Current Signal Transduction Therapy - Volume 6, Issue 2, 2011

Hepatocyte growth factor (HGF, otherwise known as scatter factor, SF) was discovered more than two decades ago. During this period, the HGF receptor, cMET has been identified, the signalling pathways downstream of HGF/cMET have been reported. Two decade on, hepatocyte growth factor, its receptor and cellular signalling have been increasingly recognised as important in a number of physiological processes and pathological conditions. Ways to utilise HGF, or to target HGF, the HGF receptor and HGF signalling pathways have been attempted, some being used in early stage of clinical studies. The current issue explores some of the leading work in this pivotal area. We are indebted to Dr. Toshikazu Nakamura, Professor Emeritus of Osaka University, who first cloned HGF in 1989 [1] and has provided his insightful and excellent views of the discovery of HGF, the evolution of studies on HGF from scientific investigation to preclinical and clinical studies as well as the therapeutic implications [2]. Perhaps it is the initial discovery of the molecule from three different directions, namely as a hepatopietic protein [3], a mitogenic protein to hepatocyte [4], and a protein causing scattering of epithelial cells [5], that has lead to the areas of subsequent investigations into the biological and clinical impact of the molecule. It is now known that the molecule is widely involved in the pathophysiology of the liver, in the morphogenesis regulation of varying tissues and cells, and a powerful regulator of angiogenesis and lymphangiogenesis. A number of clinical and therapeutic implication have been developed along these main function of the cells as indicated by Professor Nakamura [2]. The clinical and therapeutic implication of HGF and its signalling is clearly discussed by Oka et al., [6]. Being one of the most powerful protein mitogen for hepatocytes and for liver regeneration, the action of HGF on liver is well beyond on hepatocytes. It influences the fibrosis, lipidosis, inflammation and necrosis via its action on the non-parenchymal cells such as myofibroblasts. Such being the case, HGF has now been widely tested in liver conditions including various types of hepatitis and liver cirrhosis. Two examples of HGF being a useful therapeutic option in the area of regeneration are lung [7] and wound healing [8]. Mizuno et al., [7] has discussed the pivotal role of HGF in the physiology and pathology of lung conditions and documented the potential therapeutic implications of HGF in both acute and chronic lung diseases. Both HGF and its regulators, including HGF-activater (HGF-A) and HGF-A inhibitors (HAIs) are aberrant in wound healing and are indicators of abnormal wound healing [8]. Funakoshi and Nakamura have covered an area that have less well recognised in the past, the role of HGF in the neuronal development and injuries [9]. Recent evidience has shown that HGF is a novel neurotrophic factor for a variety of neurons both in vitro and in vivo. It is also fascinating to observe that apart from physically acting on the neurons, HGF has also been indicated in the behaviour regulation of the nervous system and has been shown to be linked to autism and schizophrenia, thus pointing HGF being an important target and therapeutic means in both neuronal and behaviour condition, a new horizon for HGF. The other important aspect of HGF as morphogenic regulators are discussed in relation with angiogenesis [10] and lymphangiogenesis [11], both are important biological process in cardiovascular conditions and cancer spread. HGF and its receptor have been widely studied in the context of cancer and cancer metastasis, over the last two decades. A great deal has learned with regard to the expression profile of the cytokine complex in virtually all the tumour types in humans. Apart from a direction action on cancer cells, HGF also acts on other cells and mechanisms that facility the progression of cancer, including endothelial cells, stromal and immune cells. These work has also lead to development of therapeutic means by targeting HGF, the HGF receptor and the signalling, as well as means for imaging, The importance of HGF and its signalling events in cancer and cancer therapy is well reflected by the four articles which discussed the nature of HGF signalling in cancer [12], the role of Rock/Rho signalling in HGF mediated action in cancer [13], the importance of activation of HGF-Met receptor pathway in chemotherapy and development of drug resistance [14] and the use of HGF antagonist in cancer treatment [15]. The use of small molecules to the HGF receptor, antibodies, and HGF regulators have otherwise been reviewed in recent articles [16-19] and some of the most recent results are covered by Bottaro and his colleagues [20]. As Professor Nakamura indicated [2], recombinant HGF and HGF plasmids have been under intense clinical trials for various conditions, so as the clinical trials of inhibitors to both HGF (namely NK4 and antibodies) and the HGF inhibitor (small molecules). Using HGF and the HGF receptor as targets for medical imaging have also attempted in the past decade. This exciting prospect in the treatment and diagnosis of medical conditions begins to bear fruits. We are looking forward to the next two decades and anticipating a greater application of both HGF and its receptor signalling in medicine and healthcare.

