Current Pharmaceutical Design - Volume 20, Issue 30, 2014

This special issue of Current Pharmaceutical Design is intended to provide an update on the role of melatonin, originally discovered as the major secretory product of the pineal gland, in the treatment of upper and lower of the gastrointestinal (GI) tract disorders. It has become evident that melatonin is a widely-produced and ubiquitously-distributed molecule with multiple critical functions in all organs and in all organisms but its involvement in the function and integrity of GI-tract has only recently been reviewed [1]. With this volume we decided to provide an overview of the recent advances in experimental research and clinical studies on the efficacy of endogenously secreted melatonin and exogenously applied melatonin to prevent GI injury and the contribution of this hormone to the protection of major GI-tract organs including the esophagus, stomach, intestine, pancreas and liver. In this issue, Reiter and colleagues [2] review the potential sources of melatonin in the human body with focus to the local production of this indoleamine in the enterohepatic system, which seems to be independent from pineal synthesis of this indole. They conclude that the high concentration of melatonin in the bile and enterohepatic circulation plays an important role in the mechanism of protection of the liver and biliary tract [2]. All these information’s seem to be of great importance for the understanding of mechanism of hepatic and biliary protection from oxidative stress and damaging action of various chemicals. Reiter et al. [2] have also provided the recent advances on GI microbiome and transplantations of abdominal organs with relation to melatonin synthesis. This review is essential in our understanding of prophylactic and therapeutic efficacies of melatonin providing the reader with an insight into clinical usefulness of this indole [2]. Extensive research in the last decade has revealed that melatonin, in addition to being the major sleep hormone which exhibits a circadian rhythm with maximal release during the night hours, exerts protective functions in the upper and lower GI-tract and the hepatobiliary system [3]. High concentrations of melatonin in the GI epithelium reflecting the abundant activity of key enzymes of the melatonin biosynthetic pathway arylalkylamine-N-acetyltransferase (NAT) and hydroxy indole O-methyltransferase (HIOMT) and the presence of enterochromaffin cells (EC) which synthesize the melatonin precursor, serotonin, appear to be critical for the local activity of this indoleamine in the gut [2, 3]. The published data has documented the exceptionally high concentrations of melatonin in the hepatocytes, bile and enterohepatic circulation which can influence the function of the biliary tree and the liver independently of pineal-derived melatonin [2, 3]. The concentration of melatonin is decreased with age and the ratio of 5-hydroxy tryptamine (5-HT) to melatonin has been shown to be altered during aging along with a rise in the incidence of GI-tract disorders due to the aging-related decrease in the efficiency of natural protective factors which maintain the mucosal barrier [4]. In this issue, Bertrand and colleagues [5] have concentrated in their expert review on functions of melatonin as a product of serotonin metabolic pathway in physiology of the upper and the lower gut with a major attention addressed to pioneered author’s method of detection of melatonin released from GI endothelium. The method of this measurement available so far include the determination of kinetics of this indoleamine and the ratio of 5-HT to melatonin in particular regions of GI-tract [5]. This local excessive release of melatonin could serve as explanatory for the protective effects of melatonin against the intestinal damage [5]. Interestingly, the impairment of aged GI-mucosa is restored by supplementation with melatonin thus accounting for some of the therapeutic efficacy of this hormone [4, 5]. Membrane bound melatonin receptors (MT1 and MT2) are present on some smooth muscles, neurons, and epithelial cells. Melatonin also acts as a potent free radical scavenger (a receptor - independent action) and provides GI cell protection against reactive oxygen metabolite-induced organ damage. These actions of this indole are best documented in the stomach, liver and biliary system [4-6]. The accumulated evidence indicates that melatonin is effective against the damage induced by experimental reflux esophagitis and prevents the incidence of GERD in humans [7, 8]. In this issue, Brzozowska et al. [9] has focused on various aspects of protective and ulcer healing activities of melatonin in the upper gut. This review was designed to summarize the involvement of melatonin, conventionally considered as a major hormone of the pineal gland, in the maintenance of gastric mucosal integrity, gastroprotection, ulcer healing and intestinal disorders [9]. Authors emphasized that the protective functions of melatonin in the esophagus and stomach are mediated by both receptor-mediated and receptor-independent actions of this indole affecting the release of protective mediators such as nitric oxide (NO), prostaglandins and vasodilatory neuropeptides such as calcitonin gene related peptide (CGRP) [7-10]. These Authors also provide the evidence that treatment with melatonin accelerates the healing of chronic gastric ulcers via a rise in gastric blood flow at the ulcer edge mediated by NO and PG, and the scavenging of reactive oxygen metabolites and the inhibition of gastric acid secretion by this indoleamine [7, 11]. Melatonin has also been implicated in the protection of lower GI-tract disorders, e.g., inflammatory bowel disease (IBD) in experimental models of ulcerative colitis and in Crohn’s disease in human subjects [12]. This topic has been reviewed in this issue of the journal by Talero et al. [13] who focused on the pathophysiology of IBD in experimental animals and human subjects. According to the evidence accumulated in this review [13], IBD is a complex process mediated by cytokines, chemokines, adhesion molecules, cytoplasm nuclear receptors, among others. Recent data also support a participation of the endoplasmic reticulum (ER) stress, process of autophagy and mitochondrial dysfunctions in pathogenesis of IBD [13, 14]. Authors have concentrated on the intriguing mechanism of autophagy reflecting duality of effect of melatonin on this process, which could be either beneficial or detrimental [13]. In this issue, Talero et al. [13] presented recent advances in the understanding of the process of autophagy that could be linked with the development and progression of IBD and the modulation of the process of fatty liver graft preservation. Although autophagy is actually considered more a pro-survival than a pro-death pathway, these two features of this process are relevant in human diseases and there is therapeutic potential for both activators and inhibitors of autophagy [13]. Melatonin can act as a potential activator or sometimes as the inhibitor of this process demonstrating a duality