Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis

Abstract

Introduction: The identification of tumor cells that can be potential metastatic seeds would reach two key aims-prognosis of metastasis risk and appointment of the optimal adjuvant therapy to prevent metastatic disease. Single tumor cells (STCs) located out of multicellular structures can most likely demonstrate features that are needed to initiate metastasis.Methods: One-hundred-and-thirty-five patients with invasive breast carcinoma of no special type have been enrolled. Molecular subtypes of breast cancer were categorized according to St. Gallen recommendations. Hematoxylin and eosin staining was used to identify STCs with epithelial-like morphology (eSTCs) in breast tumors. Immunofluorescence staining was applied to evaluate stemness and epithelial-mesenchymal transition (EMT) in STCs. The correlation between STCs and recurrence and metastasis-free survival (MFS) was performed using the Kaplan-Meier method and the log-rank test.Results: Distant metastasis was more frequent in eSTC-positive than eSTC-negative patients (28.0% vs. 9.4%, p = 0.007). When tumor types were analyzed separately, distant metastasis tended to be more frequent in eSTC-positive than eSTC-negative patients for HER2-positive cancer [75.0% (3/4) vs. 12.5% (1/8), p = 0.066]. In luminal A [22.7% (5/22) vs. 10.0% (3/30), p = 0.259], luminal B [21.1% (4/19) vs. 6.7% (2/30), p = 0.189], and triple-negative [40.0% (2/5) vs. 11.8% (2/17), p = 0.209] cancers, distance metastasis was not associated with eSTCs. Median MFS was not reached in eSTC-positive and eSTC-negative patients. eSTC-positive patients had a higher risk of breast cancer metastasis [hazard ratio (HR) 3.57, 95% confidence interval (CI): 1.46-8.71; p = 0.001]. When tumor types were analyzed separately, a higher risk of breast cancer metastasis occurred only in HER2-positive patients (HR 8.49, 95% CI: 1.29-55.59; p = 0.016). Immunofluorescence analysis revealed mesenchymal-like STCs (mSTCs) and inter-and intra-tumor heterogeneity in STCs. There were breast tumors with either eSTCs or mSTCs and tumors with Tashireva et al.Single Tumor Cells Are Associated With Metastasis both types of STCs. Both eSTCs and mSTCs were represented by cells with different stem and/or EMT phenotypes.Conclusions: STCs with epithelial-like morphology contribute to breast cancer metastasis and represent an attractive model for studying mechanisms of metastatic seeding. The assessment of STCs in histological sections of breast tumors can be a simple and effective method for the prediction of metastasis risk.

Mutational drivers of cancer cell migration and invasion

“… 198 The presence of alveolar and trabecular structures in breast tumours is associated with increased lymph-node metastasis 200 , 201 and distant recurrence in patients treated with neoadjuvant chemotherapy. 202 Distant metastases are also frequently detected in breast cancers with single tumour cells with epithelial-like morphology, 203 and in breast cancers that express kinesin-14 (KIF14) and mitochondria-eating protein (Mieap), but lack ezrin (EZR) at the tips of torpedo-like structures. 199 The nature of torpedo-like structures, e.g., their EMT features, remains to be elucidated; however, KIF14, Mieap and EZR proteins are known to be important regulators of tumour cell migration and invasion.…”

The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

“…Trabecular structures, small groups of tumor cells, and single tumor cells display a pronounced mesenchymal phenotype and a dramatic decrease in epithelial traits [ 12 , 13 ]. Breast cancers with trabecular structures or single tumor cells show increased metastatic potential [ 14 , 15 ]. Based on these results, we assumed that tubular and alveolar structures show decreased invasive potential, whereas solid and trabecular structures, as well as single tumor cells, are highly invasive [ 12 ].…”

Development of a Scoring Function for Comparing Simulated and Experimental Tumor Spheroids

“…The worldwide challenge of fighting cancer is as urgent as ever [1,2]. When trying to understand the mechanisms driving the disease, one is faced with a complex and wildly inhomogeneous landscape of cellular properties and interactions, which vary both within and between cancer types [3][4][5]. Furthermore, cancer is not one single disease, but rather refers to a large number of diseases with shared characteristics, those characteristics are captured in the hallmarks of cancer [2,6].…”