Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer–host partnership?

Abstract

A major clinical manifestation of bone cancers is bone destruction. It is widely accepted that this destruction is not caused by the malignant cells themselves, but by osteoclasts, multinucleated cells of monocytic origin that are considered to be the only cells able to degrade bone. The present study demonstrates that bone-resorbing osteoclasts from myeloma patients contain nuclei with translocated chromosomes of myeloma B-cell clone origin, in addition to nuclei without these translocations, by using combined FISH and immunohistochemistry on bone sections. These nuclei of malignant origin are transcriptionally active and appear fully integrated amongst the other nuclei. The contribution of malignant nuclei to the osteoclast population analysed in this study was greater than 30%. Osteoclast-myeloma clone hybrids contained more nuclei than normal osteoclasts and their occurrence correlated with the proximity of myeloma cells. Similar hybrid cells were generated in myeloma cell-osteoclast co-cultures, as revealed by tracing myeloma nuclei using translocations, bromo-deoxyuridine, or the Y chromosome of male myeloma cells in female osteoclasts. These observations indicate that hybrid cells can originate through fusion between myeloma cells and osteoclasts. In conclusion, malignant cells contribute significantly to the formation of bone-resorbing osteoclasts in multiple myeloma. Osteoclast-myeloma clone hybrids reflect a previously unrecognized mechanism of bone destruction in which malignant cells participate directly. The possibility that malignant cells corrupt host cells by the transfer of malignant DNA may have been underestimated to date in cancer research.

Bone-Resorbing Cells in Multiple Myeloma: Osteoclasts, Myeloma Cell Polykaryons, or Both?

“…Work in progress in our lab supports this hypothesis [70]. The demonstration that OC-myeloma cell hybrids are also detectable in vivo [16] is of interest and emphasizes the basic mechanisms of cell fusion in vivo, multinuclearity, and the ability to resorb the bone matrix. These cells are bone-resorbing polykaryons and have been postulated to have derived from macrophages originated by dedifferentiated clonal B cells that are able to fuse their membrane and generate multinuclear cells.…”

“…Recent observations suggest that malignant plasma cells take part in bone destruction. This OC-like activity has been shown by ourselves [17] and is indicated by other findings [16] that support the capability of these cells to form in vitro polykaryons with functional properties similar to OCs.…”

“…New pathogenetic studies on myeloma osteoclastogenesis, however, indicate that malignant plasma cells can transdifferentiate to functional OC-like cells in the marrow microenvironment and directly participate in bone resorption [15][16][17]. This would reconcile the severe progression of MBD with the paucity of marrow OC activity in patients with a defective marrow matrix.…”

Viewing Malignant Melanoma Cells as Macrophage-tumor Hybrids

“…34 As mentioned above, there are three reports that in vivo passage of melanoma cells produced host-melanoma hybrids. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] B16F10 melanoma cells expressed the same phenotype as these hybrids: high metastatic potential, chemotactic motility, hyperpigmentation, high expression of GnT-V and β1,6-branched oligosaccharides, and autophagic coarse melanin (Fig. , right panel).…”

Viewing Malignant Melanoma Cells as Macrophage-tumor Hybrids

“…Tumor cells fuse with a variety of normal cell types including cells of the endothelium, 6 stroma, 7 and bone marrow-derived cells. [8][9][10][11] In vivo fusions between bone marrow-derived cells and human renal carcinoma cells, 8,9 colon carcinoma cells, 10 and between myeloma cells and osteoclasts 11 have been reported. Of the more than 30 studies of tumor cell fusion in vivo, none has failed to detect hybrids.…”