Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis

Abstract

Tumour hypoxia has been shown to increase mutation rate, angiogenesis, and metastatic potential, and decrease response to conventional therapeutics. Improved tumour oxygenation should translate into increased treatment response. Exogenous recombinant erythropoietin (rEpo) has been recently shown to increase tumour oxygenation in a mammary carcinoma model. The mechanism of this action is not yet understood completely. The presence of Epo and its receptor (EpoR) have been demonstrated on several normal and neoplastic tissues, including blood vessels and various solid tumours. In addition, rEpo has been shown in two recent prospective, randomized clinical trials to negatively impact treatment outcome. In this study, we attempt to characterize the direct effects of rEpo on tumour growth and angiogenesis in two separate rodent carcinomas. The effect of rEpo on R3230 rat mammary adenocarcinomas, CT-26 mouse colon carcinomas, HCT-116 human colon carcinomas, and FaDu human head and neck tumours, all of which express EpoR, was examined. There were no differences in tumour growth or proliferation (measured by Ki-67) between placebo-treated and rEpo-treated tumours. In the mammary window chamber, vascular length density (VLD) measurements in serial images of both placebo-treated and Epo-treated rats revealed no difference in angiogenesis between the Epo-treated tumours and placebo-treated tumours at any time point. These experiments are important because they suggest that the recent clinical detriment seen with the use of Epo is not due to its tumour growth effects or angiogenesis. These studies also suggest that further preclinical studies need to examine rEpo's direct tumour effects in efforts to improve the therapeutic benefits of Epo in solid tumour patients.

Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

“…Yet, Wnt1 also may rely upon the central pathways of Akt1 that have been shown to promote cellular integrity and survival during free radical injury [16,19], oxidative stress [17,18], tumor invasion [36], cell longevity [37], and amyloid toxicity [13][14][15]. Evidence for the dependence of Wnt1 on the Akt pathway can be drawn from a variety of cell populations.…”

Recombinant human erythropoietin α modulates the effects of radiotherapy on colorectal cancer microvessels

“…In keeping with others (Hardee et al, 2005), we were unable to demonstrate any effect of rhEPO on angiogenesis, as reflected by the similar MVD in both groups. Density of microvessels, however, is only one functional aspect of a tumour microvascular bed.…”

“…On the other hand, EPO has been shown to exert direct effects on angiogenesis and tumour growth mediated by presence of the EPO receptor on endothelial cells and a number of malignant cell types (Jaquet et al, 2002;Jelkmann and Wagner, 2004). Preclinical studies investigating the effect of exogenous rhEPO on tumour growth and angiogenesis are at present inconclusive (Hardee et al, 2005). Similarly, whereas some preclinical data suggest that rhEPO increases response to RT, chemotherapy or photodynamic therapy, other studies did not identify any effects of rhEPO (Stuben et al, 2003;Pinel et al, 2004;Kirkpatrick et al, 2006).…”

“…Yasuda et al (2003) noted the inhibition of angiogenesis and tumour cell survival in stomach and melanoma xenografts following blockade of EPO signalling. The results of Hardee et al (2005), however, suggested that administration of rhEPO did not affect angiogenesis or tumour growth in human colon and head and neck xenografts.The importance of tumour oxygenation for RT response is well established, and there has been considerable interest in modulating tumour oxygenation and RT response by rhEPO administration. Experimentally, exogenous rhEPO has been shown to improve or restore radioresponsiveness in both anaemic and nonanaemic animals (Thews et al, 1998;Stuben et al, 2003;Pinel et al, 2004).…”

“…Yasuda et al (2003) noted the inhibition of angiogenesis and tumour cell survival in stomach and melanoma xenografts following blockade of EPO signalling. The results of Hardee et al (2005), however, suggested that administration of rhEPO did not affect angiogenesis or tumour growth in human colon and head and neck xenografts.…”