title: USP44+ Cancer Stem Cell Subclones Contribute to Breast Cancer Aggressiveness by Promoting Vasculogenic Mimicry.
abstract: Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, describes the functional plasticity of aggressive cancer cells that form vascular networks. In our previous study, breast cancer stem cells (CSC) were shown to potentially participate in VM formation. In this study, breast CSCs presented centrosome amplification (CA) phenotype and ubiquitin-specific protease 44 (USP44) upregulation. USP44 expression contributed to the establishment of bipolar spindles in breast CSCs with supernumerary centrosomes by localizing at pole-associated centrosomes. The bipolar spindle patterns of breast CSCs with CA, including planar-like and apico-basal-like, functioned differently during the VM process of CSCs. Moreover, the ability of transendothelial migration in VM-forming cells was increased. In vivo experiment results showed that CSC xenografts presented linearly patterned programmed cell necrosis, which provided a spatial foundation for VM formation as well as angiogenesis. Breast CSCs further showed increased levels of IL6 and IL8. However, USP44 silencing induced spindle multipolarity, abated VM, reduced transendothelial migration, and consequently decreased IL6 and IL8 levels in breast CSCs. Finally, USP44(+) CSC subclones (ALDH1(+)/USP44(+)/IL6(+)/IL8(+)) were identified in breast cancer specimens through consecutive sections scanning. The subclones were related not only to CA, but also to VM. Statistical analysis suggested that USP44(+) CSC subclones could be used as an independent prognostic biomarker of poor clinical outcomes in patients with breast cancer. Collectively, the identification of USP44(+) CSC subclones may contribute to the prediction of VM formation and aggressive behavior. This study provides novel insights into the therapy for advanced breast cancer.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Tieju
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China. Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China. sunbaocun@aliyun.com baocunsun@gmail.com.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China. Department of Pathology, General Hospital of Tianjin Medical University, Tianjin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Jindan
authors.initials: J
authors.lastname: An
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D057705:Transendothelial and Transepithelial Migration; D047368:Tumor Burden; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D016209:Interleukin-8; D064096:Aurora Kinase A; C579216:USP44 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases