Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma

Weeraratna, Ashani T.; Jiang, Yuan; Hostetter, Galen; Rosenblatt, Kevin P.; Duray, Paul H.; Bittner, Michael; Trent, Jeffrey M.

doi:10.1016/s1535-6108(02)00045-4

Cited by 868 publications

(862 citation statements)

References 33 publications

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“…Although evidence has been accumulated that Wnt5a is expressed in various cancers (Weeraratna et al, 2002;Veeman et al, 2003;Huang et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006;Kikuchi and Yamamoto, 2008;Yamamoto et al, 2009), how Wnt5a is upregulated in cancer cells has not been determined. It has been shown that Wnt5a is upregulated at the transcriptional level in PCa by hypomethylation in the 5 0 -untranslated region and that three CpG sites were consistently methylated in normal tissues but not in primary PCa (Wang et al, 2007).…”

Section: Mechanism By Which Wnt5a Promotes Aggressiveness Of Pcamentioning

confidence: 99%

“…Wnt5a is a representative of the Wnt proteins that activate the b-catenin-independent pathway, which includes multiple pathways, and Wnt5a activates distinct routes (Veeman et al, 2003;Kurayoshi et al, 2007;Kikuchi and Yamamoto, 2008). It has been shown that Wnt5a stimulates migration in some cancer cells and that its expression is correlated with the aggressiveness of melanoma, breast cancer, lung cancer and gastric cancer (Weeraratna et al, 2002;Veeman et al, 2003;Huang et al, 2005;Kurayoshi et al, 2006;Pukrop et al, 2006;Kikuchi and Yamamoto, 2008;Yamamoto et al, 2009), suggesting that Wnt5a has oncogenic properties. Other reports indicate that Wnt5a acts as a tumor suppressor based on the finding that Wnt5a has an ability to inhibit proliferation, migration and invasiveness in thyroid tumor and colorectal cancer cell lines (Dejmek et al, 2005;Kremenevskaja et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

et al. 2010

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Wnt5a is a representative ligand that activates the b-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/ b-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the b-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and b-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and b-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of b-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy.

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Section: Mechanism By Which Wnt5a Promotes Aggressiveness Of Pcamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

et al. 2010

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“…Furthermore, it has been reported that Wnt5a inhibits cell growth, migration, and invasiveness of thyroid carcinoma cells and colorectal cancer cells (Dejmek et al, 2005;Kremenevskaja et al, 2005). However, there are several lines of evidence indicating that sustained or increased Wnt5a expression is critically involved in various types of cancer (Iozzo et al, 1995;Weeraratna et al, 2002;Kurayoshi et al, 2006;Pukrop et al, 2006). Thus, at present the roles of Wnt5a in human cancers are controversial, although this discrepancy may be attributable to differences in receptor context or cell context of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that Ror2 mediates Wnt5a signaling by activating the Wnt/JNK pathway and inhibiting the b-catenin-TCF pathway (Oishi et al, 2003;Mikels and Nusse, 2006). Studies using cultured mammalian cells show that Wnt5a promotes cell migration (Weeraratna et al, 2002;Kodama et al, 2004;Masckauchan et al, 2006), and that Ror2 mediates Wnt5a-induced cell migration through its association with the actin-binding protein, filamin A (Nishita et al, 2006). In addition, it has recently been reported that Wnt5a regulates cell polarity in cooperation with Par/Atypical protein kinase C pathway (Schlessinger et al, 2007), and that Ror2 mediates Wnt5a-induced polarized cell migration by activating JNK through its association with filamin A (Nomachi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

