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Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog.

ABSTRACT: Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pathways as particularly attractive targets for efficient anticancer therapies, especially in advanced primary tumors and metastatic cancers. Metastasis is the worst feature of cancer development. This feature results from a cascade of events emerging from the hijacking of epithelial-mesenchymal transition, angiogenesis, migration, and invasion by transforming cells and is associated with poor survival, drug resistance, and tumor relapse. In the present review, we summarize and discuss experimental data suggesting pivotal roles for developmental pathways in cancer development and metastasis, considering the therapeutic potential. Emerging targeted antimetastatic therapies based on Notch, Wnt, and Hedgehog pathways are also discussed.

SUBMITTER: Nwabo Kamdje AH

PROVIDER: S-EPMC5444923 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog.

Nwabo Kamdje Armel Herve AH Takam Kamga Paul P Tagne Simo Richard R Vecchio Lorella L Seke Etet Paul Faustin PF Muller Jean Marc JM Bassi Giulio G Lukong Erique E Kumar Goel Raghuveera R Mbo Amvene Jeremie J Krampera Mauro M

Cancer biology & medicine 20170501 2

Master developmental pathways, such as Notch, Wnt, and Hedgehog, are signaling systems that control proliferation, cell death, motility, migration, and stemness. These systems are not only commonly activated in many solid tumors, where they drive or contribute to cancer initiation, but also in primary and metastatic tumor development. The reactivation of developmental pathways in cancer stroma favors the development of cancer stem cells and allows their maintenance, indicating these signaling pa ...[more]

PMID: 28607802

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Project description:Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed and deadliest cancers worldwide, with roughly half of all patients initially presenting with both primary and metastatic disease. While the major events in the metastatic cascade have been identified, a mechanistic understanding of how NSCLC routinely and successfully colonizes the brain is largely unknown. Recent studies have begun demonstrating the role of epigenetic misregulation during tumorigenesis and metastasis, including widespread changes in DNA methylation and histone modifications. To better understand the role of altered DNA methylation in NSCLC metastasis to the brain, we measured DNA methylation during disease progression for 12 patients, globally profiling the methylation status of normal lung, primary lung tumor, and brain metastasis samples. The variation in methylation was similar during metastatic spread and primary tumorigenesis but less coordinated across genomic features during metastasis. The greatest recurrent changes during metastatic progression were methylation gains in DNA methylation valleys (DMV) harboring the constitutive heterochromatin mark H3K9me3 as well as bivalent marks H3K27me3 and H3K4me1. In a lymph node-derived cancer cell line, EZH2 binding within DMVs was lost, accompanied by an increase in DNA methylation, exemplifying epigenetic switching. The vast majority of the differentially methylated region-associated DMVs harbored developmental genes, suggesting that altered epigenetic regulation of developmentally important genes may confer a selective advantage during metastatic progression. The characterization of epigenetic changes during NSCLC brain metastasis identified recurrent methylation patterns that may be prognostic biomarkers and contributors to disease progression.SignificanceAltered DNA methylation in lung cancer brain metastases corresponds with loss of EZH2 occupancy at developmental genes, which could promote stem-like phenotypes permissive of dissemination and survival in different microenvironments.

Dataset Information

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog.

Publications

Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog.

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