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Canonical Wnt Signaling Pathway02:54

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The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
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Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
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Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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The Soft Agar Colony Formation Assay
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Cholangiocarcinoma, gone without the Wnt?

Anne Tr Noll1, Thorsten Cramer1, Steven Wm Olde Damink1

  • 1Anne TR Noll, Steven WM Olde Damink, Frank G Schaap, Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands.

World Journal of Hepatology
|September 24, 2016
PubMed
Summary

Wnt signaling drives cholangiocarcinoma (CCA) development. Targeting this pathway, particularly Wnt7B and Wnt10A, shows promise for treating this bile duct cancer.

Keywords:
CarcinogenesisIntrahepatic cholangiocarcinomaLiver neoplasmsWnt proteinsWnt signaling pathwayWnt7B protein

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Cholangiocarcinoma (CCA) is a rare bile duct cancer with poor prognosis, often presenting at advanced stages.
  • Chronic inflammation and cholestasis create a microenvironment conducive to CCA development and progression.
  • The Wnt signaling pathway is implicated in various cancers, but its specific role in cholangiocarcinogenesis requires further elucidation.

Discussion:

  • The study demonstrates progressive activation of the canonical Wnt pathway during CCA development in experimental models.
  • Elevated Wnt ligands (Wnt7B and Wnt10A) are observed in human CCA tissue and correlate with disease progression.
  • Macrophages are identified as a significant source of Wnt7B, contributing to Wnt pathway activation in the tumor microenvironment.

Key Insights:

  • Experimental evidence strongly suggests that cholangiocarcinoma is a Wnt-driven malignancy.
  • Targeting Wnt signaling, through macrophage depletion or specific pathway inhibitors (ICG-001, C-59), significantly reduces tumor burden.
  • Wnt10a upregulation precedes tumor growth, while Wnt7b induction parallels tumor progression in CCA models.

Outlook:

  • Modulating Wnt signaling presents a promising therapeutic strategy for cholangiocarcinoma management.
  • Combination therapies involving Wnt pathway inhibitors with existing treatments (surgery, chemotherapy) may improve patient outcomes.
  • Further research into the intricate crosstalk between Wnt signaling, macrophages, and CCA is warranted.