Wnts and the hallmarks of cancer
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Wnts and the hallmarks of cancer Zheng Zhong 1
&
Jia Yu 1
&
David M. Virshup 1,2
&
Babita Madan 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Since the discovery of the first mammalian Wnt proto-oncogene in virus-induced mouse mammary tumors almost four decades ago, Wnt signaling pathway and its involvement in cancers have been extensively investigated. Activation of this evolutionarily conserved pathway promotes cancer development via diverse mechanisms. Cancer is a complex disease and one outstanding conceptual framework for understanding its biology is the “Hallmarks of Cancer”. In this review, we focus on the involvement of Wnt signaling in the ten hallmarks of human cancer. These widespread roles of Wnt signaling in human cancers highlight the importance and feasibility of targeting this signaling pathway for cancer treatment. Keywords Wnt signaling . Cancer . Genome instability . TERT . Telomeres . Metastasis . Angiogenesis . Metabolism . Inflammation . Immune evasion
1 Introduction Wnt signaling has been present in animals since the first metazoans. Wnt signaling has evolved to perform diverse functions in normal development and physiology [1–3]. Our scientific understanding of Wnt/β-catenin signaling has long been intertwined with cancer biology. Wnts in mammals were first discovered because overexpressed Wnt1 caused mouse mammary tumors [4]. The adenomatous polyposis coli (APC) gene truncating mutations that stabilize β-catenin are highly prevalent in colorectal cancer, making APC one of the most mutated genes in human cancers [5]. β-catenin accumulation driven by active Wnt signaling results in the formation of a transcriptional complex, together with T cell factor/lymphoid enhancer factor (TCF/LEF) family members, that directly binds to the promoters of Wnt target genes and regulate their expression. The specifics and mechanisms of the Wnt signaling transduction cascade are well studied and well reviewed Zheng Zhong and Jia Yu contributed equally to this work. * David M. Virshup [email protected] * Babita Madan [email protected] 1
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
2
Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA
elsewhere [5–7]. However, how activated Wnt/β-catenin signaling contributes to multiple facets of cancer development is less clear. Our goal here is to highlight the myriad ways that aberrant Wnt signaling contributes to the development and progression of human cancers. One outstanding conceptual framework for understanding how signaling pathways contribute to cancer is the “Hallmarks of Cancer,” starting with the review of Hanahan and Weinberg in 2000 [8], and updated in 2011 [9]. In this review, we evaluate some of the contributions of aberrant Wnt signaling to each of the hallmark pathways that are critical to cancer development, highlighting the complexity of the Wnt pathways and crosstalk with other signaling
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