Abstract 1630: Cell-cell fusion in vivo transfers genes for human malignancy, metastasis, and the donor tumors’ organoid phenotype to stromal hamster cells.
Authors: Goldenberg David M. , Liu Donglin , Loo Meiyu , Gold David V. , Chang Chien-Hsing , Jaffe Elaine S. 
Published: August 2014

Cell-cell fusion in vitro has been a method for investigating oncogenesis, gene mapping, and gene regulation. Whether such mechanisms occur in vivo requires similar studies with in-vivo cell fusion, particularly whether genes for malignancy, metastasis, and organoid features can be transmitted horizontally to adjacent stromal cells. We describe our experiences with the transplantation of a human glioblastoma multiforme and two Hodgkin lymphomas from patient specimens directly to the hamster cheek pouch, resulting in highly malignant tumors that metastasize in their rodent hosts within the initial transplantation passage and subsequently over passage for many years. The resulting glioblastoma cell line, GB-749, showed heterosynkaryon formation between the tumor and hamster host cells by karyology and FISH, and the retention of 7 human genes, VIM, CD74, CXCR4, TP53, PLAGL2, GFAP, and EGFR, by PCR, of which 3 showed protein translation in vivo by immunohistochemistry; namely, CD74, CXCR4, and PLAGL2. These 3 genes have been implicated with malignancy or, particularly, glioblastoma.

In the second example of two Hodgkin lymphomas grafted to hamsters, FISH again demonstrated stable human-hamster heterosynkaryons, while PCR showed the retention of 7 human genes in the GW-532 and GW-584 cell lines propagated for 5-6 years in-vivo (VIM, CD74, CXCR4, CD19, CD20, CD71, and CD79b). Thus, the glioblastoma and Hodgkin tumor hybrids retained different genes after cell-cell fusion with hamster cells, but VIM, CD74, and CXCR4 were common, surprisingly, to all three tumor hybrid lines. The hybrid transplants also retained the morphological appearance of their original donor tumors, thus retaining their organoid genes providing the tumor's morphological phenotype. In the glioblastoma, GB-749, these included PLAGL2, GFAP, and EGFR, while in the Hodgkin lymphoma lines, GW-532 and GW-584, the B-cell-lineage genes, CD19, CD20, CD79b, were retained. We believe these are the first examples of in-vivo cell-cell fusion between human tumor and rodent host cells showing stable heterosynkaryon formation and propagation over many years, and with the retention of select human genes implicated in the malignant phenoytype, metastasis, and organoid gene signatures. Thus, at least in this model, human cancer cells can transmit malignant and organoid genes to stromal cells in their microenvironment, perhaps representing a basic mechanism for the tumor heterogeneity observed clinically. Whether such fusion events occur during the progression of cancers in patients remains to be determined.

Citation Format: David M. Goldenberg, Donglin Liu, Meiyu Loo, David V. Gold, Chien-Hsing Chang, Elaine S. Jaffe. Cell-cell fusion in vivo transfers genes for human malignancy, metastasis, and the donor tumors’ organoid phenotype to stromal hamster cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1630. doi:10.1158/1538-7445.AM2013-1630