The intestinal stem cell regulating gene ASCL2 is required for L1-mediated colon cancer progression

Basu, Sayon; Gavert, Nancy; Brabletz, Thomas; Ben-Ze’ev, Avri

doi:10.1016/j.canlet.2018.03.022

Cited by 20 publications

(37 citation statements)

References 37 publications

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“…The L1-mediated induction of NF-κB signaling and the activation of stemness-associated genes support studies demonstrating that NF-κB activation induces dedifferentiation and the establishment of CSCs in the intestinal epithelium 66 . In both mammary epithelial and CRC cells, L1 can suppress E-cadherin and induce nuclear β-catenin accumulation 67 , 68 . In CRC cells, the L1-mediated increase in β-catenin–TCF transactivation results in increased ASCL2, a TF that determines intestinal stem cell fate by regulating various stemness-associated genes 69 .…”

Section: Signaling Via Cell Adhesion Molecules In Cancer Stem Cellsmentioning

confidence: 99%

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

2018

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Changes in cell adhesion and motility are considered key elements in determining the development of invasive and metastatic tumors. Co-opting the epithelial-to-mesenchymal transition (EMT) process, which is known to occur during embryonic development, and the associated changes in cell adhesion properties in cancer cells are considered major routes for tumor progression. More recent in vivo studies in tumor tissues and circulating tumor cell clusters suggest a stepwise EMT process rather than an “all-or-none” transition during tumor progression. In this commentary, we addressed the molecular mechanisms underlying the changes in cell adhesion and motility and adhesion-mediated signaling and their relationships to the partial EMT states and the acquisition of stemness traits by cancer cells.

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Section: Signaling Via Cell Adhesion Molecules In Cancer Stem Cellsmentioning

confidence: 99%

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

2018

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“…Constitutive activation of NF‐κB can be induced by binding of L1 to integrins, aggravating the release of inflammatory mediators that, in turn, further promotes malignant progression 28,29 . Moreover, elevated L1 expression has been shown to confer CSC properties in different types of cancer, such as glioma, ovarian cancer, endometrial cancer and CRC 16,27,30‐40 Similar to the observations in the study by Ganesh et al, 8 pointing to the association of L1 with LGR5 expressing cells in CRC cells, 30 the depletion of LGR5 in glioblastoma also reduced L1 expression 36 . The link of L1 expression with CSC properties may also explain the observation that L1‐expressing pancreatic ductal epithelial cells exhibit an enhanced tumorigenic potential leading to tumor growth and liver metastasis in an orthotopic pancreatic tumor mouse model, 37 as well as in a mouse model for CRC cell metastasis to the liver 16 .…”

Section: Figurementioning

confidence: 61%

Recent insights into the role of L1CAM in cancer initiation and progression

Altevogt

Ben-Ze’ev

Gavert

et al. 2020

Intl Journal of Cancer

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First described as a neuronal cell adhesion molecule, L1CAM was later identified to be present at increased levels in primary tumors and metastases of various types of cancer. Here, we describe the multifaceted roles of L1CAM that are involved in diverse fundamental steps during tumor initiation and progression, as well as in chemoresistance. Recently, Ganesh et al reported that L1CAM identifies metastasisinitiating cells in colorectal carcinoma exhibiting stem-like cell features, increased tumorigenic potential and enhanced chemoresistance. In this review, we highlight recent advances in L1CAM research with particular emphasis on its role in de-differentiation processes and cancer cell stemness supporting the view that L1CAM is a powerful prognostic factor and a suitable target for improved therapy of metastatic and drug-resistant tumors.

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“…We have recently demonstrated that L1 can induce downstream targets also by enhancing β-catenin localization to the nucleus and increasing β-catenin-TCF transactivation [20]. Since inhibiting GSK3 increases β-catenin-TCF transactivation [21], we have used LiCl to inhibit GSK3 and analyzed CTSD levels in L1-expressing LS 174T cells.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have identified several signaling pathways involved in the downstream induction of genes by L1 overexpression in CRC cells, including NF-κB [12, 19], STAT-1 [14] and Wnt/β-catenin signaling [20]. In this study, we found that the induction of CTSD in L1-expressing CRC cells involves Wnt/β-catenin signaling, since by stimulating this pathway with the GSK3 inhibitor LiCl, we observed an increase in CTSD expression, while suppressing NF-κB signaling had no effect on CTSD levels.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of cathepsin D is required for L1-mediated colon cancer progression

et al. 2019

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Hyperactivation of Wnt/β-catenin target genes is considered a key step in human colorectal cancer (CRC) development. We previously identified the immunoglobulin-like cell adhesion receptor L1 as a target gene of β-catenin/TCF transactivation that is localized at the invasive edge of CRC tissue. Using gene arrays, we discovered a number of downstream target genes and signaling pathways conferred by L1 overexpression during colon cancer progression. Here, we have used a proteomic approach to identify proteins in the secretome of L1-overexpressing CRC cells and studied the role of the increase in the aspartate protease cathepsin D (CTSD) in L1-mediated colon cancer development. We found that in addition to the increase in CTSD in the secretome, the RNA and protein levels of CTSD were also induced by L1 in CRC cells. CTSD overexpression resulted in elevated proliferation under stress and increased motility, tumorigenesis and liver metastasis, although to a lesser extent than after L1-transfection. The suppression of endogenous CTSD in L1-expressing cells blocked the increase in the proliferative, motile, tumorigenic and metastatic ability of CRC cells. Enhancing Wnt/β-catenin signaling by the inhibition of GSK3β resulted in increased endogenous CTSD levels, suggesting the involvement of the Wnt/β-catenin pathway in CTSD expression. In human CRC tissue, CTSD was detected in epithelial cells and in the stromal compartment at the more invasive areas of the tumor, but not in the normal mucosa, indicating that CTSD plays an essential role in CRC progression.

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The intestinal stem cell regulating gene ASCL2 is required for L1-mediated colon cancer progression

Cited by 20 publications

References 37 publications

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

Recent insights into the role of L1CAM in cancer initiation and progression

Increased expression of cathepsin D is required for L1-mediated colon cancer progression

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