in action thus affording the protection against development of chronic inflammation, the damage to intestinal mucosa, the pancreatic tissue and even colon cancer [13, 14]. The mechanism of this protective action of melatonin against colonic damage may involve the immunoregulatory reduction of T cell, modulation of macrophage activity, suppression of NFκB activity, inhibition of proinflammatory cytokines and cell adhesion molecules, attenuation of COX-2 and iNOS expression and the subsequent production of PGE2 and NO, the reduction of matrix metalloproteinase (MMP) -2 and -9 activity, and modulation of apoptosis [13, 14]. Recently, there has been an increased interest in the roles of sleep, circadian rhythms and melatonin regulators of inflammation in the GI tract [3, 15]. Undoubtedly, the advances in our understanding of the molecular machinery of the circadian clock, and the discovery of clock genes in the GI tract are opening up new avenues of research for a role of sleep in IBD [15]. Of note, chronodisruption significantly worsens the development of colitis in animal models, and preliminary human studies have shown that patients with IBD are at increased risk for altered sleep patterns [3, 15]. Regarding other abdominal organs, the results of numerous experimental studies using animal models of liver damage have confirmed the hepatoprotective role of melatonin [6]. Preliminary trials in human subjects have revealed that the beneficial effect of exogenous melatonin as well as that converted from its precursor, L-tryptophan, are effective in the prevention of ulcerative colitis, colon cancer, and the amelioration of non-alcoholic fatty liver disease (NAFLD) and the complications associated with partial resection of the liver in human subjects [16-19]. In this issue, Chojnacki et al. [20] has provided an updated review on the beneficial effect of melatonin on the liver and the potential usefulness of this indoleamine as the preventive and therapeutic strategy in the treatment of liver disorders such as non-alcoholic steatohepatitis (NASH) and the NAFLD. They emphasized that melatonin protects the hepatocytes from free radical damage by means of its direct free radical scavenging activity, a process which is receptor independent, and via receptor mediated action which involve the stimulation of antioxidant enzymes [20]. These authors pioneered and confirmed the effectiveness of melatonin and its biological precursor, L-tryptophan in the treatment of human NAFLD and during surgical procedure of partial liver resection in human subjects [20]. The pancreas regulates the process of digestion and intestinal absorption of nutrients from ingested food but this organ is susceptible to damage induced by the activation of pancreatic enzyme cascades that may lead to the development of acute pancreatitis which is considered as a critical risk for the patient [21]. In this issue, Jaworek et al. [22] review the role of endogenous melatonin produced both, the pineal gland and the GI-tract in the mechanism of pancreatic protection against caerulein- and taurocholate-induced pancreatic damage thus preventing the development of pancreatitis. These studies can be of potential interest for clinical gastroenterologists since there is no effective therapy against this disorder currently available. Jaworek et al. [22] provided an evidence that both melatonin and its precursor L-tryptophan have been shown to protect the isolated pancreatic cells in vitro and the pancreas in vivo against acute pancreatitis and to attenuate pancreatic tissue damage through an increase in the pancreatic microcirculation and the attenuation of the oxidative stress possibly mediated by an activation of pro-apoptotic signaling pathways . The mechanism of melatonin-induced pancreatic protection involves a direct scavenging effect against radical oxygen and nitrogen species, the activation of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase), and stimulation of apoptosis and heat shock protein (mainly HSP70), while increasing pancreatic regeneration [22, 23]. In line with observations originally accumulated in studies on the gastric mucosa, the removal of the pineal gland markedly lowered the plasma levels of this indoleamine and exacerbated the incidence and severity of experimental pancreatitis [22]. Moreover, Jaworek et al. [22] documented in their review that the low plasma levels of melatonin are associated with an increased risk of severe acute pancreatitis which is consistent with the observation that the blockade of MT2 receptors by luzindole aggravated pancreatitis. There is considerable agreement that endogenous melatonin produced in the GI system could contribute to the natural defense system thereby protecting the gastrointestinal mucosa and pancreatic tissue against acute aggressive factors such as ethanol, bile and pancreatic proteases. Melatonin also influences many metabolic processes in the human body affecting e.g. insulin secretion both in vivo and in vitro [24, 25]. Lardone et al. [26] reported in this issue that the night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes and this is linked with a single nucleotide polymorphism of the human melatonin receptors which is linked to an increased risk of type 2 diabetes development. This review is important since melatonin may yet play a role in diabetes and associated metabolic disturbances affecting insulin secretion but at the same time this anti-inflammatory indoleamine provides protection against reactive oxygen species [26]. These notion is based on the fact that pancreatic β-cells are particularly susceptible to oxidative stress because they possess only low anti-oxidative capacity [26]. Novel conformationally restricted analogues of agomelatine were recently synthesized and pharmacologically evaluated at MT1 and MT2 melatoninergic receptors [27]. Great interest has developed in the search for new molecules capable of mimicking or antagonizing the responses to melatonin. These novel compounds have been derived from the indole ring or its bioisosteres such as naphthalene [28]. The development of high-affinity conformational-locked compounds appear to be an interesting and rational approach to obtain a clear insight into the structural parameters involved in the binding to the receptor site, as well as information about the selectivity for both receptor subtypes. The non-selective naphthalene strict structural analogue of melatonin, agomelatine (Valdoxan), was the first found to control circadian rhythm disorders and is now marketed for the treatment of depression due to its antagonist activity at the 5-HT2C receptor subtype [28, 29]. This is of particular importance since the stress plays a predominant role in the development and progression of GI-tract disorders, for instance, irritable bowel syndrome (IBS) patients most frequently suffer from psychosomatic symptoms [30]. This promising new chemical design result opens new perspectives on the development of agonists of melatonin MT1 and MT2 receptors that could mimic some of the beneficial effects of melatonin’s in clinical practice.

