Wnt Signaling In Tumorigenesis Research Articles

Wnt signaling and tumors (Review).

Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in-depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.

Ectodysplasin A receptor (EDAR) promotes colorectal cancer cell proliferation via regulation of the Wnt/β-catenin signaling pathway

Colorectal cancer is the second leading cause of cancer mortality worldwide with poor prognosis and high recurrence. Aberrant Wnt/β-catenin signaling promotes oncogenesis by transcriptional activation of c-Myc and its downstream signals. EDAR is characterized as an important effector of canonical Wnt signaling in developing skin appendages, but the interplay between EDAR and Wnt signaling in tumorigenesis and progression remains to be elucidated. In this study, we revealed that EDAR expression is prevalently elevated in colorectal cancer tissues compared with normal tissues. Further analysis suggests there is a strict correlation between EDAR expression and colorectal cancer progression. EDAR silencing by shRNA in colorectal cancer cells showed proliferative suppression via retarding cell cycle at G1 phase. Xenograft mice transplanted with shEDAR-transduced tumor cells significantly alleviated tumor burden in comparison with control mice. Furthermore, downregulation of EDAR was accompanied by reduction of β-catenin, c-Myc and other G1 cell cycle regulators, while β-catenin agonist restored the expression of these proteins and overrode the proliferative block induced by EDAR knockdown. These findings indicate that EDAR functions as a component of Wnt/β-catenin signaling pathway, and is a potential modulator in colorectal carcinogenesis.

Nanodiamonds Interfere with Wnt-Regulated Cell Migration and Adipocyte Differentiation in Cells and Embryonic Development In Vivo

Biocompatible nanoparticles hold a great promise for biomedical applications, whereas their biosafety has raised extensive concerns. Nanodiamonds (NDs) are generally regarded as “inert” nanocarriers and widely employed in biomedical studies; however, it is yet to explore their biological effects in more general contexts. In this study, the authors observe that intracellular NDs block signal transduction of the Wnt signaling pathway, an effect that is not caused by general cytotoxicity. The authors find that NDs attenuate activities of Wnt signaling in several types of cell lines and in Zebrafish, and interfere with Wnt signaling-controlled biological processes, including cancer cell migration, adipocyte differentiation, and embryonic development. Significantly, the authors show that intracellular NDs trigger degradation of the disheveled protein, a key component of Wnt signaling cascade, while they do not affect protein stability of other Wnt signal transducers or other signaling molecules. This work thus illustrates a novel crosstalk between nanoparticles and the Wnt signaling pathway, and expands the understanding of biological effects induced by nanoparticles. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, this study also provides the rationale for potential applications of NDs in cancer therapies.

Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish.

Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as “inert” nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness.

Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity

Recently, heterozygous mutations in exon 2 of the mediator complex subunit 12 gene have been described in 50% to 70% of uterine leiomyomas; the recurrent nature of these mutations suggests an important role in their pathogenesis. Mediator complex subunit 12 is involved in regulation of transcription and Wnt signaling. So far, little is known about the pathogenesis of the different subtypes of extrauterine leiomyomas and leiomyosarcomas. We performed mutation analysis of mediator complex subunit 12 and immunohistochemistry for β-catenin, using 69 tumors of 64 patients including 19 uterine leiomyomas, 6 abdominal leiomyomas, 9 angioleiomyomas, 5 piloleiomyomas, and 7 uterine and 23 soft tissue leiomyosarcomas. In line with previous observations, 58% of uterine leiomyomas carried a mediator complex subunit 12 mutation. However, all other extrauterine leiomyomas were negative with the exception of 1 abdominal leiomyoma with a likely primary uterine origin. Of the 30 leiomyosarcomas, only 1 uterine tumor harbored a mutation. A new observation is the identification of 3 tumors with a homozygous mutation; a monosomy X or interstitial deletion was excluded. β-Catenin immunohistochemistry showed nuclear positivity in only 55% of the mediator complex subunit 12-mutated uterine leiomyomas, suggesting the involvement of pathways other than canonical Wnt signaling in tumorigenesis. Interestingly, 80% of mediator complex subunit 12 wild-type sporadic piloleiomyomas displayed nuclear β-catenin positivity, indicating its involvement in this leiomyoma subtype. The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway, emphasizing the genetic heterogeneity of smooth muscle tumors.

Abstract 3287: Intra- and intercellular Wnt pathway induction synergistically accelerates FGFR1-mediated prostate tumorigenesis

Abstract Cancer growth and metastasis requires proliferation, cell migration, and stromal remodeling, functions also found during organogenesis and wound repair. The fibroblast growth factor (FGF) and canonical Wnt/β-catenin signaling pathways are two pathways central to these functions. FGFs and their receptors (FGFRs) are expressed in most tissues and play pivotal roles in development, wound healing and neovascularization, and are also upregulated in many solid cancers, including prostate, mammary, renal, kidney, bladder, and testicular tumors. We previously demonstrated in the JOCK1 (juxtaposition of CID and kinase) prostate cancer (PCa) mouse model that chemically induced dimerization (CID) of FGFR1 signaling in the prostate is sufficient for tumor initiation and early tumor maintenance and prolonged (42 weeks) FGFR1 activation results in PCa with distant metastasis. The Wnt pathway is also vital for proper embryogenesis and homeostasis of adult tissues by regulating stem cell self-renewal, pluripotency, and differentiation in several tissues, including colon, hair shaft, and chondrocyte stem/progenitor cells. The uncontrolled activation of this important stem pathway is also associated with various cancers, including colon, breast and prostate. Recently, we have discovered that induced crosslinking of the Wnt co-receptor LRP5 is sufficient to induce canonical Wnt signaling and nuclear localization of β-catenin. We subsequently developed two novel mouse models where Wnt can be specifically activated in the prostate epithelium, Pro-Cat (prostate-targeted inducible β-catenin), or in virtually every tissue sub-layer, Ubi-Cat (ubiquitously expressed inducible β-catenin). Consistent with previous literature, induced Pro-Cat mice never progressed beyond prostatic hyperplasia, however, after a year of pathway induction, 2 out of 6 Ubi-Cat mice developed adenocarcinoma, indicating a yet unexplored role for stromal Wnt signaling in tumorigenesis. In order to delineate possible crosstalk and synergism between FGF and Wnt pathways, we bred JOCK1 mice unto Pro-Cat and Ubi-Cat transgenic lines. Both Pro-Cat/JOCK1 and Ubi-Cat/JOCK1 mice developed widespread hyperplasia, high-grade PIN and adenocarcinoma with an extensive reactive stroma by 24 weeks of CID injections. Fascinatingly, Pro-Cat/JOCK1 mice do not continue to progress beyond the timeline established by JOCK1 induction alone whereas Ubi-Cat/JOCK1 mice continue to progress to advanced transitional sarcomatoid lesions. These results suggest that intracellular crosstalk between Wnt and FGFR1 in the epithelia is sufficient to accelerate tumor initiation, however accelerated progression requires intercellular crosstalk between the stroma and the epithelia. Additional experiments necessary to definitively implicate the stroma in accelerated tumorigenesis are underway and will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3287. doi:1538-7445.AM2012-3287