Studies on the role of recombinant human erythropoietin in the growth regulation of human nonhematopoietic tumor cells in vitro

Berdel, W. E.; Oberberg, D; Reufi, B; Thiel, Eckhard

doi:10.1007/bf01714953

Cited by 50 publications

(24 citation statements)

References 20 publications

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“…37 Indeed, when tested over a wide concentration range, Epo neither altered viability nor growth rate, as assessed by MTTassay, in the present cancer cell lines. This result is in line with several reports, 17,[38][39][40][41][42][43] though not with all. 19,44,45 The reason for these discrepant findings is not clear, but one should be aware that minute amounts of Epo stabilizing additives may affect cell viability when protein-free culture medium is used.…”

Section: Discussionsupporting

confidence: 92%

Lack of functional erythropoietin receptors of cancer cell lines

Laugsch¹,

Metzen²,

Svensson³

et al. 2007

Intl Journal of Cancer

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Erythropoietin (Epo) therapy reduces red cell transfusion requirements and improves the quality of life of anemic cancer patients receiving chemotherapy. However, there is concern that Epo may promote tumor growth. We investigated by real‐time RT‐PCR, immunofluorescence microscopy, Western blotting and cell growth analysis whether human cancer cell lines (SH‐SY5Y, MCF7, HepG2, U2‐OS, HeLa, HEK293T, RCC4, HCT116, 7860wt and SW480) possess functional Epo receptors (EpoR). We detected EpoR mRNA in all cell lines. Neither hypoxia nor Epo treatment altered the level of EpoR mRNA expression. Four commonly used commercial antibodies proved to be unsuitable for immunoblot procedures because they cross‐reacted with several proteins unrelated with EpoR. Depending on the antibody used, EpoR was localized to the plasma membrane, the cytoplasm or the nucleus. Experiments with small interfering RNA showed that EpoR protein was not expressed by the tumor cells except by UT7/Epo leukemia cells, which served as an EpoR positive control line, and by cells transfected with the human EpoR gene. Apart from UT7/Epo, none of the tumor cell lines responded to Epo treatment with phosphorylation of signaling molecules or with cell proliferation. © 2007 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 92%

Lack of functional erythropoietin receptors of cancer cell lines

Laugsch¹,

Metzen²,

Svensson³

et al. 2007

Intl Journal of Cancer

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“…This level of surface receptor was reportedly sufficient to induce low-level signalling and survival responses (Um et al, 2007). A proliferative effect of rHuEpo was reported in MCF-7 cells (Acs et al, 2001), but seven other studies reported no proliferative effect in MCF-7 cells (Berdel et al, 1991(Berdel et al, , 1992Mundt et al, 1992;Rosti et al, 1993;Gewirtz et al, 2006;Li et al, 2006;Laugsch et al, 2008). Also, rHuEpo reportedly increased the survival of parental HeLa cells in one study (Acs et al, 2003) but not in another study (Pajonk et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, most clinical studies have found no increase in tumour progression or decrease in survival when ESAs are administered to cancer patients (Bohlius et al, 2006). Furthermore, many studies have found tumour cell lines are unresponsive to ESAs, including proliferation and survival of tumour cell lines in vitro (Berdel et al, 1991;Mundt et al, 1992;Rosti et al, 1993;Selzer et al, 2000;Westphal et al, 2002), and, of most physiological relevance, tumour growth in vivo (Silver and Piver, 1999;Mittelman et al, 2001;Stuben et al, 2001Stuben et al, , 2003Thews et al, 2001;Golab et al, 2002;Pinel et al, 2004;Sigounas et al, 2004;Ning et al, 2005). Thus, there is conflicting evidence for the role of EpoR in tumour growth.…”

mentioning

confidence: 99%

Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells

et al. 2008

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Erythropoietin receptor (EpoR) has been reported to be overexpressed in tumours and has raised safety concerns regarding the use of erythropoiesis-stimulating agents (ESAs) to treat anaemia in cancer patients. To investigate the potential for EpoR to be overexpressed in tumours, we have evaluated human tumours for amplification of the EPOR locus, levels of EPOR transcripts, and expression of surface EpoR protein. Gene amplification analysis of 1083 solid tumours found that amplification of the EPOR locus was rare with frequencies similar to other non-oncogenes. EPOR transcript levels in tumours and tumour cell lines were low in comparison with bone marrow and were equivalent to, or lower than, levels in normal tissues of tumour origin. Although EpoR mRNA was detected in some tumour lines, no EpoR could be detected on the cell surface using 125 I-Epo binding studies. This may be due to the lack of EpoR protein expression or lack of cell-surface-trafficking factors, such as Jak2. Taken together, we have found no evidence that EpoR is overexpressed in tumours or gets to the surface of tumour cells. This suggests that there is no selective advantage for tumours to overexpress EpoR and questions the functional relevance of EpoR gene transcription in tumours.

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“…neuroprotective effects of EpO have been shown to be exerted via EpOr expressed in cerebral neurons during radiotherapy (3,9). initial concerns concerning the use of EpO have been raised by the detection of EpOr in glioma cells (10,19). in functional studies, EpO protected cultured glioblastoma cells from cisplatin cytotoxicity and promoted their invasiveness (11).…”

Section: Discussionmentioning

confidence: 99%

“…moreover, EpO has been shown to exert neuroprotective potential during radiotherapy through EpOr expression on cerebral neurons (3,9). On the other hand, EpOr has also been detected on glioma cells (10), raising concern about the safety of EpO treatment in glioma patients (11).…”

Section: Introductionmentioning

confidence: 99%

High expression levels of erythropoietin and its receptor are not correlated with shorter survival in human glioblastoma

Brunotte¹,

Bock

Brück

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Erythropoietin (EpO) is used to treat anemia in neoplastic disease. EpO also exerts neuroprotective effects on neuronal cells, making a prophylactic use against the neurocognitive effects of radiochemotherapy probable. however, EpO/ EpO-receptor (EpOr) signalling has been also detected in glioblastoma cells. data collected in vitro and in vivo show conflicting results on the effect of EPO on malignant gliomas. the association between EpO and EpOr expression and the prognosis of human glioblastomas was analyzed. probes of human glioblastomas with complete documentation of clinical course and treatment were assessed by immunohistochemistry for the expression of EpO and EpOr (n=80). using univariate and multivariate survival analysis, the association with age, gender, radiation, chemotherapy and extent of resection was determined. high levels of EpOr were correlated with a median survival advantage of 7 months (p<0.01). By univariate, but not multivariate, analysis, high levels of EpO and EpOr were associated with a significant prolongation of 7 months median survival when compared to low levels of both molecules. in patients treated with radiochemotherapy adjuvant to surgery, the median survival was 6.5 months longer in patients with high levels of EpOr (p<0.04). according to previous studies, longer patient survival is associated with EpOr expression. therefore, EpO appears to be safe for the treatment of anemia in glioblastoma patients. Ηowever, a prophylactic use, i.e., for neuroprotection, is not recommended in light of the functional studies described in the literature.

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Studies on the role of recombinant human erythropoietin in the growth regulation of human nonhematopoietic tumor cells in vitro

Cited by 50 publications

References 20 publications

Lack of functional erythropoietin receptors of cancer cell lines

Lack of functional erythropoietin receptors of cancer cell lines

Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells

High expression levels of erythropoietin and its receptor are not correlated with shorter survival in human glioblastoma

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