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Background. Bone morphogenetic proteins (BMPs) are potent inducers of bone formation. Functional and immunohistochemical studies have identified BMPs in a subset of osteosarcomas. In the present study, the authors extend the analysis of BMP expression to other bone and soft tissue sarcomas. Methods. Monoclonal antibody AbH3b2/17 against human BMP-2 and BMP-4 was used in avidin-biotin-immunoperoxidase assays with frozen sections of bone tumors (71 specimens), soft tissue sarcomas (69 specimens), and normal tissues. Results. Among bone tumors, BMP was detected in osteosarcomas (17 of 29 samples), malignant fibrous histiocytomas (MFHs) (6 of 6), and the spindle cell sarcomatous components of spindle cell (dedifferentiated) chondrosarcomas (4 of 4), but not in conventional chondrosarcomas (0 of 10) or Ewing's sarcomas (0 of 14). Histologic subtypes of osteosarcoma differed for BMP expression, with 8 of 9 fibrohistiocytic, 9 of 13 osteoblastic, and 0 of 5 chondroblastic lesions showing immunostaining. In all BMP-positive bone tumors, immunostaining was localized in the cytoplasm of primitive mesenchymal cells, with little or no staining in tumor matrix and more mature osteoblastic/chondrocytic cells. Among soft tissue sarcomas, MFHs (11 of 12), liposarcomas (5 of 11), leiomyosarcomas (3 of 9), and malignant schwannomas (3 of 8) showed cytoplasmic BMP immunostaining. Synovial sarcomas (0 of 9), rhabdomyosarcomas (0 of 8), and fibrosarcomas (0 of 7) were BMP-negative. All normal human tissues tested, including the tissues of a 16-week-old fetus, lacked BMP immunoreactivity. Conclusions. Bone morphogenetic protein is expressed in a subset of osteosarcomas, a high proportion of MFHs of bone and soft tissue, and in spindle cell chondrosarcomas. In these tumors, BMP is localized predominantly to the cytoplasm of malignant cells with primitive mesenchymal features; no or little BMP is detected in the more differentiated elements of bone and soft tissue sarcomas. Different histologic types of bone and soft tissue sarcomas may mimic discrete stages of mesenchymal differentiation as defined by BMP expression and histologic criteria. Cancer 1994; 74:842-7. Key words: bone morphogenetic protein, monoclonal antibody, immunohistochemistry, osteosarcoma, malignant fibrous histiocytoma, spindle cell chondrosarcoma.

Background. Bone morphogenetic proteins (BMP) induce ectopic bone formation in vivo and may play a role in normal bone development. In addition, bone morphogenetic activity, as measured in a bone-forming assay in immunodeficient, athymic nu/nu mice, is present in a proportion of osteosarcomas; this activity, which may be mediated by BMP, is correlated with a poor prognosis. Methods. The development of a monoclonal antibody against recombinant human BMP-2, AbH3b2/17, has allowed immunohistochemical localization of BMP in tumor tissues. Cryostat sections of osteosarcomas (21 tumor samples), chondrosarcomas (5 samples), and Ewing's sarcomas of bone (5 samples) were examined with AbH3b2/17 using the avidin-biotin-immunoperoxidase method. Results. The authors found AbH3b2/17 immunoreactivity in 12 of the 21 osteosarcoma samples (57% sensitivity) obtained from 20 patients. For one patient, samples of the primary lesion and a subsequent metastasis were tested, and only the latter showed AbH3b2/17 immunoreactivity. The chondrosarcomas and Ewing's sarcomas examined showed no immunoreactivity. In antigen-positive osteosarcomas, AbH3b2/17 immunostaining was localized predominantly in the cytoplasm of tumor cells. Moreover, the proportion of AbH3b2/17-reactive cells varied among osteosarcomas with disparate histologic features.

We have generated six high affinity monoclonal antibodies (MoAbs) to the human erythropoietin receptor (hEPO-R) polypeptide. All six MoAbs bind to the extracytoplasmic domain of the hEPO-R, and all immunoprecipitate 35S-labeled hEPO-R from metabolically labeled Ba/F3-hEPO-R cells. Four of the MoAbs neutralize the EPO-dependent growth of Ba/F3-hEPO-R cells, whereas two MoAbs are non-neutralizing. None of the MoAbs inhibit the EPO-dependent growth of Ba/F3 cells expressing the murine EPO-R (mEPO-R), even though the hEPO-R and mEPO-R share 82% amino acid identity. All six of the anti-EPO-R MoAbs bind to the cell surface human EPO-R but none bind to the cell surface murine EPO-R. Of the four neutralizing MoAbs, the one-half maximal inhibition occurs at MoAb concentrations ranging from 1 nmol/L to 50 nmol/L. These MoAbs also compete with radiolabeled EPO for hEPO-R binding. The two non-neutralizing MoAbs fail to inhibit EPO-dependent growth or compete with EPO-binding, even at antibody concentrations as high as 500 nmol/L. The four neutralizing MoAbs, designated group I, compete with each other for an epitope of the hEPO-R polypeptide required for EPO-binding. The two non-neutralizing MoAbs recognize discrete epitopes, and are designated group II and group III MoAbs. In conclusion, this is the first description of MoAbs specific for the hEPO-R. The MoAbs, which recognize three discrete epitopes, may be useful in characterizing the spectrum of cells that display the hEPO-R and in further defining the role of EPO in hematopoiesis.