Effect of P-Glycoprotein Expression on Outcome in the Ewing Family of Tumors

Perri, Tamar; Fogel, Mina; Mor, Sillia; Horev, Gadi; Meller, I.; Loven, David; Issakov, Josephine; Kollender, Yehuda; Smirnov, Asya; Zaizov, Rina; Cohen, Ian J.

doi:10.1080/088800101300312591

Cited by 20 publications

(11 citation statements)

References 25 publications

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“…In agreement with the current work, Perri et al (2001) did not observe a correlation between Pgp protein expression and time to a first event ( P =0.87) or OS ( P =0.79) in patients at diagnosis. However, protein expression of Pgp has been associated with poor response to therapy ( P <0.08; Roessner et al , 1993) in pre- and post-diagnosis ESFTs.…”

Section: Discussionsupporting

confidence: 92%

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Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Roundhill

Burchill

2013

Br J Cancer

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Background:Primary Ewing's sarcoma family of tumours (ESFTs) may respond to chemotherapy, although many patients experience subsequent disease recurrence and relapse. The survival of ESFT cells following chemotherapy has been attributed to the development of resistant disease, possibly through the expression of ABC transporter proteins.Methods:MRP-1 and Pgp mRNA and protein expression in primary ESFTs was determined by quantitative reverse-transcriptase PCR (RT-qPCR) and immunohistochemistry, respectively, and alternative splicing of MRP-1 by RT-PCR.Results:We observed MRP-1 protein expression in 92% (43 out of 47) of primary ESFTs, and cell membrane MRP-1 was highly predictive of both overall survival (P<0.0001) and event-free survival (P<0.0001). Alternative splicing of MRP-1 was detected in primary ESFTs, although the pattern of splicing variants was not predictive of patient outcome, with the exception of loss of exon 9 in six patients, which predicted relapse (P=0.041). Pgp protein was detected in 6% (38 out of 44) of primary ESFTs and was not associated with patient survival.Conclusion:For the first time we have established that cell membrane expression of MRP-1 or loss of exon 9 is predictive of outcome but not the number of splicing events or expression of Pgp, and both may be valuable factors for the stratification of patients for more intensive therapy.

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Section: Discussionsupporting

confidence: 92%

“…To date, Pgp is the only MDR protein to have been investigated in ESFTs. However, the results of published studies are contradictory, one suggesting that Pgp was not predictive of prognosis (Perri et al , 2001) and a second significantly linking expression of Pgp to poor response to chemotherapy (Roessner et al , 1993). …”

mentioning

confidence: 99%

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Roundhill

Burchill

2013

Br J Cancer

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“…Indeed, a single detection method for ABCB1 expression could hardly provide relevant data for the MDR phenotype evaluation. Despite this principle is not novel, there still exist a large number of reports relying on a simple correlation between ABCB1 expression and clinical outcome in haematological malignancies as well as in solid tumours .…”

Section: Discussionmentioning

confidence: 99%

Can the assessment of ABCB1 gene expression predict its function in vitro?

Kosztyu

Doležel

Václavíková

et al. 2015

European J of Haematology

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Increased expression of the ABCB1 gene in cancer cells is usually connected with occurrence of multidrug resistance (MDR) and poor prognosis. However, the correlation between ABCB1 expression and MDR phenotype is difficult to prove in clinical samples. Most of the researchers believe that these difficulties are due to the poor reliability and sensitivity of assays for detection of ABCB1 expression in clinical samples. However, the complexity of P-gp mediated resistance cannot be reduced to the methodical difficulties only. Here, we addressed the question how widely used methods for detection of ABCB1 expression levels could predict its functional activity and thus its contribution to drug resistance in defined conditions in vitro. The ABCB1 expression was assessed at the mRNA level by quantitative real-time polymerase chain reaction (qRT-PCR), and at the protein level by flow cytometry using UIC2 antibody. The ABCB1 function was monitored using a calcein AM accumulation assay. We observed that K562 cells have approximately 320 times higher level of ABCB1 mRNA than HL-60 cells without detectable function. In addition, resistant K562/Dox cells exhibited significantly higher ABCB1 mRNA expression than resistant K562/HHT cells. However, the functional tests clearly indicated opposite results. Flow cytometric assessment of P-gp, although suggested as a reliable method, contradicted the functional test in K562/ Dox and K562/HHT cells. We further used a set of MDR cells expressing various levels of P-gp. Similarly here, flow cytometry not always corresponded to the functional analysis. Our results strongly suggest that an approach which exclusively relies on a simple correlation between ABCB1 expression, either at the mRNA level or protein level, and overall resistance may fail to predict actual contribution of P-gp to overall resistance as the data indicating transporter expression reflect its function only roughly even in welldefined in vitro conditions.

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“…Therefore, CCN3 may be one of the few molecular markers with prognostic relevance in this neoplasm. Indeed, although several clinical factors have been reported to have a prognostic value (Bacci et al, 2000), few genetic and molecular markers have clearly emerged so far (de Alava et al, 1998Wei et al, 2000;Lopez-Guerrero et al, 2001;Ozaki et al, 2001;Perri et al, 2001;Zielenska et al, 2001;Hattinger et al, 2002;Manara et al, 2002;Ohali et al, 2003) and for none of them there is a general consensus since findings are often sporadic and in conflict. Moreover, the biological basis for the supposed prognostic impact of all these markers has not been clarified.…”

Section: Discussionmentioning

confidence: 99%

In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type

et al. 2005

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Altered expression of CCN3 has been observed in a variety of musculoskeletal tumours, including Ewing's sarcoma (ES). Despite its widespread distribution, very little is known about its biological functions and molecular mechanisms of action. We transfected CCN3 gene into a CCN3-negative ES cell line and analysed the in vitro and in vivo behaviours of stably transfected clones. Forced expression of CCN3 significantly reduced cell proliferation in vitro, growth in anchorage-independent conditions, and tumorigenicity in nude mice. Despite the antiproliferative effect, CCN3-transfected ES cells displayed increased migration and invasion of Matrigel. The decreased expression of a2b1 integrin receptor and the increased amount of cell surface-associated matrix metalloproteinase (MMP)-9 following the expression of CCN3 may be the basis for the increased migratory abilities of transfected cells. Cells lacking a 2 b 1 are less facilitated to have stable anchorage since the predominant collagen extracted from ES tissue is indeed type I collagen, and proMMP-9 was recently found to provide a cellular switch between stationary and migratory ES cell phase. Our findings are in line with those recently obtained in glioblastoma. However, the underlying molecular mechanisms appear to be different, further highlighting the importance of the cellular context in the regulation of function of CCN proteins.

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Effect of P-Glycoprotein Expression on Outcome in the Ewing Family of Tumors

Cited by 20 publications

References 25 publications

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Membrane expression of MRP-1, but not MRP-1 splicing or Pgp expression, predicts survival in patients with ESFT

Can the assessment of ABCB1 gene expression predict its function in vitro?

In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type

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