Melatonin is a widely-produced and ubiquitously-distributed molecule with multiple critical functions in all organs and organisms. These functions are mediated by both receptor-mediated and receptor-independent actions of the indole. This survey reviews the reports documenting the presence and function of melatonin in the hepatobiliary system. The published data document the exceptionally high concentrations of melatonin in the bile; herein, we speculate on the significance of these high melatonin levels to the function of the biliary tree. Moreover, we suggest that the elevated concentrations of melatonin in the bile fluid may be a consequence of its recirculation in what is referred to as the enterohepatic circulation. The article also examines the published reports related to melatonin levels in hepatocytes, which appear to be independent of pineal-derived melatonin. In both the biliary system and liver, melatonin provides protection against free radicals in cells of these organs. This is particularly important in these organs since they are under constant assault by highly toxic agents/processes that could compromise their critical physiology. As in other tissues, melatonin provides hepatocytes and cholangiocytes with a buffer against free radicals that are persistently produced and thereby this indole protects against oxidative molecular damage and metabolic dysfunction. Melatonin achieves this protection via the diverse free radical scavenging mechanisms of it and its metabolites (known as the antioxidant cascade), due to its ability to reduce electron leakage from the respiratory complexes in the inner mitochondrial membrane (radical avoidance) and as a result of the stimulation of antioxidative enzymes.

