Abstract
BackgroundRecurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy.MethodsWe investigated cellular dormancy in vitro and in vivo using breast cancer cell lines and cell and molecular biology techniques.ResultsWe demonstrated cellular dormancy in breast cancer bone metastasis, associated with haematopoietic stem cell (HSC) mimicry, in vivo competition for HSC engraftment and non-random distribution of dormant cells at the endosteal niche. Notch2 signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon co-culture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner. Blocking this signal by in vivo acute administration of the γ-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Sorted Notch2HIGH breast cancer cells exhibited a unique stem phenotype similar to HSCs and in vitro tumour-initiating ability in mammosphere assay. Human samples confirmed the existence of a small Notch2HIGH cell population in primary and bone metastatic breast cancers, with a survival advantage for Notch2HIGH vs Notch2LOW patients.ConclusionsNotch2 represents a key determinant of breast cancer cellular dormancy and mobilisation in the bone microenvironment.
Highlights
Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy
Since the endosteal location is known to host LT-haematopoietic stem cell (HSC),[10,11,27] we investigated whether these two cell types competed for bone marrow HSC engraftment in an in vivo competition assay
Our analysis showed that they expressed high levels of mRNA for the HSC markers Stem Cell Antigen[1] (SCA1), TEK Receptor Tyrosine Kinase (TIE2), CD34 and C-X-C Motif Chemokine Receptor 4 (CXCR4) (Fig. 2i), and flow cytometry revealed that the MDAGFPNotch2HIGH cell population was enriched in surface CD34, c-kit and Notch[1] proteins (Fig. 2j–l), while the same markers were poorly expressed in the MDAGFPNotch2LOW cell population (Fig. 2j–l)
Summary
Recurrence after >5-year disease-free survival affects one-fifth of breast cancer patients and is the clinical manifestation of cancer cell reactivation after persistent dormancy. Notch[2] signal implication was demonstrated by immunophenotyping the endosteal niche-associated cancer cells and upon coculture with sorted endosteal niche cells, which inhibited breast cancer cell proliferation in a Notch2-dependent manner Blocking this signal by in vivo acute administration of the γ-secretase inhibitor, dibenzazepine, induced dormant cell mobilisation from the endosteal niche and colonisation of visceral organs. Inside the bone marrow cavity, neoplastic cells are nourished by a plethora of signals received by the osteogenic and the haematogenous microenvironments In most cases, these signals stimulate tumour cell growth and enhance aggressiveness.[8] Intriguingly, inside this dynamic organ, there are the long-term haematopoietic stem cells (LT-HSCs), characterised by multipotent stemness and prolonged quiescence, reminiscent of dormancy. Others ruled out the involvement of this osteoblast subpopulation in LT-HSC maintenance.[12]
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