Receptor-type protein tyrosine phosphatases in cancer

Du, Yu; Grandis, Jennifer R.

doi:10.5732/cjc.014.10146

Cited by 69 publications

(72 citation statements)

References 84 publications

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“…In this study, we aimed to focus instead on investigating the 3D microenvironment-related factors and mechanisms that may have contributed to the enhanced migration of glioma cells when encapsulated in 3D CS-GAG matrices as observed in the in vitro microfluidics based migration assays. We specifically focused on evaluating the gene and protein expression patterns of the chemokine CXCL12 and its high-affinity receptor CXCR4; as well as the cell surface receptor LAR since these factors have been implicated in CS-GAG mediated glioma cell haptotaxis, and CSPG binding respectively 18, 46–48 . Previous evidence also suggests that the extracellular tumor microenvironment could facilitate cytoskeletal rearrangement leading to glioma cell invasion 49–52 .…”

Section: 0 Discussionmentioning

confidence: 99%

“…LAR protein tyrosine phosphatases have also been documented as being overabundant in a multitude of different cancers as a marker of invasiveness 46 . We found that the presence of sulfated CS-GAGs in the extracellular microenvironment stimulates the significant overexpression of the CSPG binding LAR transcript in encapsulated glioma cells, which may have contributed to the observed increase in F-actin polymerization and colocalization of cytoskeletal adhesion proteins in encapsulated glioma cells.…”

Section: 0 Discussionmentioning

confidence: 99%

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Glioma cell invasion is significantly enhanced in composite hydrogel matrices composed of chondroitin 4- and 4,6-sulfated glycosaminoglycans

et al. 2016

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Glioblastoma multiforme (GBM) is the most aggressive form of astrocytoma accounting for a majority of primary malignant brain tumors in the United States. Chondroitin sulfate proteoglycans (CSPGs) and their glycosaminoglycan (GAG) side chains are key constituents of the brain extracellular matrix (ECM) implicated in promoting tumor invasion. However, the mechanisms by which sulfated CS-GAGs promote brain tumor invasion are currently unknown. We hypothesize that glioma cell invasion is triggered by the altered sulfation of CS-GAGs in the tumor extracellular environment, and that this is potentially mediated by independent mechanisms involving CXCL12/CXCR4 and LAR signaling respectively. This was tested in vitro by encapsulating the human glioma cell line U87MG-EGFP into monosulfated (4-sulfated; CS-A), composite (4 and 4,6-sulfated; CS-A/E), unsulfated hyaluronic acid (HA), and unsulfated agarose (AG; polysaccharide) hydrogels within microfluidics-based choice assays. Our results demonstrated the enhanced preferential cell invasion into composite hydrogels, when compared to other hydrogel matrices (p<0.05). Haptotaxis assays demonstrated the significantly (p<0.05) faster migration of U87MG-EGFP cells in CXCL12 containing CS-GAG hydrogels when compared to other hydrogel matrices containing the same chemokine concentration. This is likely due to the significantly (p<0.05) greater affinity of composite CS-GAGs to CXCL12 over other hydrogel matrices. Results from qRT-PCR assays further demonstrated the significant (p<0.05) upregulation of the chemokine receptor CXCR4, and the CSPG receptor LAR in glioma cells within CS-GAG hydrogels compared to control hydrogels. Western blot analysis of cell lysates derived from glioma cells encapsulated in different hydrogel matrices further corroborate qRT-PCR results, and indicate the presence of a potential variant of LAR that is selectively expressed only in glioma cells encapsulated in CS-GAG hydrogels. These results suggest that sulfated CS-GAGs may directly induce enhanced invasion and haptotaxis of glioma cells associated with aggressive brain tumors via distinct mechanisms.

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Section: 0 Discussionmentioning

confidence: 99%

Section: 0 Discussionmentioning

confidence: 99%

Glioma cell invasion is significantly enhanced in composite hydrogel matrices composed of chondroitin 4- and 4,6-sulfated glycosaminoglycans

et al. 2016

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“…The tumor suppressive functionality of PTPs, including the PTPRD gene, is further supported by homozygous deletions and loss-of-function mutations observed in various human neoplasms. 1,3,11,12 Nevertheless, considering the frequency of transcriptional silencing of PTPRD, additional mechanism must be co-responsible for its inactivation. In line with this hypothesis, in the eight LSCC cell lines sequenced in this study, which showed no expression of the PTPRD gene, beside the observed SNPs, none harbored a loss-of-function mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Therein, the inactivating PTPs function in a delicate balance with the activating protein tyrosine kinases. 1 Various alterations resulting in loss of function of the PTP genes observed in neoplasms emphasize their suppressive role in cancer formation. 2 Recently, we reported homozygous deletions that target the PTPRD gene in laryngeal squamous cell carcinoma (LSCC) cell lines.…”

