title: Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack.
abstract: Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM⁺/CK⁺) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a "surrogate" of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well.
authors: Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy. michela.bulfoni@alice.it.
authors: Michela
authors: M
authors: Bulfoni
authors: Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy. matteosalotto@gmail.com.
authors: Matteo
authors: M
authors: Turetta
authors: Department of Clinical Pathology, CRO Aviano National Cancer Institute, via F. Gallini 2, 33081 Aviano, Italy. fdbf13@gmail.com.
authors: Fabio
authors: F
authors: Del Ben
authors: Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy. carla.diloreto@uniud.it.|Institute of Pathology, University Hospital of Udine-ASUIUD, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy. carla.diloreto@uniud.it.
authors: Carla
authors: C
authors: Di Loreto
authors: Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy. antonio.beltrami@uniud.it.
authors: Antonio Paolo
authors: AP
authors: Beltrami
authors: Department of Medical and Biological Sciences, University of Udine, Piazzale M. Kolbe 4, 33100 Udine, Italy. daniela.cesselli@uniud.it.
authors: Daniela
authors: D
authors: Cesselli
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor
keywords: circulating tumor cells; epithelial-to-mesenchymal transition; metabolism; metastatic breast cancer; spatial and temporal heterogeneity; stemness