Comment on Sridharan V et al., ‘Effects of radiation on the epidermal growth factor receptor pathway in the heart’

Sir: We read the interesting article by Dr Sridharan et al. (Sridharan et al. 2013). The authors investigated the effects of local irradiation on the epidermal growth factor receptor (EGFR) pathway in the rat heart and examined whether tocotrienols may modify radiation-induced changes in this pathway. Their results suggested that irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 h up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. Moreover, they demonstrated that using neoadjuvant tocotrienols modified the effects of radiation on the EGF pathway when examined 2 weeks after irradiation.

We have couple of concerns regarding this article. ErbB2 gene belongs to a family of EGFR (EGFR, human epidermal growth factor receptor 2 (HER2), HER3 and HER4) that regulate many essential cell type-specific functions, particularly cell growth, proliferation and survival (Chen 2000). ErbB2 is thought to participate in an important pathway for growth, repair, and survival of adult cardiomyocytes. Therefore, reduction of ErbB2 signaling induces cardiomycyte apoptosis, while augmentation of ErbB2 signaling in cardiomyocytes confers to protection and improves myocardial function. The authors showed that local heart irradiation caused long-term changes in the EGFR pathway. We think that this is a very important finding which emphasizes the need for further studies about the interaction of EGFR and radiation.

Even though the endothelial cells compromise only a minor fraction of cardiac cells, it has been demonstrated that endothelial cell injury is the key point in radiation-induced cardiovascular toxicity (Adams et al. 2003). The sequence of endothelial injury, cell detachment, thrombosis and fibrosis results in significant tissue injury that often limits radiation oncologists in attempting to deliver curative doses to a nearby tumor. Fajardo and Stewart have demonstrated that damage to the myocardium develops through three phases of injury (Stewart et al. 1995). The acute inflammation phase occurs about 6 hours (h) after radiotherapy, and a neurophilic infiltrate develops involving all layers of heart. The second phase is also known as the latent phase in which a slight progressive fibrosis begins about 2 days after exposure. However, electron microscopy of the myocardial capillary endothelial cells demonstrates progressive damage leading to obstruction of the lumen and thrombi of fibrin and platelets. Though healthy endothelial cell replication in the vicinity occurred, it is generally inadequate and an inevitable ischemia leads to progressive fibrosis. Animals begin to die at approximately the 70th day due to extensive fibrosis (Adams et al. 2003). The hallmark of this late stage is extensive fibrosis. Therefore we wonder why the authors used the time points as 2 h to 9 months after irradiation. Their results may not include the latent phase findings adequately since they sacrificed the animals at 4 days and 2 weeks after irradiation during this phase. On the other hand, there are many studies in the literature using lower doses of irradiation in order to determine radiation-induced cardiac changes. Also, we wonder why the authors chose the dose as high as 21 Gy, because the effects of radiation on the EGFR receptor pathway as well as the severity of this effect may be dose-dependent. Moreover, in a recent study we evaluated the effects of concomitant trastuzumab (Herceptin^®; Genentech Inc, South San Francisco, CA, USA) with radiotherapy on the thoracic aorta (Yavas et al. 2011). In this study we applied two different doses of radiotherapy (8 and 15 Gy) to the mediastinal region of the Wistar Albino rats. However just before the 70th day of radiotherapy, two rats from the concomitant trastuzumab and 15 Gy radiotherapy group died. Post-mortem analysis revealed extensive fibrosis in the thoracic aorta samples. We wonder whether an animal death was observed or not during follow-up and if so, post-mortem examination was performed or not?

The authors point out a very important subject in this experimental study evaluating the effects of radiation on the EGFR pathway in the rat heart. Also, we have designed an experimental study evaluating the effect of radiation and/or trastuzumab on EGFR receptor in the heart, lung and thoracic aorta samples of Wistar Albino rats. Our study has just finished and we are collating our results. The results of our study may give an answer to the question: ‘how radiation may interact with cardiotoxic effects of EGFR inhibitor?’.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.