The mechanism for ingenious tissue regeneration in mammals is roughly divided into two distinct systems. One is a system in which undifferentiated, vigorously proliferative stem cells assume the principal role in tissue regeneration. It operates to regenerate and repair tissues comprising differentiated cells that are no longer capable of proliferation, such as the hemopoietic tissue of bone marrow, nerve tissues and muscles. The other, termed the simple duplication system, is the regeneration for tissues whose cellular components are mature and differentiated, yet vitally capable of proliferation as seen in the regeneration of parenchymal organs such as the liver, kidney, and lung. Therefore, for organs with complicated multi-cellular architecture such as the liver, kidney, and lung, treatment of an injury by activation of simple duplication system will be a means of therapy in accordance with nature.

Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.

Hepatocyte growth factor (HGF) has been shown to have multiple effects on the wound healing process. Several in vitro and ex vivo models using HGF have been shown to promote wound healing. The expression of HGF and its receptor cMet are different in chronic and acute wounds. HGF treatments in chronic wounds have not lived up to the expectations of the in vitro and ex vivo models. This review looks at the different expression of the HGF receptor and HGF agonists in chronic wounds compared to acute wounds. This aberrant expression may have a value in identifying early the wounds at risk of becoming chronic. A greater understanding of HGF and HGF agonists expression will have a direct implication for a protein engineering approach to the management of chronic wounds.

Hepatocyte growth factor (HGF), which was originally identified and molecularly cloned as a potent mitogen for primary hepatocytes, exhibits multiple biological effects, such as mitogenic, motogenic, morphogenic, and antiapoptotic activities, in the liver and other organs throughout the body by binding to the c-Met/HGF receptor tyrosine kinase (c-Met). In addition to hepatotrophic activities, HGF and c-Met are expressed in both developing and adult mature brains and nerves, and plays functional roles in the central as well as peripheral nervous systems. A large number of studies have accumulated evidence showing that HGF is a multipotent growth factor that functions as a novel neurotrophic factor for a variety of neurons, including the hippocampal, cerebral cortical, midbrain dopaminergic, motor, sensory, sympathetic, parasympathetic and cerebellar granule neurons in vitro. In vivo, HGF exerts neuroprotective effects in the animal model of cerebrovascular diseases, spinal cord injury, neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), and neuroimmune diseases, preventing neuronal cell death and functioning on glial, vascular and immune cells. The multiple activities of HGF, in addition to highly potent neurotrophic activities, suggest that HGF is a potential therapeutic agent for the treatment of various diseases of the nervous system. Furthermore, the anxiolytic activity of HGF and an association of c-met with autism, as well as neurorecognition and schizophrenia, have been reported, suggesting a role for HGF in emotional and psychiatric status. This review describes the role of HGF in the nervous systems during development and focuses on the therapeutic potential of HGF for a variety of neurological, neuroimmunological and psychiatric diseases among adults.

Hepatocyte growth factor (HGF) is a known angiogenic factor that has profound effects on vascular endothelial cells. In recent years, it has been reported that the factor also acts as a lymphagiogenic factor that induces lymphangenesis from lymphatic endothelial cells. The current article debates some of the recent evidence showing such an effect and also discusses the clinical studies that link to lymphatic related conditions, together with clinical implications.

