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Circulating tumor microemboli: Progress in molecular understanding and enrichment technologies
Authors:Muhammad Umer  Ramanathan Vaidyanathan  Nam-Trung Nguyen  Muhammad J.A. Shiddiky
Affiliation:1. Queensland Micro- and Nanotechnology Centre (QMNC), Griffith University, Nathan Campus, QLD 4111, Australia;2. Department of Biomedical Engineering, National University of Singapore (NUS), 117581, Singapore;3. School of Environment and Science, Griffith University, Nathan Campus, QLD 4111, Australia
Abstract:Circulating tumor cells (CTCs) and their clusters, also known as circulating tumor microemboli (CTM), have emerged as valuable tool that can provide mechanistic insights into the tumor heterogeneity, clonal evolution, and stochastic events within the metastatic cascade. However, recent investigations have hinted that CTM may not be mere aggregates of tumor cells but cells comprising CTM exhibit distinct phenotypic and molecular characteristics in comparison to single CTCs. Moreover, in many cases CTM demonstrated higher metastatic potential and resistance to apoptosis as compared to their single cell counterparts. Thus, their evaluation and enumeration may provide a new dimension to our understanding of cancer biology and metastatic cancer spread as well as offer novel theranostic biomarkers. Most of the existing technologies for isolation of hematogenous tumor cells largely favor single CTCs, hence there is a need to devise new approaches, or re-configure the existing ones, for specific and efficient CTM isolation. Here we review existing knowledge and insights on CTM biology. Furthermore, a critical commentary on current and emerging trends in CTM enrichment and characterization along with recently developed ex-vivo CTC expansion methodologies is presented with the aim to facilitate researchers to identify further avenues of research and development.
Keywords:Circulating tumor cells (CTCs)  Circulating tumor microemboli (CTM)  CTC clusters  Metastasis  Epithelial to mesenchymal transition (EMT)  CTC  circulating tumor cells  CTM  circulating tumor microemboli  VEGF-A  vascular endothelial growth factor A  DCIS  ductal carcinoma in situ  DTC  disseminated tumor cells  EMT  epithelial-mesenchymal transition  ECM  extracellular matrix  SCLC  small cell lung cancer  K14  keratin 14  TGF-β  transforming growth factor β  MET  mesenchymal-epithelial transition  FGF  fibroblast growth factor  HER2  human epithelial growth factor receptor 2  EGFR  epidermal growth factor receptor  PSA  prostate specific antigen  CK  cytokeratin  WBC  white blood cells  ISET  isolation by size of epithelial cells  CAM  collagen adhesion matrix  FMS  flexible micro spring array  iFISH  immuno-Fluorescence in situ Hybridization  eDAR  ensemble-decision aliquot ranking  APD  avalanche photodiodes  HB-Chip  herringbone chip  DLD  deterministic lateral displacement  PDMS  poly(dimethylsiloxane)  SLB  supported lipid bilayer  CMx  cells captured in maximum  PMMA  poly(methyl methacrylate  CRC  colorectal cancer  MCA  microcavity array  DFF  dean flow fractionation    RBC  red blood cells
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