The role of melatonin in the gastrointestinal (GI) tract had previously been limited to its well-described anti-oxidant properties. Recent studies have, however, expanded the role of melatonin in the intestine, showing that it acts as a hormone with local paracrine actions to modulate GI function and the release of other hormones. The GI epithelium produces melatonin from the active precursor serotonin, which is thought to come from the serotonin synthesising enterochromaffin cells (EC). The receptors for melatonin, the membrane bound melatonin receptors 1 and 2, are present on some smooth muscles, neurons, and epithelium. Endogenous release of melatonin has been linked with secretory reflexes and the ileal brake reflex, while exogenous application of melatonin in pharmacological doses has been associated with reduced inflammation in a variety of animal models. Recent studies have begun to look at melatonin release from the GI epithelium using real-time electrochemical detection methods. Using these techniques, the time course of melatonin production shows similarities to that of 5-HT release while the ratio of 5-HT to melatonin is altered during aging. In addition, the effects of melatonin supplementation on the production of endogenous melatonin and its precursor serotonin are suppressed. In summary, the role of melatonin in the GI tract is coming of age. There are many studies showing a clear role for endogenously produced melatonin and clear effects of melatonin supplementation. Newly developed electrochemical techniques for exploring melatonin availability in real-time promise to accelerate our understanding of GI melatonin in the years to come.

Melatonin is a potent reactive oxygen metabolite scavenger and antioxidant that has been shown to influence many physiological functions of the gastrointestinal (GI) tract including secretion, motility, digestion and absorption of nutrients. The role of melatonin in gastroduodenal defense and ulcer healing has been the subject of recent investigations. Melatonin produced in the GI mucosa plays an important role in protection against noxious agents thus contributing to the maintenance of GI integrity and to esophageal protection, gastroprotection and ulcer healing. This review was designed to summarize the involvement of melatonin, conventionally considered as a major hormone of the pineal gland, in the maintenance of gastric mucosal integrity, gastroprotection, ulcer healing and intestinal disorders. Melatonin was originally shown to attenuate gastric mucosal lesions but controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole, or rather gastrointestinal melatonin plays predominant role in gastroprotection. Intragastric and central administration of exogenous melatonin and L-tryptophan, this indoleamine precursor, affords protection against gastric hemorrhagic damage caused by the exposure of gastric mucosa to variety of non-topical and topical ulcerogens such as stress, ethanol and ischemia-reperfusion. The speed of ulcer healing in experimental animals and humans is accelerated by melatonin. This indoleamine could be also effective against the esophageal lesions provoked by reflux esophagitis in animal models and prevents the incidence of GERD in humans. The melatonin-induced gastroprotection is accompanied by an increase in gastric blood flow, plasma melatonin concentration, enhancement in mucosal generation of PGE2, luminal NO content and plasma gastrin levels. Melatonin scavenges reactive oxygen metabolites, exerts anti-oxidizing and anti-inflammatory actions and inhibits the formation of metalloproteinases- 3 and -9; both implicated in the pathogenesis of gastrointestinal injury and formation of gastric ulcers. Blockade of MT2 receptors by luzindole, significantly attenuated melatonin- and L-tryptophan-induced protection and increased the speed of ulcer healing and these effects were accompanied by an increase in the GBF and luminal content of NO suggesting that melatonin exhibits gastroprotection and hyperemia via activation of MT2 receptors and release of NO. The accumulated evidence indicates that the melatonin-induced gastroprotection and the enhancement in healing rate of gastric ulcers may involve the gastroprotective factors derived from the activation of PG/COX and NO/NOS systems as well as gastrin which also was shown to exhibit protective and trophic effects in the upper GItract. Interestingly, pinealectomy, which suppressed plasma melatonin levels, markedly exacerbated gastric lesions induced by topical and non-topical ulcerogens and these effects are counteracted by a concurrent supplementation with melatonin. Evidence is provided that exogenous melatonin and that converted from its precursor, L-tryptophan, attenuates acute gastric lesions and accelerates ulcer healing via interaction with MT2 receptors due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from NOS and COX-1 and COX-2 overexpression and activity. The pineal gland plays an important role in the limitation of gastric mucosal injury and the acceleration of ulcer healing via releasing endogenous melatonin, which attenuates oxidative stress and exerts antiinflammatory action.

