Horizontal Transmission of Malignancy: In-Vivo Fusion of Human Lymphomas with Hamster Stroma Produces Tumors Retaining Human Genes and Lymphoid Pathology

Abstract

We report the in-vivo fusion of two Hodgkin lymphomas with golden hamster cheek pouch cells, resulting in serially-transplanted (over 5–6 years) GW-532 and GW-584 heterosynkaryon tumor cells displaying both human and hamster DNA (by FISH), lymphoma-like morphology, aggressive metastasis, and retention of 7 human genes (CD74, CXCR4, CD19, CD20, CD71, CD79b, and VIM) out of 24 tested by PCR. The prevalence of B-cell restricted genes (CD19, CD20, and CD79b) suggests that this uniform population may be the clonal initiating (malignant) cells of Hodgkin lymphoma, despite their not showing translation to their respective proteins by immunohistochemical analysis. This is believed to be the first report of in-vivo cell-cell fusion of human lymphoma and rodent host cells, and may be a method to disclose genes regulating both organoid and metastasis signatures, suggesting that the horizontal transfer of tumor DNA to adjacent stromal cells may be implicated in tumor heterogeneity and progression. The B-cell gene signature of the hybrid xenografts suggests that Hodgkin lymphoma, or its initiating cells, is a B-cell malignancy.

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

“…It was also suggested that the heterosynkaryons of Hodgkin lymphoma with their Hodgkin Reed-Sternberg (HRS) cells retained their B-cell origin [37], confirming other evidence for a B-cell origin of this neoplasm [67], and again corroborated herein by gene probe analysis disclosing B-cell genes ( CD20, CD22 ) in these specimens. As described, these tumors were observed within 2 weeks of their first transplantation, and showed evidence of metastasis in the hamster within 3–4 weeks [10], [37], suggesting that the hamster host's early response to the foreign tissue graft may have contributed to this process. Indeed, inflammation and wound healing are known to facilitate cell fusion [68]–[70].…”

“…For example, we reported that after long-term propagation of human-hamster hybrid tumors derived from a glioblastoma multiforme [33] and two Hodgkin lymphomas, human DNA and genes could be confirmed by fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR), and their donor organoid features by histology [36], [37]. Translation of some of these gene products was found by immunohistochemistry (IHC) in the glioblastoma multiforme transplants, even after propagation for over a year [36].…”

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.…”

Human pontine glioma cells can induce murine tumors

“…Although not yet described for DIPG tumors, the occurrence of mouse tumors after injection of human tumor cells has been previously reported as a sporadic event [2,15,17,18,41,45,46,51], and may be attributable to viral transformation [2], human growth factor stimulation [50], cell fusion [13,14,16,17] or transference of human DNA into the mouse host cells [18]. Such events may lead to single catastrophic events causing the rapid and reproducible onset of mouse DIPG tumors as observed here [47].…”