Spontaneous Formation of Tumorigenic Hybrids between Breast Cancer and Multipotent Stromal Cells Is a Source of Tumor Heterogeneity

• Published in: The American journal of pathology Vol. 180; no. 6; pp. 2504 - 2515
• Main Authors: Rappa, Germana, Mercapide, Javier, Lorico, Aurelio
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.06.2012; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Fusion; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Coculture Techniques; Female; Gene Expression Profiling - methods; Genetic Heterogeneity; Gynecology. Andrology. Obstetrics; Humans; Hybrid Cells - pathology; Investigative techniques, diagnostic techniques (general aspects); Mammary gland diseases; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Microscopy, Fluorescence; Multipotent Stem Cells - pathology; Neoplasm Transplantation; Neoplastic Stem Cells - pathology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Ploidies; Polymorphism, Single Nucleotide; Regular; Stromal Cells - pathology; Transplantation, Heterologous; Tumor Cells, Cultured; Tumors; Breast disease; Stem cell; Spontaneous; Hybrid; Breast cancer; Tumorigenicity; Malignant tumor; Mammary gland diseases; Heterogeneity; Anatomic pathology; Multipotent cell; Stromal cell; Tumor cell; Cancer
• ISSN: 0002-9440; 1525-2191
• DOI: 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 immunodeficient 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.