Spontaneous Formation of Tumorigenic Hybrids between Breast Cancer and Multipotent Stromal Cells Is a Source of Tumor Heterogeneity
Spontaneous Formation of Tumorigenic Hybrids between Breast Cancer and Multipotent Stromal Cells Is a Source of Tumor Heterogeneity
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DOI：
10.1016/j.ajpath.2012.02.020
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发表时间：
2012-06-01
影响因子：
6
通讯作者：
Lorico, Aurelio
中科院分区：
文献类型：
--
作者：
Rappa, Germana;Mercapide, Javier;Lorico, Aurelio
乳腺癌的进展涉及癌细胞异质性，即在原发肿瘤的非转移性细胞群中产生侵袭性/转移性乳腺癌细胞。连续基因突变、上皮间质转化、与局部基质的相互作用以及癌细胞与正常骨髓来源细胞之间杂交体的形成已被认为是肿瘤进展机制。我们在此报告了人骨髓源性多能基质细胞（MSC）与两种不同乳腺癌细胞系MDA-MB-231（MDA）和MA11之间自发体外形成异型杂交体。杂交体主要表现出间充质形态特征、混合基因表达谱和增加的 DNA 倍性。 MA11和MDA杂交体在无缺陷小鼠中均具有致瘤性，并且一些MDA杂交体具有增加的转移能力。无论是在培养物中还是在异种移植物中，杂交体都经历了DNA倍性减少和形态学逆转为乳腺癌样形态特征，同时保持了混合的乳腺癌-间质表达谱。通过RNA测序对编码单核苷酸多态性进行分析揭示了父母双方对杂交肿瘤和转移的遗传贡献。由于 MSC 迁移并定位于乳腺癌，我们的研究结果表明 MSC-乳腺癌细胞杂交体的形成是产生侵袭性/转移性乳腺癌细胞的潜在机制。我们的研究结果将癌症进展的融合理论与乳腺癌转移通常是非整倍体而非四倍体，并且在组织病理学上与原发肿瘤相似的常见观察结果相一致。 （Am J Pathol 2012 年，180：2504-2515；http://dx.doi.org/10.1016/j.ajpath.2012.02.020）
Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in inununodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm. (Am J Pathol 2012, 180:2504-2515; http://dx.doi.org/10.1016/j.ajpath.2012.02.020)