Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas
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Mortality in breast cancer is linked to metastasis and recurrence yet there is no acceptable biological model for cancer relapse. We hypothesise that there might exist primary tumour cells capable of escaping surgery by migration and resisting radiotherapy and chemotherapy to cause cancer recurrence. We investigated this possibility in invasive ductal carcinoma (IDC) tissue and observed the presence of solitary primary tumour cells (SPCs) in the dense collagen stroma that encapsulates intratumoural cells (ICs). In IDC tissue sections, collagen was detected with either Masson’s Trichrome or by second harmonics imaging. Cytokeratin-19 (CK-19) and vimentin (VIM) antibodies were, respectively, used to identify epithelial-derived tumour cells and to indicate epithelial to mesenchymal transition (EMT). Confocal/multiphoton microscopy showed that ICs from acini were mainly CK-19+ve and were encapsulated by dense stromal collagen. Within the stroma, SPCs were detected by their staining for both CK-19 and VIM (confirming EMT). ICs and SPCs were subsequently isolated by laser capture microdissection followed by multiplex tandem-PCR studies. SPCs were found to be enriched for pro-migratory and anti-proliferative genes relative to ICs. In vitro experiments using collagen matrices at 20 mg/cm3, similar in density to tumour matrices, demonstrated that SPC-like cells were highly migratory but dormant, phenotypes that recapitulated the genotypes of SPCs in clinical tissue. These data suggest that SPCs located at the breast cancer perimeter are invasive and dormant such that they may exceed surgical margins and resist local and adjuvant therapies. This study has important connotations for a role of SPCs in local recurrence.
KeywordsBreast cancer Single cell dormancy Cell migration Dense stroma Tumour microenvironment Laser capture microdissection
Circulating tumour cells
Ductal carcinoma in situ
Disseminated tumour cells
Epithelial mesenchymal transition
Invasive ductal carcinoma
Laser capture microdissection
Solitary primary tumour cells
This work was supported by National Health and Medical Research Council (#402510 and #571200), Australian Research Council (#DP0881012) and Victorian Breast Cancer Research Consortium. We gratefully acknowledge AMMRF, ACMM, Sydney, Australia for use of the facility and Ms Ellie Kable, Dr Renee Whan, Mr Vivek Ravichandran and Mr Dennis Dwarte for their kind assistance. We thank Prof. John Condeelis for kindly providing the MTLn3 cells and Assoc. Prof. Prue Hill, St. Vincent’s Pathology, Melbourne, for assistance with histopathological assessments of tissues.
Conflict of interest
The authors declare that they have no conflict of interest.
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