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Abstract

Studies were conducted on the hypothesis that melanoma metastasis might be initiated through the generation of hybrids comprised of cells of the primary tumor and tumor-infiltrating leukocytes. Fusion hybrids were generated in vitro between weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages. Hybrids were implanted s.c. in the tail and mice were monitored for metastases. Controls included parental S91 cells, autologous S91 x S91 hybrids, and B16F10 melanoma cells. Of 35 hybrids tested, most were more aggressive than the parental melanoma cells, producing metastases sooner and in more mice. A striking characteristic was heterogeneity amongst hybrids, with some lines producing no metastases and others producing metastases in up to 80% of mice. With few exceptions, hybrids with the highest metastatic potential also had the highest basal melanin content whereas those with the lowest metastatic potential were basally amelanotic, as were the parental melanoma cells. A spontaneous in vivo supermelanotic hybrid between an S91 tumor cell and DBA/2J host cell was one of the most metastatic lines. Hybrids with the highest metastatic potential also exhibited markedly higher chemotaxis to fibroblast-conditioned media. Histologically, the metastatic hybrids demonstrated vascular invasion and spread to distant organs similar to that of metastatic melanomas in mice and humans. Thus previous findings of enhanced metastasis in leukocyte x lymphoma hybrids can now be extended to include leukocyte x melanoma hybrids. Whether such hybridization is a natural cause of metastasis in vivo remains to be determined; however the fusion hybrids with genetically-matched parents described herein so closely resembled naturally-occurring metastatic melanoma cells that they could serve as useful new models for studies of this complex and deadly phenomenon.

“Stealth” Melanoma Cells in Histology-negative Sentinel Lymph Nodes

“…It has been suggested that cancer cells may spontaneously fuse with host cells to produce hybrids (17, 18, 35, 49, 50). Evidence in support of cancer cell fusion with macrophages or other bone marrow-derived cells has been reported from studies of animal models of human cancer (6, 9-11, 49, 52, 53, 59). Hybrid cells formed from macrophages and melanoma cells may possess the malignant potential of the melanoma cells and the migratory phenotype of the macrophages.…”

Tumor Associated Macrophage × Cancer Cell Hybrids May Acquire Cancer Stem Cell Properties in Breast Cancer

“…The idea that cell fusion contributes to cancer progression was introduced almost 100 years ago with a proposal that malignancy is a consequence of hybridization between leukocytes and somatic cells, and Melanoma × macrophage hybrids with enhanced metastatic potential [40]. Years later, this idea was expanded to encompass that cell fusion promotes the phenotypic and genotypic diversity of tumors and that the fusion of tumor cells with leukocytes results in metastatic cells [41], [42].…”

Pro-tumor activities of macrophages in the progression of melanoma

“…At least some of these hybrids become metastatic, exhibiting both motility and continuous cell division 70 . It has been demonstrated that hybrids of weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages can be created in vitro with use of polyethylene glycol -induced fusion 71 . Compared to the parental melanoma cells, most daughters of the 35 hybrids tested were found to be more aggressive, with the result being that metastases onset was more rapid and observed in greater numbers of mice 71 .…”

“…It has been demonstrated that hybrids of weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages can be created in vitro with use of polyethylene glycol -induced fusion 71 . Compared to the parental melanoma cells, most daughters of the 35 hybrids tested were found to be more aggressive, with the result being that metastases onset was more rapid and observed in greater numbers of mice 71 . The majority of these hybrid clones showed markedly enhanced chemotactic motility toward a variety of attractants in 2-chambered culture systems, a hallmark of metastatic cells 72 .…”