The intestinal epithelium forms a barrier against the intestinal contents and the wider environment, allowing entry of selected molecules for nutrition and programming of the mucosal immune system, but excluding toxins and most microorganisms. Many receptors and signalling pathways are coupled and implicated in the epithelial control and significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD) and in the introduction of biologics. However, not all of the patients respond and many lose their response. Data from experimental studies have documented that the pineal secretory product melatonin exerts important inmunoregulatory and antiinflammatory effects in different models of colitis. These actions have been associated to a variety of mechanisms, such as reduction of T cells number, modulation of macrophage activity, suppression of NFκB activity, inhibition of cell adhesion molecules and proinflammatory cytokines , suppression of COX-2 and iNOS levels and the consequent synthesis of PGE2 and NO, reduction of matrix metalloproteinase (MMP) -2 and -9 activity, and modulation of apoptosis. In addition, the beneficial effects of melatonin in IBD are related to its scavenger effect on free radicals and the activation of several antioxidant enzymes. However, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. There is a considerable bulk of information supporting the connection between autophagy and human diseases, including IBD, and although autophagy is actually considered more a pro-survival than a pro-death pathway, these two features of its action are relevant in human diseases, having therapeutic potential for both activators and inhibitors of autophagy. Some of the opposite effects than have been reported for melatonin in IBD could be related to the duality of its effects on autophagy, which itself can be beneficial or detrimental. In this review, new data for melatonin in IBD are discussed, trying to provide recent information of different molecular mechanism including the role of the autophagy regulation.

The liver plays a key role in the detoxification of numerous molecules which results in the formation of an excessive number of toxic reactive oxygen species. This results in oxidative damage to the hepatocytes, which when severe, compromises the function of this critical organ. A variety of antioxidants protect the liver from free radical-mediated damage, one of the best of which is melatonin. Clinical studies have confirmed the melatonin, as well as it precursor tryptophan, protect the liver from non-alcoholic liver disease and also during the surgical procedure of partial liver resection.

Acute pancreatitis is a disease, which could be manifested as either a mild edematous form or a more severe necrotizing pancreatitis which has a poor prognosis. The etiology and pathogenesis of this ailment is not completely clear. Melatonin is an indoleamine which is produced from L-tryptophan in the pineal gland and in the other tissue including gastrointestinal tract. Both melatonin and its precursor have been demonstrated to protect the pancreas against acute pancreatitis and to attenuate pancreatic tissue damage. In the pancreas melatonin and L-tryptophan activate complex mechanisms which involve direct scavenging of the radical oxygen and nitrogen species, activation of antioxidant enzymes (catalase, superoxide dysmutase, glutation peroxidase), reduction of pro-inflammatory cytokines and prostaglandins, activation of heat shock protein, and a decrease of necrosis and increase of regeneration in the pancreas. There are several arguments for the idea that endogenous melatonin produced in the pineal gland and in the gastrointestinal system could be the part of a native mechanisms for protecting the pancreas against acute damage: 1/ the melatonin precursor L-tryptophan exerts similar protective effect as melatonin, 2/ application of the melatonin receptor antagonist, luzindole aggravates acute pancreatitis, 3/ pinealectomy results in the exacerbation of acute pancreatitis, 4/ low melatonin plasma levels are associated with an increased risk of severe acute pancreatitis. These observations leads to the idea that perhaps melatonin could be used in clinical trials as supportive therapy in acute pancreatitis.

