TY - JOUR
T1 - Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance
AU - De Angelis, Maria Laura
AU - Zeuner, Ann
AU - Policicchio, Eleonora
AU - Russo, Giorgio
AU - Bruselles, Alessandro
AU - Signore, Michele
AU - Vitale, Sara
AU - De Luca, Gabriele
AU - Pilozzi, Emanuela
AU - Boe, Alessandra
AU - Stassi, Giorgio
AU - Ricci-Vitiani, Lucia
AU - Amoreo, Carla Azzurra
AU - Pagliuca, Alfredo
AU - Francescangeli, Federica
AU - Tartaglia, Marco
AU - De Maria, Ruggero
AU - Baiocchi, Marta
N1 - de maria corresponding author
PY - 2016
Y1 - 2016
N2 - Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents.Wepropose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance.
AB - Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents.Wepropose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance.
KW - Anti-EGFR therapy
KW - Cancer stem cells
KW - Cetuximab
KW - Colorectal cancer
KW - Proteomic arrays
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U2 - 10.5966/sctm.2015-0214
DO - 10.5966/sctm.2015-0214
M3 - Article
AN - SCOPUS:84961257417
VL - 5
SP - 511
EP - 523
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 4
ER -