Efficient acquisition of dual metastasis organotropism to bone and lung through stable spontaneous fusion between MDA-MB-231 variants

Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2009; 106(23):9385-90. DOI: 10.1073/pnas.0900108106
Source: PubMed


Cell fusion is involved in many critical developmental processes, including zygote formation and organogenesis of placenta, bone, and skeletal muscle. In adult tissues, cell fusion has been shown to play an active role in tissue regeneration and repair, and its frequency of occurrence is significantly increased during chronic inflammation. Fusion between tumor cells and normal cells, or among tumor cells themselves, has also been speculated to contribute to tumor initiation, as well as phenotypic evolution during cancer progression and metastasis. Here, we show that dual metastasis organotropisms can be acquired in the same cell through in vitro or in vivo spontaneous fusion between bone- and lung-tropic sublines of the MDA-MB-231 human breast cancer cell line. The synkaryonic hybrids assimilate organ-specific metastasis gene signatures from both parental cells and are genetically and phenotypically stable. Our study suggests cell fusion as an efficient means of phenotypic evolution during tumor progression and additionally demonstrates the compatibility of different metastasis organotropisms.

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    • "The differential phenotype of the M13HS hybrid cell lines among themselves as well as in comparison to their parental derivatives is most likely attributed to the fact that they originated from different parental cell types exhibiting a differential gene expression profile and epigenetic background. Lu and Kang demonstrated that hybrid cells, derived from highly specific MDA-MB-231 lung and bone metastatic variants, co-expressed lung and bone metastasis signature genes and were highly metastatic to both lung and bone suggesting a phenotypic overlap [73]. However, the authors argued that this phenotypic overlap was most likely attributed to the co-existence of regulatory epigenetic mechanisms from both fusion partners, thereby giving rise to hybrid cells expressing a dual set of organ-specific metastasis genes [73]. "
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    ABSTRACT: The biological phenomenon of cell fusion has been linked to tumor progression because several data provided evidence that fusion of tumor cells and normal cells gave rise to hybrid cell lines exhibiting novel properties, such as increased metastatogenic capacity and an enhanced drug resistance. Here we investigated M13HS hybrid cell lines, derived from spontaneous fusion events between M13SV1-EGFP-Neo breast epithelial cells exhibiting stem cell characteristics and HS578T-Hyg breast cancer cells, concerning CCL21/CCR7 signaling. Western Blot analysis showed that all cell lines varied in their CCR7 expression levels as well as differed in the induction and kinetics of CCR7 specific signal transduction cascades. Flow cytometry-based calcium measurements revealed that a CCL21 induced calcium influx was solely detected in M13HS hybrid cell lines. Cell migration demonstrated that only M13HS hybrid cell lines, but not parental derivatives, responded to CCL21 stimulation with an increased migratory activity. Knockdown of CCR7 expression by siRNA completely abrogated the CCL21 induced migration of hybrid cell lines indicating the necessity of CCL21/CCR7 signaling. Because the CCL21/CCR7 axis has been linked to metastatic spreading of breast cancer to lymph nodes we conclude from our data that cell fusion could be a mechanism explaining the origin of metastatic cancer (hybrid) cells.
    PLoS ONE 05/2013; 8(5):e63711. DOI:10.1371/journal.pone.0063711 · 3.23 Impact Factor
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    • "Not only do these lymphoid tumors show similar highly malignant features as the GBM, thus confirming this process in two different cell types xenografted, but they displayed appropriate morphological differentiation by having similar lymphoid features to the original human Hodgkin malignancies grafted. Other studies of cell fusion have elucidated organ-specific metastatic gene signatures [26], supporting our view that genetic transfer of organoid features also is likely. "
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    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.
    PLoS ONE 02/2013; 8(2):e55324. DOI:10.1371/journal.pone.0055324 · 3.23 Impact Factor
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    • "Tumors were weighed and collected for various experiments. Then, the lungs were removed, washed, and fixed with Bouin's solution for 24 h to facilitate counting of tumor nodules as described previously (Lu and Kang 2009). The number of tumor nodules on the whole surface of lungs was counted using a dissecting microscope . "
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    ABSTRACT: Gambogic acid (GA) is considered a potent anti-tumor agent for its multiple effects on cancer cells in vitro and in vivo. Low concentrations of GA (0.3-1.2 µmol/L) can suppress invasion of human breast carcinoma cells without affecting cell viability. To get a whole profile of the inhibition on breast cancers, higher concentrations of GA and spontaneous metastatic animal models were employed. Treatment with GA (3 and 6 µmol/L) induced apoptosis in MDA-MB-231 cells and the accumulation of reactive oxygen species (ROS). Furthermore, GA induced PARP cleavage, activation of caspase-3, caspase-8, and caspase-9, as well as an increased ratio of Bax/Bcl-2. Moreover, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c (Cyt c) from mitochondria were observed, indicating that GA induced apoptosis through accumulation of ROS and mitochondrial apoptotic pathway. GA also inhibited cell survival via blocking Akt/mTOR signaling. In vivo, GA significantly inhibited the xenograft tumor growth and lung metastases in athymic BALB/c nude mice bearing MDA-MB-231 cells. Collectively, these data provide further support for the multiple effects of GA on human breast cancer cells, as well as for its potential application to inhibit tumor growth and prevent metastasis in human cancers.
    Biochemistry and Cell Biology 12/2012; 90(6):718-30. DOI:10.1139/o2012-030 · 2.15 Impact Factor
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