The role of melatonin in glucose homeostasis is an active area of investigation. There is a growing body of evidence suggesting a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Furthermore, melatonin has been found to influence insulin secretion both in vivo and in vitro, and night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes. In several recent studies, a single nucleotide polymorphism of the human melatonin receptor 1B has been described as being causally linked to an increased risk of developing type 2 diabetes. Taken together, these data suggest that endogenous as well as exogenous melatonin may play a role in diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species, considering pancreatic β-cells are particularly susceptible to oxidative stress because they possess only low-antioxidative capacity.

The Neuregulin1 proteins and HER receptor tyrosine kinases are pivotal for function and disease development of multiple organ systems, including breast cancer and the heart [1, 2]. The HER2 receptor is mutated or overexpressed in about 20-30% of metastatic breast cancers [3]. Therefore, it is a major drug target of breast cancer therapy. Trastuzumab, a monoclonal antibody that directly binds and blocks the HER2 receptor, is among the first drugs approved by the US Food and Drug Administration for targeted cancer therapy, which proven to be effective for improving the overall survival of breast cancer patients [4]. However, Trastuzumab can cause severe heart failure in patients, especially when used in combination with the chemotherapy drug doxorubicin [4]. Clinical studies show that the New York Heart Association class III/IV heart failure is significantly increased in breast cancer patients treated concurrently with Trastuzumab and doxorubicin compared to doxorubicin alone (16 vs. 4 %), suggesting the HER2 receptor is necessary for protecting the heart from doxorubicin-induced cardiotoxicity [4]. This clinical finding led to a decade of vigorous research on the HER signaling in heart failure, as well as the identification of Neuregulin1 as a cardio-protective factor [5-10]. Clinical trials are ongoing to test the therapeutic effects of using recombinant Neuregulin1 for the treatment of heart failure [11]. With the success of inhibiting the HER2 signals in cancer and using Neuregulin1 for heart failure, major clinical challenges remain which are: how to inhibit the HER signaling for cancer therapy while sparing the heart, and whether Neuregulin1 proteins can be safely used in patients without exacerbating the existing cancer burden or increasing the risk of cancer. In this issue, scientists from both the oncology and cardiology fields are getting together to review the current knowledge of the Neuregulin1-HER signaling in breast cancer and the heart. In the paper “Neuregulin Signaling in Pieces – Evolution of the Gene Family”, Mark Marchionni utilizes gene structure and protein sequence searches and alignments, as well as construction of phylogenetic tree to illustrate how Neuregulins and HER receptor tyrosine kinases evolve during evolution to form a complex signaling network that is currently known. In the paper “Heregulin in Breast Cancer: Old Story, New Paradigm”, Ruth Lupu et al. review Neuregulins’ biological role in the development, progression and maintenance of breast cancer. In the paper “Breast Cancer Biomarkers: Risk Assessment, Diagnosis, Prognosis, Prediction of Treatment Efficacy and Toxicity, and Recurrence”, Adedayo Onitilo et al. review the biomarker development for assisting breast cancer diagnosis, prediction of prognosis, therapeutic response and toxicity. In the paper “Cardiovascular Effects of Neuregulin1-1/ErbB Signaling: Role in Vascular Signaling and Angiogenesis”, Kerry Russell et al. review the role of Neuregulin-HER signaling in endothelial cell angiogenesis, vascular smooth muscle cell proliferation and migration, and maintenance of vascular structure and function. This paper also reviews the cross-talk between cardiac endothelial cells and cardiomyocytes, Neuregulin1 and VEGF signaling, as well as Neuregulin1 and inflammatory cytokines. In the paper “The Developing Role of Neuregulin1 in Cardiac Regenerative Stem Cell Therapy”, James Morgan et al. review the findings of using Neuregulin1 proteins to direct stem cell differentiation into the cardiac lineage in cell culture and discuss the potential use of Neuregulin1 to improve the therapeutic efficacy of stem cell therapy for heart failure. In the paper “Anti-HER2 Cancer Therapy and Cardiotoxicity”, Xinhua Yan et al. review the current anti-HER2 therapies, the preclinical and clinical data on cardiotoxicity induced by anti-HER2 therapy and the mechanisms of how HER2 signaling protects the heart from stress. In the paper “Tumor Dormancy and the Angiogenic Switch: Possible Implications of Bone Marrow-Derived Cells”, Nava Almog et al. review the molecular and cellular regulators, including growth stimulatory signals for angiogenic switch in dormant tumors. In the paper “Mathematical Modeling of Tumor Growth and Treatment”, Heiko Enderling et al. discuss how to use mathematic modeling to simulate the dynamic biological process of tumor growth, tumor-host interactions and to predict treatment response.