Section: Introductionmentioning

confidence: 99%

Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma

et al. 2017

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Cellular processes like differentiation, mitotic cycle, and cell growth are regulated by tyrosine kinases with known oncogenic potential and tyrosine phosphatases that downmodulate the first. Therefore, tyrosine phosphatases are recurrent targets of gene alterations in human carcinomas. We and others suggested recently a tumor suppressor function of the PTPRD tyrosine phosphatase and reported homozygous deletions of the PTPRD locus in laryngeal squamous cell carcinoma. In this study, we investigated other gene-inactivating mechanisms potentially targeting PTPRD, including loss-of-function mutations and also epigenetic alterations like promoter DNA hypermethylation. We sequenced the PTPRD gene in eight laryngeal squamous cell carcinoma cell lines but did not identify any inactivating mutations. In contrast, by bisulfite pyrosequencing of the gene promoter region, we identified significantly higher levels of methylation (p = 0.001 and p = 0.0002, respectively) in 9/14 (64%) laryngeal squamous cell carcinoma cell lines and 37/79 (47%) of primary laryngeal squamous cell carcinoma tumors as compared to normal epithelium of the upper aerodigestive tract. There was also a strong correlation (p = 0.0001) between methylation and transcriptional silencing for the PTPRD gene observed in a cohort of 497 head and neck tumors from The Cancer Genome Atlas dataset suggesting that DNA methylation is the main mechanism of PTPRD silencing in these tumors. In summary, our data provide further evidence of the high incidence of PTPRD inactivation in laryngeal squamous cell carcinoma. We suggest that deletions and lossof-function mutations are responsible for PTPRD loss only in a fraction of cases, whereas DNA methylation is the dominating mechanism of PTPRD inactivation.

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“…PTPs have also been indicated as important regulators in tumorigenesis and angiogenesis (15–18). Receptor-like protein tyrosine phosphatase beta (PTPRB, also known as vascular endothelial VE-PTP), for example, plays a crucial role in the angiogenesis of breast cancer by regulating several signalling pathways such as the Tie-2 pathway (19).…”

Section: Introductionmentioning

confidence: 99%

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors

Park

Chen

Mason

et al. 2017

International Journal of Oncology

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A potential role may be played by receptor-type protein tyrosine phosphatase kappa (PTPRK) in angiogenesis due to its critical function in coordinating intracellular signal transduction from various receptors reliant on tyrosine phosphorylation. In the present study, we investigated the involvement of PTPRK in the cellular functions of vascular endothelial cells (HECV) and its role in angiogenesis using in vitro assays and a PTPRK knockdown vascular endothelial cell model. PTPRK knockdown in HECV cells (HECVPTPRKkd) resulted in a decrease of cell proliferation and cell-matrix adhesion; however, increased cell spreading and motility were seen. Reduced focal adhesion kinase (FAK) and paxillin protein levels were seen in the PTPRK knockdown cells which may contribute to the inhibitory effect on adhesion. HECVPTPRKkd cells were more responsive to the treatment of fibroblast growth factor (FGF) in their migration compared with the untreated control and cells treated with VEGF. Moreover, elevated c-Src and Akt1 were seen in the PTPRK knockdown cells. The FGF-promoted cell migration was remarkably suppressed by an addition of PLCγ inhibitor compared with other small inhibitors. Knockdown of PTPRK suppressed the ability of HECV cells to form tubules and also impaired the tubule formation that was induced by FGF and conditioned medium of cancer cells. Taken together, it suggests that PTPRK plays dual roles in coordinating angiogenesis. It plays a positive role in cell proliferation, adhesion and tubule formation, but suppresses cell migration, in particular, the FGF-promoted migration. PTPRK bears potential to be targeted for the prevention of tumour associated angiogenesis.

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Receptor-type protein tyrosine phosphatases in cancer

Cited by 69 publications

References 84 publications

Glioma cell invasion is significantly enhanced in composite hydrogel matrices composed of chondroitin 4- and 4,6-sulfated glycosaminoglycans

Glioma cell invasion is significantly enhanced in composite hydrogel matrices composed of chondroitin 4- and 4,6-sulfated glycosaminoglycans

Recurrent epigenetic silencing of the PTPRD tumor suppressor in laryngeal squamous cell carcinoma

Dual roles of protein tyrosine phosphatase kappa in coordinating angiogenesis induced by pro-angiogenic factors

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