title: Disseminated breast cancer cells acquire a highly malignant and aggressive metastatic phenotype during metastatic latency in the bone.
abstract: BACKGROUND
  Disseminated tumor cells (DTCs) in the bone marrow may exist in a dormant state for extended periods of time, maintaining the ability to proliferate upon activation, engraft at new sites, and form detectable metastases. However, understanding of the behavior and biology of dormant breast cancer cells in the bone marrow niche remains limited, as well as their potential involvement in tumor recurrence and metastasis. Therefore, the purpose of this study was to investigate the tumorigenicity and metastatic potential of dormant disseminated breast cancer cells (prior to activation) in the bone marrow.
  
  
  RESULTS
  Total bone marrow, isolated from mice previously injected with tumorspheres into the mammary fat pad, was injected into the mammary fat pad of NUDE mice. As a negative control, bone marrow isolated from non-injected mice was injected into the mammary fat pad of NUDE mice. The resultant tumors were analyzed by immunohistochemistry for expression of epithelial and mesenchymal markers. Mouse lungs, livers, and kidneys were analyzed by H+E staining to detect metastases. The injection of bone marrow isolated from mice previously injected with tumorspheres into the mammary fat pad, resulted in large tumor formation in the mammary fat pad 2 months post-injection. However, the injection of bone marrow isolated from non-injected mice did not result in tumor formation in the mammary fat pad. The DTC-derived tumors exhibited accelerated development of metastatic lesions within the lung, liver and kidney. The resultant tumors and the majority of metastatic lesions within the lung and liver exhibited a mesenchymal-like phenotype.
  
  
  CONCLUSIONS
  Dormant DTCs within the bone marrow are highly malignant upon injection into the mammary fat pad, with the accelerated development of metastatic lesions within the lung, liver and kidney. These results suggest the acquisition of a more aggressive phenotype of DTCs during metastatic latency within the bone marrow microenvironment.
authors.affiliation: Department of Structural and Cellular Biology, The Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Carolyn G
authors.initials: CG
authors.lastname: Marsden
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Wright
authors.forename: Latonya
authors.initials: L
authors.lastname: Carrier
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Moroz
authors.forename: Brian G
authors.initials: BG
authors.lastname: Rowan
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D007267:Injections; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D010641:Phenotype; D059016:Tumor Microenvironment