Wnt5a Suppresses Colon Cancer by Inhibiting Cell Proliferation and Epithelial–Mesenchymal Transition

Cheng, Run-Fen; Sun, Baocun; Li, Yong; Zhao, Xiulan; Qi, Lisha; Li, Yixian; Gu, Qing

doi:10.1002/jcp.24566

Cited by 72 publications

(67 citation statements)

References 35 publications

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“…It plays an important role in endothelial cell differentiation, vascular development and angiogenesis [58], especially Wnt5a, a member of the non-canonical Wnt signaling. However, the role of Wnt5a in cancer is still being debated: in certain settings has been described as a tumor suppressor, but it is generally involved as a pro-metastatic factor [59]. …”

Section: Ve-cadherin-dependent and Independent Signaling In Vmmentioning

confidence: 99%

Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin

et al. 2017

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Vasculogenic mimicry (VM) is a blood supply system independent of endothelial vessels in tumor cells from different origins. It reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature. The presence of VM is associated with a high tumor grade, short survival, invasion and metastasis. Endothelial cells (ECs) express various members of the cadherin superfamily, in particular vascular endothelial (VE-) cadherin, which is the main adhesion receptor of endothelial adherent junctions. Aberrant extra-vascular expression of VE-cadherin has been observed in certain cancer types associated with VM. In this review we focus on non-endothelial VE-cadherin as a prominent factor involved in the acquisition of tubules-like structures by aggressive tumor cells and we summarize the specific signaling pathways, the association with trans-differentiation and stem-like phenotype and the therapeutic opportunities derived from the in-depth knowledge of the peculiarities of the biology of VE-cadherin and other key components of VM.

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Section: Ve-cadherin-dependent and Independent Signaling In Vmmentioning

confidence: 99%

Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin

et al. 2017

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“…Dickkopf-1, an antagonist of the Wnt/ß-catenin signaling pathway, partially reversed expression of EMT-associated proteins and VM in Wnt3a-overexpressing cells [40]. Conversely, Wnt5a suppressed colon cancer invasion by inhibiting EMT and VM [41]. …”

Section: Vm and Emtmentioning

confidence: 99%

Epithelial-to-endothelial transition and cancer stem cells: two cornerstones of vasculogenic mimicry in malignant tumors

et al. 2016

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Vasculogenic mimicry (VM) is a functional microcirculation pattern in malignant tumors accompanied by endothelium-dependent vessels and mosaic vessels. VM has been identified in more than 15 solid tumor types and is associated with poor differentiation, late clinical stage and poor prognosis. Classic anti-angiogenic agents do not target endothelium-dependent vessels and are not efficacious against tumors exhibiting VM. Further insight into the molecular signaling that triggers and promotes VM formation could improve anti-angiogenic therapeutics. Recent studies have shown that cancer stem cells (CSCs) and epithelium-to-endothelium transition (EET), a subtype of epithelial-to-mesenchymal transition (EMT), accelerate VM formation by stimulating tumor cell plasticity, remodeling the extracellular matrix (ECM) and connecting VM channels with host blood vessels. VM channel-lining cells originate from CSCs due to expression of EMT inducers such as Twist1, which promote EET and ECM remodeling. Hypoxia and high interstitial fluid pressure in the tumor microenvironment induce a specific type of cell death, linearly patterned programmed cell necrosis (LPPCN), which spatially guides VM and endothelium-dependent vessel networks. This review focuses on the roles of CSCs and EET in VM, and on possible novel anti-angiogenic strategies against alternative tumor vascularization.

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“…In this context, canonical Wnt/β‐catenin signaling has been shown to suppress 15‐PGDH expression in colorectal cancer cells (Smartt et al., 2012b). Based on demonstrations in different studies that non‐canonical WNT5A signaling has the ability to oppose canonical Wnt/β‐catenin stabilization in colon cancer cells (Cheng et al., 2014; Topol et al., 2003), we decided to investigate whether the WNT5A ligand has the ability to regulate the expression of 15‐PGDH, thus mechanistically linking these two tumor suppressors.…”

Section: Introductionmentioning

confidence: 99%

Non‐canonical WNT5A signaling up‐regulates the expression of the tumor suppressor 15‐PGDH and induces differentiation of colon cancer cells

et al. 2016

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The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme in prostaglandin E catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression. Therefore, we have in the current study investigated if the non-canonical ligand WNT5A relates to increased expression of 15-PGDH in colon cancer cells. In the same cohort of patients, we demonstrated a parallel and significant loss of 15-PGDH and WNT5A protein expression in CRC tissues compared with matched normal colon tissues. Furthermore, patients with low 15-PGDH/WNT5A expression in their tumors showed reduced survival compared with patients with high 15-PGDH/WNT5A expression. To investigate if WNT5A signaling directly affects 15-PGDH expression, we performed in vitro analyses of colon cancer cells (HT-29 and Caco-2). Both cell lines, when treated with recombinant WNT5A (rWNT5A) or Foxy-5, a WNT5A-mimicking peptide, responded by increasing their expression of 15-PGDH mRNA and protein. Our investigations showed that rWNT5A and Foxy-5 induced this increased expression of 15-PGDH through reduced β-catenin signaling as well as increased JNK/AP-1 signaling in colon cancer cells. WNT5A signaling also induced increased 15-PGDH expression in a breast cancer cell line both in vitro and in vivo. In agreement, WNT5A signaling also increased the expression of the differentiation markers sucrose-isomaltase and mucin-2 in colon cancer cells. Our results show that WNT5A signaling regulates 15-PGDH expression, thus uncovering a novel mechanism by which WNT5A acts as a tumor suppressor and suggests that increased 15-PGDH expression could be used as an indicator of a positive response to Foxy-5 in patients treated with this WNT5A agonist.

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Wnt5a Suppresses Colon Cancer by Inhibiting Cell Proliferation and Epithelial–Mesenchymal Transition

Cited by 72 publications

References 35 publications

Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin

Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin

Epithelial-to-endothelial transition and cancer stem cells: two cornerstones of vasculogenic mimicry in malignant tumors

Non‐canonical WNT5A signaling up‐regulates the expression of the tumor suppressor 15‐PGDH and induces differentiation of colon cancer cells

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