Urist M R, Grant T T, Lindholm T S, Mirra J M, Hirano H, Finerman G A
J Bone Joint Surg Am. 1979 Dec;61(8):1207-16.
Specimens of twelve osteosarcomas, five chondrosarcomas, one giant-cell tumor, and five extraskeletal soft-tissue sarcomas were transplanted into male athymic nude (nu/nu) mice. Survival of the transplant was determined by the volume-doubling time and the sex chromatin of the tumor cells obtained from two female patients. By these criteria and the similarity of the histological composition of the original tumor and the transplant, survival occurred in four of twelve osteosarcomas and four of five chondrosarcomas. Without any local infiltration of lymphocytes or plasma cells, or other evidence of cell-mediated immunity, the surviving tumors regressed by the fourth week after the operation. Transformed osteoblasts and osteoprogenitor cells were replaced by fibrous connective tissue or fibrogenic tumor-tissue cells. Osteocytes degenerated and disappeared from the lacunae. The one giant-cell tumor transplant survived, growing very slowly, but by the end of the first week after transplantation whorls of mononucleated cells appeared in sites previously occupied by multinucleated cells. Transplants of leiomyosarcoma, liposarcoma, and synovioma (one tumor of each) degenerated. One of two fibrosarcomas survived transplantation. The most striking reaction of the mouse host bed was to encompass six of twelve osteosarcomas and four of five chondrosarcomas in deposits of normal living cartilage, bone, and bone marrow. The incidence of new bone inducedy by living transplants was only slightly greater than by implants of freeze-dried killed osteosarcoma tissue. Not one of five extraskeletal sarcomas, living or dead, induced bone formation. These observations suggest that an osteoinductive agent is transmitted by some osteosarcomas and chondrosarcomas. This agent initiates differentiation of host mesenchymal cells into normal non-tumorous cartilage and bone, which later colonized by bone marrow.
Our observations present experimental evidence of the origin of the envelope of normal non-tumorous bone that may surround tumorous bone. In 1926, Phemister recognized the clinical significane of this envelope as a pitfall in the differential diagnosis of malignant bone tumors, chondrosarcoma, myositis ossificans circumscripta, and other neoplasms. He emphasized the importance of examining the entire specimen for the distribution of deposits of tumorous and normal bone. The induction of normal bone formation in the host bed surrounding transplants of osteosarcomas and some chondrosarcomas (but not transplants of fibrosarcoma, liposarcoma, or leiomyosarcoma) is evidence of a specific tumor-cell characteristic. Thus, the bone inductive response is not an unspecific reaction to injury from expansion or of tumor growth but a biological response to tumor-cell products. Transplants of human malignant tumors growing in the thymus-deficient mouse can be treated by combinations of radiation, amputation, and new chemotherapeutic agents...
将12例骨肉瘤、5例软骨肉瘤、1例巨细胞瘤和5例骨外软组织肉瘤的标本移植到雄性无胸腺裸（nu/nu）小鼠体内。通过体积倍增时间和从两名女性患者获取的肿瘤细胞的性染色质来确定移植瘤的存活情况。根据这些标准以及原发肿瘤和移植瘤组织学组成的相似性，12例骨肉瘤中有4例、5例软骨肉瘤中有4例存活。在没有淋巴细胞或浆细胞的任何局部浸润或细胞介导免疫的其他证据的情况下，存活的肿瘤在术后第4周消退。转化的成骨细胞和骨祖细胞被纤维结缔组织或纤维生成性肿瘤组织细胞取代。骨细胞从骨陷窝中退化并消失。1例巨细胞瘤移植瘤存活，生长非常缓慢，但在移植后第一周结束时，单核细胞的漩涡出现在先前由多核细胞占据的部位。平滑肌肉瘤、脂肪肉瘤和滑膜瘤（各1例）的移植瘤退化。2例纤维肉瘤中有1例存活移植。小鼠宿主床最显著的反应是在正常活软骨、骨和骨髓沉积物中包围12例骨肉瘤中的6例和5例软骨肉瘤中的4例。活移植瘤诱导新骨形成的发生率仅略高于冻干杀死的骨肉瘤组织植入物。5例骨外肉瘤，无论死活，均未诱导骨形成。这些观察结果表明，某些骨肉瘤和软骨肉瘤可传递一种骨诱导因子。这种因子启动宿主间充质细胞分化为正常非肿瘤性软骨和骨，随后被骨髓定植。
我们的观察结果提供了可能包围肿瘤性骨的正常非肿瘤性骨包膜起源的实验证据。1926年，费米斯特认识到这种包膜在恶性骨肿瘤、软骨肉瘤、局限性骨化性肌炎和其他肿瘤的鉴别诊断中的临床意义。他强调检查整个标本中肿瘤性骨和正常骨沉积物分布的重要性。骨肉瘤和一些软骨肉瘤（但不是纤维肉瘤、脂肪肉瘤或平滑肌肉瘤）移植周围宿主床中正常骨形成的诱导是肿瘤细胞特定特征的证据。因此，骨诱导反应不是对肿瘤生长扩张或损伤的非特异性反应，而是对肿瘤细胞产物的生物学反应。在胸腺缺陷小鼠中生长的人类恶性肿瘤移植瘤可以通过放疗、截肢和新的化疗药物联合治疗……
