Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling

Matzke-Ogi, Alexandra; Jannasch, Katharina; Shatirishvili, Marine; Fuchs, Beatrix; Chiblak, Sara; Morton, Jennifer P.; Tawk, Bouchra; Lindner, Thomas; Sansom, Owen J.; Alves, Frauke; Warth, Arne; Schwager, Christian; Mier, Walter; Kleeff, Jörg; Ponta, Helmut; Abdollahi, Amir; Orian-Rousseau, Véronique

doi:10.1053/j.gastro.2015.10.020

Cited by 77 publications

(57 citation statements)

References 44 publications

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“…Notably, inhibition of CD44v3 and CD44v6 function by copolymers carrying multiple copies of their targeted peptides blocks tumor invasion and metastatic colonization [59]. The peptide inhibitors of CD44v6 isoforms block tumor growth and metastasis in several independent models of pancreatic cancer [60]. However, in the present study, we show that CHI3L1 specifically binds to CD44v3 but not CD44v6 or CD44s, which indicated that the CD44v3 isoform in particular plays a critical role in CHI3L1 signaling.…”

Section: Discussioncontrasting

confidence: 50%

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Geng

Pan

Zhao

et al. 2018

J Exp Clin Cancer Res

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BackgroundEnzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis.MethodsCHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function.ResultsCHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with β-catenin signaling by phosphorylating β-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis.ConclusionsCHI3L1 binding to CD44v3 activates Erk, Akt, and β-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0876-2) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 50%

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Geng

Pan

Zhao

et al. 2018

J Exp Clin Cancer Res

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“…Matzke-Ogi found that peptide inhibitors of CD44v6 could block tumor growth and metastasis in several independent models of pancreatic cancer. This study also suggested that the CD44v6 peptide was more efficient than the MET inhibitor crizotinib and the VEGFR-2 inhibitor pazopanib in reducing xenograft tumor metastasis [37]. CD44v6 may also promote ovarian cancer cell invasion by promoting β-catenin and TGF-β expression [38].…”

Section: Discussionmentioning

confidence: 99%

CD44v6 overexpression related to metastasis and poor prognosis of colorectal cancer: A meta-analysis

Wang

Lin

et al. 2016

Oncotarget

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CD44v6 has recently been reported as a biomarker for colorectal cancer. However, the clinical and prognostic significance of CD44v6 in colorectal cancer remains controversial. Therefore, we performed a meta-analysis to clarify this issue. A comprehensive literature search was performed using Medline, Embase and Web of Science, and the statistical analysis was conducted using Stata software. A total of twenty-one studies including 3918 colorectal cancer cases were included. The pooled analysis showed that CD44v6 overexpression in colorectal cancer was an independent prognostic marker correlating with lower 5-year overall survival rate (OR=0.78, 95%CI =0.67-0.91, p=0.001). CD44v6 overexpression was also associated with more lymph node invasion (OR=1.48, 95%CI= 1.02-2.15, p=0.04), and advanced Dukes stage (OR=2.47, 95%CI= 1.29-4.73, p=0.01). In addition, while excluding Zolbec's study, CD44v6 overexpression was associated with distance metastasis (OR=1.65, 95%CI =1.13-2.40, p=0.01). Taken together, this meta-analysis suggested that CD44v6 is an efficient prognostic factor in colorectal cancer.

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“…171,172 Increased levels of CD44v6 mRNA in human pancreatic CSCs, lung CSCs, and colon CSCs promote migration and metastasis through the activation of β-catenin. [173][174][175] In the cytoplasm, TAZ/YAP interacts directly with β-catenin and restricts β-catenin degradation, 176 but TIAM1 antagonizes TAZ/YAP accumulation and translocation from the cytoplasm to the nucleus. 177 Moreover, CDH11 inhibits the migration and invasion of colorectal CSCs by inhibiting Wnt/ β-catenin and AKT/RhoA signaling.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

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768

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling

Cited by 77 publications

References 44 publications

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

Chitinase 3-like 1-CD44 interaction promotes metastasis and epithelial-to-mesenchymal transition through β-catenin/Erk/Akt signaling in gastric cancer

CD44v6 overexpression related to metastasis and poor prognosis of colorectal cancer: A meta-analysis

Targeting cancer stem cell pathways for cancer therapy

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