Collective invasion in ductal and lobular breast cancer associates with distant metastasis

Antoine A Khalil,Peter Bult,Paul N Span,Olga Ilina,Peter Friedl,Pavlo G Gritsenko

doi:10.1007/s10585-017-9858-6

Abstract

Breast cancer undergoes collective tissue invasion and, in experimental models, can collectively metastasize. The prevalence of collective invasion and its contribution to distant metastasis in clinical disease, however, remains poorly defined. We here scored the adipose tissue invasion of primary invasive ductal carcinoma (IDC), expressing E-cadherin, and E-cadherin negative invasive lobular carcinoma (ILC) and identified predominantly collective invasion patterns (86/86 samples) in both carcinoma types. Whereas collective invasion in IDC lesions retained adherens junctions, multicellular clusters and “Indian files” in ILC, despite the absence of adherens junctions (AJ) proteins E-cadherin and β-catenin, retained CD44 at cell–cell contacts. By histomorphological scoring and semi-automated image analysis, we show that the extent of collective invasion into the adipose tissue correlated with decreased distant metastasis-free survival (5-year follow-up; hazard ratio: 2.32 and 2.29, respectively). Thus, collective invasion represents the predominant invasion mode in breast cancer, develops distinct junctional subtypes in IDC and ILC, and associates with distant metastasis, suggesting a critical role in systemic dissemination.

Highlights

Metastatic progression of breast cancer is initiated by cancer cells traversing the basement membrane of the epithelium of origin, followed by migration through the peritumoral stroma until they enter blood vessels, circulate and seed at distant sites [1,2,3]
Individual cell invasion results from the downregulation of cell–cell junctions in response to activation signals, e.g. as part of epithelial-to-mesenchymal transition (EMT), whereas collective invasion and metastasis critically depend upon intact junctions between cancer cells, adherens junctions (AJ) and desmosomal adhesions [8, 9]
In mouse models for invasive ductal carcinoma (IDC) and 3D analysis of selected human IDC samples, multicellular invasion is associated with E-cadherin expression along cell–cell junctions, whereby partial E-cadherin downregulation and upregulation of EMT markers were noted in small subregions of collective invasion [10, 11]

Summary

Introduction

Metastatic progression of breast cancer is initiated by cancer cells traversing the basement membrane of the epithelium of origin, followed by migration through the peritumoral stroma until they enter blood vessels, circulate and seed at distant sites [1,2,3]. In mouse models for breast cancer in vivo both individual and clustered circulating tumor cells (CTCs) can be isolated from peripheral blood and both are able to colonize distant organs [6, 7]. In mouse models for invasive ductal carcinoma (IDC) and 3D analysis of selected human IDC samples, multicellular invasion is associated with E-cadherin expression along cell–cell junctions, whereby partial E-cadherin downregulation and upregulation of EMT markers were noted in small subregions of collective invasion [10, 11]. This indicates molecular variability of collectively invading cancers

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Conclusion