Hepatocyte growth factor/scatter factor (HGF/SF) acts as a mitogen, motogen and morphogen as well as an important angiogenic factor. In cancer cells, HGF/SF acts mainly as an inducer of cell migration and invasion with multiple motility signals mediated by the HGF receptor, c-MET. An important component in this signalling chain is the Rho/ROCK pathway, with resultant changes in cytoskeletal arrangement leading to cell motility/migration. This article outlines knowledge of HGF/SF in relation to cancer cell motility from previous reviews and focuses on more recent studies on the effect of HGF/SF in relation to RhoC GTPase and ROCK in breast cancer cells.

Since their discovery in the late 1980's, Hepatocyte growth factor (HGF) and it's receptor, c-MET, have become the focus of intense scrutiny as regards their role in cancer and metastasis [1, 2]. HGF is now known to be a potent morphogen that can regulate tissue and organ regeneration and modulate cell morphology, it is a motogen that can stimulate cell motility and migration, and is a mitogen able to regulate cell growth and death and is a powerful angiogenic and lymphangiogenic factor [3-5]. The diverse range of functions that can be ascribed to HGF/c-MET is transmitted via a variety of cell signaling pathways. This review will focus on recent work demonstrating the importance of HGF/c-MET in regulating these signaling events, how they are related to cancer metastasis and where they may be targeted for patient intervention.

Hepatocyte growth factor (HGF) and Met receptor participate in the malignant progression of cancer, particularly in invasive growth, metastasis, and drug resistance. Recent studies indicate that the HGF-Met pathway participates in the spreading and maintenance of cancer stem cells, at least in some types of cancers. HGF and Met have become molecular targets of much attention in anticancer therapy. Based on the functional assignment of each domain in HGF, and in the structures of the HGF-Met interface, polypeptide HGF-Met inhibitors have been identified, including NK4, NK1 mutants, and HB10. NK4 is composed of the N-terminal (N) and four kringle domains (K4) of HGF. NK4 binds to the Met without its activation, thereby competitively inhibiting HGF-dependent Met activation. Moreover, independent of the HGF-antagonist action, NK4 inhibits angiogenesis, and this action is mediated by NK4-perlecan interaction. In a variety of tumor models, NK4 inhibited the HGF-Met pathway and angiogenesis, and these actions were associated with inhibition of invasive growth and metastasis. Thus, therapeutic approaches using NK4, the first discovered inhibitor against HGF-Met, revealed the significance of HGF-Met inhibition in cancer treatment. In addition to NK4, different types of HGF-Met inhibitors have been developed, including small molecule inhibitors for Met tyrosine kinase and neutralizing monoclonal antibodies against HGF or Met. During the past few decades, the success of drug development targeting growth factors and their receptor tyrosine kinases in human cancer has triggered a new therapeutic strategy for treating cancer. Preclinical and clinical development of HGF-Met inhibitors will provide further advances in molecular-targeted therapy of cancer.

It has been more than 25 years since HGF was discovered as a mitogen of adult rat hepatocytes. HGF is produced in stromal cells, and stimulates epithelial cell proliferation, motility, morphogenesis and angiogenesis in various organs via tyrosine phosphorylation of its receptor, c-Met. There is now growing evidence to show that stroma-derived HGF is important for organogenesis in embryo and a recovery from diseased conditions in adults. In the liver, HGF has mitogenic, morphogenic and anti-apoptotic effects on hepatocytes and endothelium. HGF exerts anti-inflammatory functions via direct effect on hepatic macrophages during sepsis. Notably, HGF targets hepatic myofibroblasts and elicits anti-fibrogenic responses, resulting in resolution of liver cirrhosis. Inversely, the inhibition of HGF-c-Met signals by anti-HGF antibody, or c-Met gene destruction, leads to the accelerated progression of hepatitis. These findings demonstrated that HGF-c-Met axis confers a host defense system to “minimize” acute and chronic hepatitis. Under pathological conditions, however, HGF production is insufficient and occasionally retarded, and such a loss in self-repair system allow for progression of hepatic failure. Based on these backgrounds, we emphasized a rationale for exogenous HGF supplement therapy during hepatitis. The present review focuses on both the physiological roles of HGF in liver regeneration and the therapeutic potential of HGF-c-Met signaling to prevent or restore liver diseases. “Growth factor therapy” to treat hepatitis may open up an avenue for the future development of other cell-signal transduction therapies.

