scholarly journals Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role

2021 ◽  
Vol 14 (8) ◽  
pp. 810
Author(s):  
Irina Giralt ◽  
Gabriel Gallo-Oller ◽  
Natalia Navarro ◽  
Patricia Zarzosa ◽  
Guillem Pons ◽  
...  
Keyword(s):  
Cell Fate ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Cancer Therapeutics ◽  
Cell Fate Determination ◽  
Oncogenic Potential ◽  
Wide Range ◽  
Pharmacological Potential ◽  
Pathway Deregulation

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed.

scholarly journals Targeting Wnt signaling in colorectal cancer. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

2015 ◽  
Vol 309 (8) ◽  
pp. C511-C521 ◽  
Author(s):  
Laura Novellasdemunt ◽  
Pedro Antas ◽  
Vivian S. W. Li
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Evolutionarily Conserved

The evolutionarily conserved Wnt signaling pathway plays essential roles during embryonic development and tissue homeostasis. Notably, comprehensive genetic studies in Drosophila and mice in the past decades have demonstrated the crucial role of Wnt signaling in intestinal stem cell maintenance by regulating proliferation, differentiation, and cell-fate decisions. Wnt signaling has also been implicated in a variety of cancers and other diseases. Loss of the Wnt pathway negative regulator adenomatous polyposis coli (APC) is the hallmark of human colorectal cancers (CRC). Recent advances in high-throughput sequencing further reveal many novel recurrent Wnt pathway mutations in addition to the well-characterized APC and β-catenin mutations in CRC. Despite attractive strategies to develop drugs for Wnt signaling, major hurdles in therapeutic intervention of the pathway persist. Here we discuss the Wnt-activating mechanisms in CRC and review the current advances and challenges in drug discovery.

scholarly journals A Review of the Role of Wnt in Cancer Immunomodulation

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 771 ◽  
Author(s):  
Whitney N. Goldsberry ◽  
Angelina Londoño ◽  
Troy D. Randall ◽  
Lyse A. Norian ◽  
Rebecca C. Arend
Keyword(s):  
Tumor Microenvironment ◽  
Wnt Signaling ◽  
Immune Suppression ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Cancer Therapeutics ◽  
Multiple Cancer ◽  
Pathway Activation ◽  
Tumor Types

Alterations in the Wnt signaling pathway are associated with the advancement of cancers; however, the exact mechanisms responsible remain largely unknown. It has recently been established that heightened intratumoral Wnt signaling correlates with tumor immunomodulation and immune suppression, which likely contribute to the decreased efficacy of multiple cancer therapeutics. Here, we review available literature pertaining to connections between Wnt pathway activation in the tumor microenvironment and local immunomodulation. We focus specifically on preclinical and clinical data supporting the hypothesis that strategies targeting Wnt signaling could act as adjuncts for cancer therapy, either in combination with chemotherapy or immunotherapy, in a variety of tumor types.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

Dominant role of the niche in melanocyte stem-cell fate determination

Nature ◽  
2002 ◽  
Vol 416 (6883) ◽  
pp. 854-860 ◽  
Author(s):  
Emi K. Nishimura ◽  
Siobhán A. Jordan ◽  
Hideo Oshima ◽  
Hisahiro Yoshida ◽  
Masatake Osawa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Dominant Role ◽  
Cell Fate Determination ◽  
Stem Cell Fate ◽  
Fate Determination ◽  
Melanocyte Stem Cell

Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs)

2016 ◽  
Vol 104 (3) ◽  
pp. 324-329 ◽  
Author(s):  
Shin’ichiro Yasunaga ◽  
Yoshinori Ohno ◽  
Naoto Shirasu ◽  
Bo Zhang ◽  
Kyoko Suzuki-Takedachi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Fate ◽  
Cell Fate Determination ◽  
Hematopoietic Stem ◽  
Fate Determination

Role of extracellular matrix and YAP/TAZ in cell fate determination

2014 ◽  
Vol 26 (2) ◽  
pp. 186-191 ◽  
Author(s):  
Jin Hao ◽  
Yueling Zhang ◽  
Yating Wang ◽  
Rui Ye ◽  
Jingyi Qiu ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Fate ◽  
Cell Fate Determination ◽  
Fate Determination

scholarly journals PPARγand PPARδas Modulators of Neoplasia and Cell Fate

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Robert I. Glazer ◽  
Hongyan Yuan ◽  
Zhihui Xie ◽  
Yuzhi Yin
Keyword(s):  
Type 2 Diabetes ◽  
Cell Adhesion ◽  
Tumor Suppressor ◽  
Cell Fate ◽  
Gene Transcription ◽  
Tumor Suppressor Genes ◽  
Developmental Pathways ◽  
Cell Fate Determination

PPARγand PPARδagonists represent unique classes of drugs that act through their ability to modulate gene transcription associated with intermediary metabolism, differentiation, tumor suppression, and in some instances proliferation and cell adhesion. PPARγagonists are used by millions of people each year to treat type 2 diabetes but may also find additional utility as relatively nontoxic potentiators of chemotherapy. PPARδagonists produce complex actions as shown by their tumor promoting effects in rodents and their cholesterol-lowering action in dyslipidemias. There is now emerging evidence that PPARs regulate tumor suppressor genes and developmental pathways associated with transformation and cell fate determination. This review discusses the role of PPARγand PPARδagonists as modulators of these processes.

Targeting Wnt Signaling through Small molecules in Governing Stem Cell Fate and Diseases

2019 ◽  
Vol 19 (3) ◽  
pp. 233-246 ◽  
Author(s):  
Antara Banerjee ◽  
Ganesan Jothimani ◽  
Suhanya Veronica Prasad ◽  
Francesco Marotta ◽  
Surajit Pathak
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Wnt Signaling ◽  
Small Molecules ◽  
Signaling Pathway ◽  
Cell Fate ◽  
Wnt Pathway ◽  
Molecular Mechanisms ◽  
Wnt Signaling Pathway ◽  
Stem Cell Fate

Background:The conserved Wnt/β-catenin signaling pathway is responsible for multiple functions including regulation of stem cell pluripotency, cell migration, self-renewability and cell fate determination. This signaling pathway is of utmost importance, owing to its ability to fuel tissue repair and regeneration of stem cell activity in diverse organs. The human adult stem cells including hematopoietic cells, intestinal cells, mammary and mesenchymal cells rely on the manifold effects of Wnt pathway. The consequences of any dysfunction or manipulation in the Wnt genes or Wnt pathway components result in specific developmental defects and may even lead to cancer, as it is often implicated in stem cell control. It is absolutely essential to possess a comprehensive understanding of the inhibition and/ or stimulation of the Wnt signaling pathway which in turn is implicated in determining the fate of the stem cells.Results:In recent years, there has been considerable interest in the studies associated with the implementation of small molecule compounds in key areas of stem cell biology including regeneration differentiation, proliferation. In support of this statement, small molecules have unfolded as imperative tools to selectively activate and inhibit specific developmental signaling pathways involving the less complex mechanism of action. These compounds have been reported to modulate the core molecular mechanisms by which the stem cells regenerate and differentiate.Conclusion:This review aims to provide an overview of the prevalent trends in the small molecules based regulation of stem cell fate via targeting the Wnt signaling pathway.

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