In-Vivo Fusion of Human Cancer and Hamster Stromal Cells Permanently Transduces and Transcribes Human DNA

Abstract

After demonstrating, with karyotyping, polymerase chain reaction (PCR) and fluorescence in-situ hybridization, the retention of certain human chromosomes and genes following the spontaneous fusion of human tumor and hamster cells in-vivo, it was postulated that cell fusion causes the horizontal transmission of malignancy and donor genes. Here, we analyzed gene expression profiles of 3 different hybrid tumors first generated in the hamster cheek pouch after human tumor grafting, and then propagated in hamsters and in cell cultures for years: two Hodgkin lymphomas (GW-532, GW-584) and a glioblastoma multiforme (GB-749). Based on the criteria of MAS 5.0 detection P-values ≤0.065 and at least a 2-fold greater signal expression value than a hamster melanoma control, we identified 3,759 probe sets (ranging from 1,040 to 1,303 in each transplant) from formalin-fixed, paraffin-embedded sections of the 3 hybrid tumors, which unambiguously mapped to 3,107 unique Entrez Gene IDs, representative of all human chromosomes; however, by karyology, one of the hybrid tumors (GB-749) had a total of 15 human chromosomes in its cells. Among the genes mapped, 39 probe sets, representing 33 unique Entrez Gene IDs, complied with the detection criteria in all hybrid tumor samples. Five of these 33 genes encode transcription factors that are known to regulate cell growth and differentiation; five encode cell adhesion- and transmigration-associated proteins that participate in oncogenesis and/or metastasis and invasion; and additional genes encode proteins involved in signaling pathways, regulation of apoptosis, DNA repair, and multidrug resistance. These findings were corroborated by PCR and reverse transcription PCR, showing the presence of human alphoid (α)-satellite DNA and the F11R transcripts in additional tumor transplant generations. We posit that in-vivo fusion discloses genes implicated in tumor progression, and gene families coding for the organoid phenotype. Thus, cancer cells can transduce adjacent stromal cells, with the resulting progeny having permanently transcribed genes with malignant and other gene functions of the donor DNA. Using heterospecific in-vivo cell fusion, genes encoding oncogenic and organogenic traits may be identified.

Malignant transformation of host stromal fibroblasts derived from the bone marrow traced in a dual-color fluorescence xenograft tumor model

“…Goldenberg et al, one of the first investigators to study the malignant transformation of stromal cells, recently suggested that cell fusion of tumor and stromal cells is involved in malignancies (52). Furthermore, recent findings suggested that certain functional human genes may be involved in the malignant transformation of stromal cells (49,50). This view is also supported by other investigators (53)(54)(55).…”

“…Stromal cells within a tumor can be truly malignant and have been reported as early as 1981 (28), although it remains under investigation (30)(31)(32)(33)(34)(49)(50)(51). Since it is almost impossible to distinguish between the tumor and stroma, in vitro studies involving direct or indirect co-culturing have been performed.…”

"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

“…This process has been referred to as symphiliosis, the process of intracellular reconciliation [ 108 ], which suddenly produces new clones with emergent phenotypes. Cancer cells can transduce adjacent TME cells in vivo, and it has been suggested that in vivo fusion discloses genes implicated in tumor progression [ 109 ]. Here, we note that the MTFs present a surprisingly uniform immunophenotypic profile, in spite of the often huge differences in DNA content.…”

Macrophage-Tumor Cell Fusions from Peripheral Blood of Melanoma Patients

“…The MTFs showed a CD44 + CD24 -/low phenotype, and demonstrated increased migration, invasion, and tumorigenicity (but reduced proliferative ability) and they over-expressed EMT genes. In a related vein, other have described in vivo fusion of human cancer cells with hamster stromal cells, resulting in tumors which express the tumors oncogenic driver mutations as well as stromal characteristics [ 67 ]. Macrophage-fusion cells are not exclusive to cancers; fusion between hematopoietic and epithelial cells in adult human intestine has also been described [ 68 ].…”

“…This suddenly produces new clones with emergent phenotypes. Cancer cells can transduce adjacent TME cells in vivo, and it has been suggested that in vivo fusion discloses genes implicated in tumor progression, as well as gene families coding for the organoid phenotype [ 67 ]. Here, we note that the MTFs present a surprisingly uniform immunophenotypic profile, in spite of the often huge differences in DNA content.…”