoto K, Maeda S, Kitazawa R: "A case of EBV-associated T-cell Lymphoma presented as hemophagicytic syndrome"Shindan Byori. 18. 200-202 (2001)

Fujimoto M、Kitazawa S、Kondo T、Inoue H、Kajimoto K、Maeda S、Kitazawa R：“EBV 相关 T 细胞淋巴瘤表现为噬血细胞综合征”Shindan Byori。

Kitazawa S, Kitazawa R: "RANK ligand is requsite for cancer-associated osteoiytic lesions"J Pathol. 198. 228-236 (2002)

Kitazawa S、Kitazawa R：“RANK 配体是癌症相关溶骨性病变的必要条件”J Pathol。

Kitazawa R, Kitazawa S, Kajimoto K, et al.: "Parathyroid hormone-related protein (FTHrP) expression in multiple myeloma : a case report"Pathol Int. 52・1. 63-68 (2002)

Kitazawa R、Kitazawa S、Kajimoto K 等：“多发性骨髓瘤中甲状旁腺激素相关蛋白 (FTHrP) 的表达：病例报告”Pathol Int. 52・1 (2002)。

Kitazawa R et al.: "Gene expression during fracture healing in normal mouse : in situ hybridization on hard tissues for investigation of regenerative mechanism"Acta Histochem Cytochem. 34・5. 321-328 (2001)

Kitazawa R等：“正常小鼠骨折愈合过程中的基因表达：用于研究再生机制的原位杂交”Acta Histochem Cytochem 34・5（2001）。

Kitazawa R et al.: "Expression of parathyroid hormone-related protein (PTHrP) in parathyroid tissues of normal and pathological conditions"Histol Histopathol. 17・1. 179-184 (2002)

Kitazawa R 等人：“正常和病理条件下甲状旁腺激素相关蛋白（PTHrP）的表达”Histol Histopathol 17・1（2002）。