Abstract
Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis.
Highlights
These results suggest that circulating tumor cells (CTCs) recovered from orthotopically injected metastasis models are highly capable of metastasis, potentially due to their successful survival under the extreme selective pressures imposed in the circulation [12]
Patients with triple-negative breast cancer have a poor prognosis; relapsed tumors and distant metastases of triple-negative breast cancers are associated with cancer stem cells (CSCs) [49]. These findings suggest that an increase in CSCs highly competent for metastasis may be responsible for the worse prognosis of triple-negative breast cancer
CTCs suggest that the epithelial-to-mesenchymal transition (EMT) program provides additional advantages to cancer cells in the very different microenvironment of the circulatory system
Summary
In the United States, improved early detection and new treatments have led to a decline in the overall mortality due to breast cancer, but the survival rates for patients with metastatic disease have not improved significantly [1]. Metastasis was traditionally thought of as the final step in the linear progression of breast cancer, developing long after primary tumor formation, as multiple stepwise genetic mutations would need to accumulate before carcinoma cells could acquire the ability to migrate from the primary tumor and enter circulation [4]. Recent evidence suggests that metastasis may be a much earlier event than previously suspected, where cancer cells competent for metastasis can disseminate early during primary tumor development [4]. The development of single cell whole genome analysis allowed researchers to extend these studies to patients, where they found early disseminated breast cancer cells with fewer genetic changes than the cells from the primary tumors, suggesting that breast cancer cells can metastasize very early in tumor development, leading to the observed differences in genetic mutations between the primary tumors and the metastatic lesions [7]
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