et al. 2009

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The receptor tyrosine kinase Ror2 regulates cell migration by acting as a receptor or co-receptor for Wnt5a. Although Wnt5a has been implicated in the invasiveness of several types of tumors, the role of Ror2 in tumor invasion remains elusive. Here we show that osteosarcoma cell lines SaOS-2 and U2OS show invasive properties in vitro by activating Wnt5a/Ror2 signaling in a cell-autonomous manner. The suppressed expression of either Wnt5a or Ror2 in osteosarcoma cells inhibits cell invasiveness accompanying decreased invadopodia formation. Gene-expression profiling identified matrix metalloproteinase 13 (MMP-13) as one of the genes whose expression is downregulated in SaOS-2 cells following suppression of Ror2 expression. Reduced expression or activity of MMP-13 suppresses invasiveness of SaOS-2 cells. Moreover, expression of MMP-13 and cell invasiveness by Wnt5a/Ror2 signaling can be abrogated by an inhibitor of the Src-family protein tyrosine kinases (SFKs), suggesting the role of the SFKs in MMP-13 expression through Wnt5a/Ror2 signaling. We further show that activation of an SFK is inhibited by the suppressed expression of Ror2. Collectively, these results indicate that Wnt5a/Ror2 signaling involves the activation of a SFK, leading to MMP-13 expression, and that constitutively active Wnt5a/Ror2 signaling confers invasive properties on osteosarcoma cells in a cell-autonomous manner.

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“…30 Other novel genes that have been detected that were not hitherto implicated in melanomagenesis include WNT5A, a proto-oncogene involved in cell motility; 21 confirmatory application of an antibody that inactivates the wnt5a protein product, termed 'Frizzled-5', arrests the effects of wnt5a. 31 In addition to WNT5A, other genes are implicated in the acquisition of cell motility and angiogenesis. 25,26,[32][33][34] Hypoxia-inducible genes such as Cyr61 have shown to be constitutively upregulated in late stage melanoma.…”

Section: Molecular Adjuncts To Diagnosis: the Microarraymentioning

confidence: 99%

The future of dermatopathology

Crowson

2006

Modern Pathology

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Of the major issues that dermatopathology will face in the immediate future, two powerful challenges loom large. The first is the application of novel nondestructive imaging technologies to in vivo diagnosis in humans. The second is the application of molecular technologies to a diagnostic arena which formerly belonged exclusively to the light microscopist. The first to be considered in this context is the application of near infrared spectroscopy to the noninvasive in vivo diagnosis of neoplastic skin disease. The second will be a discussion of application, methodology and the current state of the art in microarray technologies as they apply to neoplastic dermatopathology and, in particular, the diagnosis and prognostication of melanoma. Modern Pathology (2006) 19, S155-S163. doi:10.1038/modpathol.3800513Keywords: in vivo microscope; tissue microarray; basal cell carcinoma; infrared spectroscopy Noninvasive assessment of skin lesions by near infrared (IR) spectroscopyIn the late 1990s, working with Dr Laura McIntosh and colleagues at the National Research Council of Canada, the University of Manitoba, Central Medical Laboratories and the Misericordia General Hospital in Winnipeg, Canada, we designed and patented a noninvasive tool for the diagnosis of skin tumors using visible and near IR spectroscopy in the 400-2500 nm size wavelength range. 1-5 Initially, we excised neoplasms, and processed them in the fresh state with sections for formaldehyde fixation and paraffin embedding matched to tissue elements snap frozen in liquid nitrogen and stored at À801F. Thick sections from the frozen tissue elements were interrogated by mid-IR wavelength light (Figure 1). The transmitted light generated significant spectral differences; water, hemoglobin, cytochromes, lipids and proteins all absorb light at specific frequencies ( Figure 2). In particular, the mid-IR range is rich with information about proteins including in the context of collagen and RNA. When analyzed by a sophisticated leave-one-out hierarchical classification algorithm, distinction between microanatomic compartments of the skin could be made (Figure 3). Using this methodology, we were able with an accuracy of 90-95% to distinguish basal cell carcinoma (BCC) from melanocytic nevi, seborrheic keratoses and squamous cell carcinomata in vitro. Melanocytic nevi could be subdivided into banal vs dysplastic nevi based upon their spectral differences and melanomas could be separately recognized as well. Furthermore, the different types of lesion were shown to have distinct mid-IR signatures when compared to adjacent normal epidermal and dermal compartments.Unfortunately, the diagnostic potential of mid-IR spectroscopy for in vivo applications is limited, as complete absorption of mid-IR light occurs with samples greater than 10-15 mm in thickness. In contrast, near-IR light scatters to a much greater extent than it absorbs and in consequence, tissues are relatively transparent in the near-IR region which permits the examination of larger tissue volumes and led to...

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Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma

Cited by 868 publications

References 33 publications

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

The future of dermatopathology

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