MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Zhan, Tianzuo; Ambrosi, Giulia; Wandmacher, AM; Rauscher, Benedikt; Betge, Johannes; Rindtorff, Niklas; Häussler, RS; Hinsenkamp, Isabel; Bamberg, Leonhard Valentin; Heßling, Bernd; Müller‐Decker, Karin; Erdmann, Gerrit; Burgermeister, Elke; Ebert, M; Boutros, Michael

doi:10.1055/s-0039-1695401

Cited by 30 publications

(42 citation statements)

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“…Several studies have found that the interaction between proteins produced by some coding genes and APC is involved in the promotion or inhibition of tumor proliferation via the Wnt pathway. Zhan et al[53] found that targeting MEK strongly synergized with APC in enhancing Wnt responses to the development of GC. Sox2 as a tumor suppressor gene, restrained stomach adenoma formation through modulation of APC/Wnt-responsive and intestinal genes[54].…”

Section: Discussionmentioning

confidence: 99%

High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients

Du¹,

Lin²,

Chen³

2019

WJG

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BACKGROUND Adenoma polyposis coli ( APC ) mutation is associated with tumorigenesis via the Wnt signaling pathway. AIM To investigate the clinical features and mechanism of APC expression in gastric cancer (GC). METHODS Based on APC expression profile, the related genome-wide mRNA expression, microRNA (miRNA) expression, and methylation profile in GC, the relationship between APC and GC, as well as the prognostic significance of APC were systematically analyzed by multi-dimensional methods. RESULTS We found that high expression of APC ( APC high ) was significantly associated with adverse outcomes of T4 GC patients. Genome-wide gene expression analysis revealed that varying APC expression levels in GC were associated with some important oncogenes, and corresponding cellular functional pathways. Genome-wide miRNA expression analysis indicated that most of miRNAs associated with high APC expression were downregulated. The mRNA-miRNA regulatory network analysis revealed that down-regulated miRNAs affected their inhibitory effect on tumor genes. Genome-wide methylation profiles associated with APC expression showed that there was differential methylation between the APC high and APC low groups. The number of hypermethylation sites was larger than that of hypomethylation sites, and most of hypermethylation sites were enriched in CpG islands. CONCLUSION Our research demonstrated that high APC expression is an unfavorable prognostic factor for T4 GC patients and may be used as a novel biomarker for pathogenesis research, diagnosis, and treatment of GC.

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Section: Discussionmentioning

confidence: 99%

High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients

Du¹,

Lin²,

Chen³

2019

WJG

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“…In contrast, OSM induces a stemness phenotype in non-CSCs ( 552 ). One of the major regulators of colorectal tumor plasticity (either CSCs or cancer cells) are the Wnt-ß-catenin and the KRAS/BRAF/ERK pathways, which have been implicated to regulate tumorsphere formation, self-renewal as well as resistance, as reviewed by Pereira et al ( 553 ) and Zhan et al ( 554 ). Activation of Wnt-signaling increased sphere and clone formation as well as drug resistance ( 555 , 556 ).…”

Section: The Escape Of Cancer Stem Cells From Therapymentioning

confidence: 99%

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

et al. 2020

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The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

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“…43 It has been established that abnormal activation of the Wnt pathway is the main cause of the development and progression of colorectal cancer. 44,45 In other words, our study provides additional evidence of the role of lncRNAs in regulating pathologic processes of cancers and deepens the current understanding of the participation of lncRNAs in biological regulation. [46][47][48] What's more, overexpression of ADAMTS9-AS1 could down-regulate β-catenin and correspondingly decrease the downstream genes C-Myc and cyclin D1, which is the same as E-cadherin.…”

Section: Discussionmentioning

confidence: 61%

Long non‐coding RNA ADAMTS9‐AS1 suppresses colorectal cancer by inhibiting the Wnt/β‐catenin signalling pathway and is a potential diagnostic biomarker

et al. 2020

J Cellular Molecular Medi

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MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer

Cited by 30 publications

References 0 publications

High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients

High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

Long non‐coding RNA ADAMTS9‐AS1 suppresses colorectal cancer by inhibiting the Wnt/β‐catenin signalling pathway and is a potential diagnostic biomarker

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