Paracrine and juxtacrine signaling via proteins expressed on the cell surface are an integral part of metazoan biology. More than one-half billion years ago epidermal growth factor (EGF) and its cognate receptor formed a functional binding partnership, which has been conserved through evolution in essentially all eubilaterate members of the animal kingdom. Early chordates spawned offspring of these seminal genes to begin the creation of new gene families and an expanded cell-cell signaling network, which included the Neuregulin (NRG) ligands and the erbB receptors. First appearance of ancestral NRG, represented in a NRG4-like gene in the lancelet Branchiostoma floridae, appears to have: 1) occurred in the common chordate ancestor prior to the divergence of lancelets (amphioxus), and; 2) antedated the formation of the receptor gene family. Orthologues of NRG1 and multiple erbB receptors found in the sea lamprey Petromyzon marinus suggest that several key events, which were required to expand and diversify these gene families, occurred in the common ancestor of agnathostomes and jawed vertebrates. These important inventions surely played major roles in the acquisition of multiple apomorphic features of the emerging vertebrate lineage.

Heregulin (HRG), a combinatorial ligand for the epidermal growth factor receptor family, is expressed in about 30% of breast cancer tumors. HRG induces tumorigenicity and metastasis of breast cancer cells and promotes hormone-independent growth [1]. Although HRG has been studied mostly in the context of the HRG receptor family, accumulating evidence suggests that HRG plays distinctive and causative roles in breast cancer tumorigenesis independent from the HRG receptors, demanding a comprehensive and independent study of HRG as a unique growth factor. This review provides a consolidated view of HRG and its biological role in the development, progression, and maintenance of breast cancer. Further, it provides further evidence that HRG is implicated in breast cancer resistance and targeting HRG may possibly be a beneficial tool to target a subgroup of breast carcinomas.

Breast cancer is the most common cancer amongst women in the United States and around the world. Although widespread use of adjuvant chemotherapeutic and hormonal agents has improved mortality from breast cancer, it remains challenging to determine on an individual basis who will benefit from such treatments and who will be likely to encounter toxicities. With the rising costs of healthcare and the introduction of new targeted therapies, use of biomarkers has emerged as a method of assisting with breast cancer diagnosis, prognosis, prediction of therapeutic response, and surveillance of disease during and after treatment. In the following review, prognostic and therapeutic biomarkers, their utility in the management of patients with breast cancer, and current recommendations regarding their clinical use will be discussed.

The NRG/erbB pathway has emerged as an important therapeutic target for cancer growth as well as cardiac related diseases. This discovery stems back to findings showing that overexpression of erbB2 receptors increases the metastatic potential of breast cancer in patients. Blocking this receptor using a monoclonal antibody (trastuzumab) inhibits tumor growth and offers significantly improved outcomes. However, excitement over this discovery was tempered by data showing that trastuzumab-treated patients have an increased risk of developing cardiac dysfunction, limiting the clinical potential of this novel agent. This finding suggested an important protective effect of the erbB signaling pathway on cardiac survival and homeostasis. Further investigation has shown that endothelial-derived neuregulin (a key ligand for erbB receptors) has a protective paracrine effect on cardiac cells as well as vascular smooth muscle cells in the setting of an injury. Since endothelial cells contain erbB receptors, they are also targets for autocrine signaling via this pathway, an important mediator of vascular preservation and angiogenic responses of endothelium. In this review we summarize important clinical findings as well as animal and cellular models that illustrate the signaling pathways involved in vascular cell regulation of cardiomyocyte survival and angiogenesis via the NRG/erbB pathway.

