The Journal of Bone and Joint Surgery, Vol 61, Issue 8 1207-1216, Copyright © 1979 by Journal of Bone and Joint Surgery, Inc
Induction of new-bone formation in the host bed by human bone-tumor transplants in athymic nude mice
MR Urist, TT Grant, TS Lindholm, JM Mirra, H Hirano and GA Finerman
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. Clinical Relevance: 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...
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