Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells

Roth, Wilfried; Wild-Bode, Christine; Platten, Michael; Grimmel, Cornelia; Melkonyan, Hovsep; Dichgans, J.; Weller, Michael

doi:10.1038/sj.onc.1203783

Cited by 154 publications

(124 citation statements)

References 43 publications

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“…These proteins regulate the WNT pathway by binding to WNT proteins (Ba®co et al, 1999). Importantly, SFRP1 has been shown to act as a modulator of WNT signaling (U È ren et al, 2000), and to play a role in the pathophysiology of malignant brain tumors (Roth et al, 2000). The mechanism by which SFRP1 contributes to breast cancer progression through a loss of or a reduction in mRNA expression is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of SFRP1 has been associated with apoptosis (Melkonyan et al, 1997;Zhou et al, 1998), and downregulation has been found in breast tumors (Ugolini et al, 1999;Zhou et al, 1998). SFRPs ectopic expression promotes growth and inhibits motility of malignant glioma cells (Roth et al, 2000). To document the potential involvement of SFRP1 in breast cancer, we report a detailed analysis of SFRP1 expression using an in situ hybridization method that shows associations between SFRP1 lossof-expression and clinicopathological features of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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WNT pathway and mammary carcinogenesis: Loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type

Ugolini¹,

et al. 2001

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Secreted Frizzled-related protein 1 (SFRP1) encodes a member of a protein family that contains a cysteine-rich domain similar to the WNT-binding site of Frizzled receptors and regulates the WNT pathway. The WNT pathway is frequently altered in human cancers. We have de®ned the pattern of SFRP1 mRNA expression in the progression of breast cancer. We show that SFRP1 is expressed in the epithelial component of normal breast, in the in situ component of ductal carcinomas and is lost in more than 80% of invasive breast carcinomas except the medullary type. Loss of SFRP1 expression is correlated with the presence of hormonal receptors. Conversely, the maintenance of SFRP1 in carcinomas is correlated with the presence of lymphoplasmocytic stroma. No signi®cant association was observed between SFRP1 status and the level of apoptosis in tumoral cells. Oncogene (2001) 20, 5810 ± 5817.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

WNT pathway and mammary carcinogenesis: Loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type

Ugolini¹,

et al. 2001

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“…The present study has demonstrated that MRP-1/CD9 and Wnt signaling play an important role in tumor progression. Therefore, new strategies, such as MRP-1/ CD9 gene therapy and soluble Frizzled-related proteins, could be rational treatments for cancer patients (Miyake et al, 2000;Roth et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

et al. 2004

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Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/ CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.

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“…This feature suggests that it may play a role as a messenger in the Wnt-signaling pathway (Kato et al, 2001). This pathway is involved in various developmental and oncogenic processes, including the positive regulation of cell cycle progression and the negative regulation of cell cycle exit by the b-catenin/ TCF pathway in neural precursors (Roth et al, 2000;Satoh and Kuroda, 2000;Megason and McMahon, 2002). To further characterize the expression profile of MARK4 in both committed neural progenitors as well as postmitotic differentiated cells, we exposed cultured neurospheres to differentiation conditions.…”

Section: Discussionmentioning

confidence: 99%

The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines

et al. 2003

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Alterations of 19q13 are frequently observed in glial neoplasms, suggesting that this region harbors at least one gene involved in gliomagenesis. Following our previous studies on structural 19q chromosome rearrangements in gliomas, we have undertaken a detailed FISH analysis of the breakpoints and identified a 19q13.2 intrachromosomal amplification of the MAP/microtubule affinityregulating kinase 4 (MARK4) gene in three primary glioblastoma cell lines. Recent data suggest that this gene is involved in the Wnt-signaling pathway. We observed that the expression of the alternatively spliced MARK4L isoform is upregulated in both fresh and cultured gliomas and overexpressed in all of the above three glioblastoma cell lines. Interestingly, we also found that MARK4L expression is restricted to undifferentiated neural progenitor cells or proliferating glial precursor cells, whereas its expression is downregulated during glial differentiation. Perturbation of expression using antisense oligonucleotides against MARK4 in glioblastoma cell lines, consistently induced a decreased proliferation of tumor cells. Taken together, these data show that MARK4, which is normally expressed in neural progenitors, is reexpressed in gliomas and may become a key target of intrachromosomal amplification upon 19q rearrangements.

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Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells

Cited by 154 publications

References 43 publications

WNT pathway and mammary carcinogenesis: Loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type

WNT pathway and mammary carcinogenesis: Loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines

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