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Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas

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Abstract

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.

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Abbreviations

BrCa:

Breast cancer

CK:

Cytokeratin

CTCs:

Circulating tumour cells

DCIS:

Ductal carcinoma in situ

DTCs:

Disseminated tumour cells

EMT:

Epithelial mesenchymal transition

FFPE:

Formalin-fixed-paraffin-embedded

ICs:

Intratumoural cells

IDC:

Invasive ductal carcinoma

LCM:

Laser capture microdissection

MT-PCR:

Multiplexed tandem-PCR

SPCs:

Solitary primary tumour cells

VIM:

Vimentin

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Acknowledgments

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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Authors and Affiliations

  1. Australian Centre for Microscopy and Microanalysis (ACMM), AMMRF, The University of Sydney, Madsen Building F09, Room 243, Sydney, NSW, 2006, Australia

    Vanisri Raviraj, Hui Zhang, Hsin-ya Chien & Lilian Soon

  2. Advanced Microscopy Facility, Bosch Institute, The University of Sydney, Sydney, NSW, 2006, Australia

    Louise Cole

  3. Department of Surgery, Invasion and Metastasis Unit, St. Vincent’s Institute of Medical Research and University of Melbourne, St Vincent’s Hospital, Melbourne, Australia

    Erik W. Thompson

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  1. Vanisri Raviraj
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  2. Hui Zhang
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Correspondence to Lilian Soon.

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Raviraj, V., Zhang, H., Chien, Hy. et al. Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas. Clin Exp Metastasis 29, 273–292 (2012). https://doi.org/10.1007/s10585-011-9450-4

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