Biochemistry and Tumor Biology Laboratory, Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, D-30625, Germany.
Cell Commun Signal. 2018 Jan 5;16(1):2. doi: 10.1186/s12964-018-0215-4.
Fusion of breast cancer cells with tumor-associated populations of the microenvironment including mesenchymal stroma/stem-like cells (MSC) represents a rare event in cell communication whereby the metastatic capacity of those hybrid cells remains unclear.
Functional changes were investigated in vitro and in vivo following spontaneous fusion and hybrid cell formation between primary human MSC and human MDA-MB-231 breast cancer cells. Thus, lentiviral eGFP-labeled MSC and breast cancer cells labeled with mcherry resulted in dual-fluorescing hybrid cells after co-culture.
Double FACS sorting and single cell cloning revealed two different aneuploid male hybrid populations (MDA-hyb1 and MDA-hyb2) with different STR profiles, pronounced telomerase activities, and enhanced proliferative capacities as compared to the parental cells. Microarray-based mRNA profiling demonstrated marked regulation of genes involved in epithelial-mesenchymal transition and increased expression of metastasis-associated genes including S100A4. In vivo studies following subcutaneous injection of the breast cancer and the two hybrid populations substantiated the in vitro findings by a significantly elevated tumor growth of the hybrid cells. Moreover, both hybrid populations developed various distant organ metastases in a much shorter period of time than the parental breast cancer cells.
Together, these data demonstrate spontaneous development of new tumor cell populations exhibiting different parental properties after close interaction and subsequent fusion of MSC with breast cancer cells. This formation of tumor hybrids contributes to continuously increasing tumor heterogeneity and elevated metastatic capacities.
乳腺癌细胞与肿瘤相关的微环境群体（包括间充质基质/干细胞样细胞 [MSC]）融合是细胞通讯中的罕见事件，这些杂交细胞的转移能力仍不清楚。
在体外和体内研究了自发融合和人 MSC 与人类 MDA-MB-231 乳腺癌细胞之间形成的杂交细胞后的功能变化。因此，在共培养后，慢病毒 eGFP 标记的 MSC 和用 mcherry 标记的乳腺癌细胞产生了双荧光杂交细胞。
双 FACS 分选和单细胞克隆揭示了两种不同的非整倍体雄性杂交群体（MDA-hyb1 和 MDA-hyb2），与亲本细胞相比，其具有不同的 STR 谱、明显的端粒酶活性和增强的增殖能力。基于微阵列的 mRNA 谱分析表明，参与上皮间质转化的基因明显受到调控，并且与转移相关的基因（包括 S100A4）的表达增加。皮下注射乳腺癌和两种杂交群体后的体内研究证实了体外研究的结果，即杂交细胞的肿瘤生长显著增加。此外，与亲本乳腺癌细胞相比，两种杂交群体在更短的时间内形成了各种远处器官转移。
总之，这些数据表明，在 MSC 与乳腺癌细胞密切相互作用和随后融合后，会自发形成具有不同亲本特性的新肿瘤细胞群体。这些肿瘤杂交体的形成有助于不断增加肿瘤异质性和提高转移能力。
