2013
DOI: 10.1016/j.ccr.2012.12.021
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Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1

Abstract: SUMMARY We report a paracrine effect whereby endothelial cells (ECs) promote the cancer stem cell (CSC) phenotype of human colorectal cancer (CRC) cells. We showed that, without direct cell-cell contact, ECs secrete factors that promoted the CSC phenotype in CRC cells via Notch activation. In human CRC specimens, CD133 and Notch intracellular domain-positive cells co-localized with CRC cells in perivascular regions. An EC-derived, soluble form of Jagged-1, via ADAM17 proteolytic activity, led to Notch activati… Show more

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Cited by 399 publications
(418 citation statements)
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“…JAG1, JAG2, DLL1, and FZD6 were identified as ADAM17 substrates in the proteomics studies suggesting a role for the sheddase in the maintenance of stem cells. This concept is bolstered by recent data indicating that ADAM17 colocalizes with LGR5-expressing stem cells of gastric tumors (36), stimulates Notch1 signaling in gastric cancer and glioblastoma stem cells (37), and promotes the cancer stem cell phenotype in colon cancer through shedding of JAG1 (38). The lack of regrowth of the OE21 model when treated with the combination MEDI3622 and cetuximab suggests that cancer stem cells are being killed.…”
Section: Discussionmentioning
confidence: 73%
“…JAG1, JAG2, DLL1, and FZD6 were identified as ADAM17 substrates in the proteomics studies suggesting a role for the sheddase in the maintenance of stem cells. This concept is bolstered by recent data indicating that ADAM17 colocalizes with LGR5-expressing stem cells of gastric tumors (36), stimulates Notch1 signaling in gastric cancer and glioblastoma stem cells (37), and promotes the cancer stem cell phenotype in colon cancer through shedding of JAG1 (38). The lack of regrowth of the OE21 model when treated with the combination MEDI3622 and cetuximab suggests that cancer stem cells are being killed.…”
Section: Discussionmentioning
confidence: 73%
“…Consistent with our observations, previous studies have shown that ADAM17 mediates ligand-independent Notch activation, while ADAM10 is ligand dependent 38,39 . Another study has shown that soluble form of Jagged1 activates Notch signalling without cell-cell contact 40 . Furthermore, a recent study showed that multiple GPCRs, including the S1PR, resulted in shedding of TGFa via ADAM17 activation in HEK293 cells 41 .…”
Section: Discussionmentioning
confidence: 99%
“…Even tumour‐associated endothelial cells have recently been shown to have an effect on the cancer stem cell phenotype by paracrine secretion of the Notch ligand Jagged1 61 (Figure 5). Our work in human tumours shows that aberrant epithelial and/or mesenchymally derived GREM1 expression is associated with colorectal cancer subtypes that respond poorly to current chemotherapeutic regimes and have a dismal outcome 45.…”
Section: Discussionmentioning
confidence: 99%