TY - JOUR
T1 - Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism signature
AU - D'Amico, L.
AU - Patanè, S.
AU - Grange, C.
AU - Bussolati, B.
AU - Isella, C.
AU - Fontani, L.
AU - Godio, L.
AU - Cilli, M.
AU - D'Amelio, P.
AU - Isaia, G.
AU - Medico, E.
AU - Ferracini, R.
AU - Roato, I.
PY - 2013/6/25
Y1 - 2013/6/25
N2 - Background: Bone metastases represent a common and severe complication in breast cancer, and the involvement of cancer stem cells (CSCs) in the promotion of bone metastasis is currently under discussion. Here, we used a human-in-mice model to study bone metastasis formation due to primary breast CSCs-like colonisation. Methods: Primary CD44+CD24- breast CSCs-like were transduced by a luciferase-lentiviral vector and injected through subcutaneous and intracardiac (IC) routes in non-obese/severe-combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The CSCs-like localisation was monitored by in vivo luciferase imaging. Bone metastatic CSCs-like were analysed through immunohistochemistry and flow cytometry, and gene expression analyses were performed by microarray techniques. Results: Breast CSCs-like colonised the human-implanted bone, resulting in bone remodelling. Bone metastatic lesions were histologically apparent by tumour cell expression of epithelial markers and vimentin. The bone-isolated CSCs-like were CD44+ CD24- and showed tumorigenic abilities after injection in secondary mice. CD44+CD24- CSCs-like displayed a distinct bone tropism signature that was enriched in genes that discriminate bone metastases of breast cancer from metastases at other organs. Conclusion: Breast CSCs-like promote bone metastasis and display a CSCs-like bone tropism signature. This signature has clinical prognostic relevance, because it efficiently discriminates osteotropic breast cancers from tumour metastases at other sites.
AB - Background: Bone metastases represent a common and severe complication in breast cancer, and the involvement of cancer stem cells (CSCs) in the promotion of bone metastasis is currently under discussion. Here, we used a human-in-mice model to study bone metastasis formation due to primary breast CSCs-like colonisation. Methods: Primary CD44+CD24- breast CSCs-like were transduced by a luciferase-lentiviral vector and injected through subcutaneous and intracardiac (IC) routes in non-obese/severe-combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The CSCs-like localisation was monitored by in vivo luciferase imaging. Bone metastatic CSCs-like were analysed through immunohistochemistry and flow cytometry, and gene expression analyses were performed by microarray techniques. Results: Breast CSCs-like colonised the human-implanted bone, resulting in bone remodelling. Bone metastatic lesions were histologically apparent by tumour cell expression of epithelial markers and vimentin. The bone-isolated CSCs-like were CD44+ CD24- and showed tumorigenic abilities after injection in secondary mice. CD44+CD24- CSCs-like displayed a distinct bone tropism signature that was enriched in genes that discriminate bone metastases of breast cancer from metastases at other organs. Conclusion: Breast CSCs-like promote bone metastasis and display a CSCs-like bone tropism signature. This signature has clinical prognostic relevance, because it efficiently discriminates osteotropic breast cancers from tumour metastases at other sites.
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U2 - 10.1038/bjc.2013.271
DO - 10.1038/bjc.2013.271
M3 - Article
C2 - 23801032
AN - SCOPUS:84879624825
VL - 108
SP - 2525
EP - 2536
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 12
ER -