Abstract
BackgroundTumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been posited as a mechanism for cancer metastasis. While there is much support for this from cell culture and animal studies, it has yet to be confirmed in human cancer, as tumor and marrow-derived cells from the same patient cannot be easily distinguished genetically.MethodsWe carried out genotyping of a metastatic melanoma to the brain that arose following allogeneic bone-marrow transplantation (BMT), using forensic short tandem repeat (STR) length-polymorphisms to distinguish donor and patient genomes. Tumor cells were isolated free of leucocytes by laser microdissection, and tumor and pre-transplant blood lymphocyte DNAs were analyzed for donor and patient alleles at 14 autosomal STR loci and the sex chromosomes.ResultsAll alleles in the donor and patient pre-BMT lymphocytes were found in tumor cells. The alleles showed disproportionate relative abundances in similar patterns throughout the tumor, indicating the tumor was initiated by a clonal fusion event.ConclusionsOur results strongly support fusion between a BMDC and a tumor cell playing a role in the origin of this metastasis. Depending on the frequency of such events, the findings could have important implications for understanding the generation of metastases, including the origins of tumor initiating cells and the cancer epigenome.
Highlights
Tumor cell fusion with motile leucocytes such as myeloid lineage cells or stem cells has been put forward as a unifying explanation for metastasis [1,2,3,4]
When poorly metastatic Cloudman S91 mouse melanoma cells were fused with normal mouse or human macrophages in culture, hybrids implanted in mice showed high rates of metastasis with decreased survival times of the hosts compared to those of the control melanoma cells used as fusion partners [7]
The results demonstrate the presence of donor and patient alleles in cancer cells throughout the tumor, indicating that a bone marrow-derived cells (BMDCs)-cancer cell fusion event had initiated the generation of this tumor
Summary
Tumor cell fusion with motile leucocytes such as myeloid lineage cells or stem cells has been put forward as a unifying explanation for metastasis [1,2,3,4]. Cancer cell fusion was first detected when human glioblastoma cells were implanted into hamsters and metastases developed with a human-hamster karyotype [6]. When poorly metastatic Cloudman S91 mouse melanoma cells were fused with normal mouse or human macrophages in culture, hybrids implanted in mice showed high rates of metastasis with decreased survival times of the hosts compared to those of the control melanoma cells used as fusion partners [7]. When fluorescent-labeled mouse bone marrow-derived cells were introduced through parabiosis into mice with intestinal tumors, macrophage-cancer cell hybrids formed that expressed transcriptomes characteristic of both parental fusion partners [12]. While there is much support for this from cell culture and animal studies, it has yet to be confirmed in human cancer, as tumor and marrow-derived cells from the same patient cannot be distinguished genetically
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