Myocardial infarction, heart failure, and chronic ischemic heart disease account for the majority of the cardiovascular burden. The current treatment strategies focus on limiting the progression of disease and preserving cardiac myocardium. The goal of stem cell therapy, on the other hand, is to reverse or replace damaged cardiac tissue. Over the past two decades many studies have been conducted to understand stem cell performance, survival, and the potential for cardiac repair. Neuregulin1, an epidermal growth factor family member, promotes embryonic stem cell differentiation into the cardiac lineage and improves survival in bone marrow-derived mesenchymal stem cell and embryonic endothelial progenitor cells. Current clinical trials are actively pursuing Neuregulin1's therapeutic potential in the areas of heart failure and cardiac ischemia. It is the intent of this paper to review the current knowledge of Neuregulin1in stem cell biology and discuss the potential of using Neuregulin1 to improve stem cell therapy for cardiac repair.

A significant milestone in the treatment of breast cancer is the identification of the HER2 receptor as a drug target for cancer therapies. Trastuzumab (Herceptin), a monoclonal antibody that blocks the HER2 receptor, is among the first of such drugs approved by the US Food and Drug Administration for targeted cancer therapy. Clinical studies have shown that Trastuzumab significantly improves the overall survival of breast cancer patients. However, an unforeseen significant side-effect of cardiotoxicity manifested as left ventricular dysfunction and heart failure. Concurrent studies have demonstrated the essential role of the HER2 receptor in cardiac development and maintaining the physiological function of an adult heart. The HER2 receptor, therefore, has become a critical link between the oncology and cardiology fields. In addition to Trastuzumab, new drugs targeting the HER2 receptor, such as Lapatinib, Pertuzumab and Afatinib, are either approved or being evaluated in clinical trials for cancer therapy. With the concern of cardiotoxicity caused by HER2 inhibition, it becomes clear that new therapeutic strategies for preventing such cardiac side effects need to be developed. It is the intent of this paper to review the potential cardiac impact of anti-HER2 cancer therapy.

Although escape from tumor dormancy has long been recognized as an important problem in the treatment of cancer, the molecular and cellular regulators underlying this transition remain poorly understood. The inability of the cancer cells to induce a complete and successful process of angiogenesis can result in tumor dormancy. In this case, the acquisition of sufficient angiogenic potential will result in the escape from indolence and in the initiation of tumor mass expansion. This stage in disease progression is known as the angiogenic switch. It is now becoming clear that the induction of the angiogenic switch is controlled by dynamic and complex biological processes involving the cancer cells, the associated stromal microenvironment and distant normal host cells, mostly from the bone marrow. Indeed, intricate tumor-host interactions are increasingly recognized as critical features of cancer. In particular, infiltrating cells of the immune system are crucial constituents of tumors and an important source of the growth stimulatory signals to the tumor cells. Tumor cells are surrounded by stromal cells, such as fibroblasts, lymphocytes, neutrophils, macrophages and mast cells, which communicate via a complex network of intercellular signaling pathways, mediated by surface adhesion molecules, cytokines and their receptors. However, the possible roles of these cells and molecules in the maintenance of micro-tumors in an occult state and in the induction of exit from the dormant state are not fully elucidated. In this review, we summarize recent findings and the current understanding of the role of bone marrow-derived cells, their recruitment into tumors and their interactive crosstalk with tumor cells, in leading to either the maintenance of, or exit from, tumor dormancy. Understanding the mechanisms of tumor growth and metastatic recurrence after periods of indolence is crucial for improving early detection, as well as increasing the cure rate for cancer patients.

Using mathematical models to simulate dynamic biological processes has a long history. Over the past couple of decades or so, quantitative approaches have also made their way into cancer research. An increasing number of mathematical, physical, computational and engineering techniques have been applied to various aspects of tumor growth, with the ultimate goal of understanding the response of the cancer population to clinical intervention. So-called in silico trials that predict patient-specific response to various dose schedules or treatment combinations and sequencing are on the way to becoming an invaluable tool to optimize patient care. Herein we describe fundamentals of mathematical modeling of tumor growth and tumor-host interactions, and summarize some of the seminal and most prominent approaches.