There is now ample evidence that hepatocyte growth factor (HGF) is essential for organogenesis in embryo and tissue repair for adults in almost all organs. In the lung, HGF elicits mitogenic, morphogenic and anti-apoptotic effects on bronchial and alveolar epithelial cells. HGF also elicits an angiogenic response through enhancing endothelial cell proliferation. Several studies using animal models clearly demonstrated that endogenous HGF is required for bronchial formation and alveolar septation at an embryonic stage, and of interest, even during adult diseases, such as emphysema. HGF has an anti-inflammatory effect on lung macrophages during sepsis, or on infiltrated eosinophils during asthma. HGF elicits anti-fibrogenic activities toward myofibroblasts under chronic lung injury. These multiple functions are mediated through tyrosine phosphorylation of c-Met/HGF-receptor. During the acute and chronic lung diseases, HGF is highly produced by lung stromal cells (or in distant organs), but this beneficial response is transient, insufficient and often delayed. Such a loss in HGF-c-Met signals results in the accelerated progression of respiratory dysfunction. In other words, pulmonary disorders may be defined as an HGF-deficiency or HGF-insufficiency. Indeed, supplemental therapy with recombinant HGF protein (or HGF gene) leads to improvements in pulmonary emphysema, fibrosis and hypertention, or attenuation of chronic airway inflammation in rodent models. In this review, we wish to discuss a rationale for HGF supplemental therapy, with a focus on the pulmotrophic roles of endogenous HGF in cell biology, physiology and pathology during lung diseases.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor which regulates cell growth, cell motility, and morphogenesis of various types of cells, and is thus considered a humoral mediator for morphogenic tissue interactions. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed in vascular cells and cardiac myocytes. On the other hand, recently, we demonstrated that HGF plasmid DNA transfer significantly improves the size of ulcer in patients with peripheral artery disease (PAD) at Phase III clinical trial, while vascular endothelial growth factor (VEGF) gene therapies for PAD at Phase III have not been succeeded yet. To further investigate this difference between HGF and VEGF, we showed that HGF but not VEGF improves the senescence EPC against oxidative stress through the inhibition of rac1. Moreover, we reported that HGF promotes SHIP-2 translocation from epithelial growth factor receptor (EGFR) to c-Met, and it would protect oxidative stress through EGFR degradation. By this anti-oxidative and anti-senescence effects of HGF would maintain the vessel so long in patients with PAD who receive much oxidative stress in real world. In this report, we discuss a potential therapeutic strategy using HGF in cardiovascular diseases.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic effects against non-small cell lung cancer (NSCLC) with EGFR activating mutations. However, 25%-30% of EGFR mutant lung cancer patients show intrinsic resistance, and the responders almost invariably acquire resistance to EGFR-TKIs within several years. Three mechanisms—second-site point mutation that substitutes methionine for threonine at position 790 (T790M) in EGFR, amplification of MET protooncogene, and overexpression of hepatocyte growth factor (HGF, a ligand of MET)—have been reported to contribute to resistance to EGFR-TKIs. These three factors were detected simultaneously in a population of patients with acquired resistance to EGFR-TKIs. Further investigations to develop optimal therapy based on accurate diagnosis of resistant mechanism are warranted to improve the prognosis of EGFR mutant lung cancer.

Cells regulate normal physiological function by receiving signals from outside as well as providing signals to other cells. These signals are mediated through cytokines, hormones or growth factors which bind to their cognate receptors and trigger receptor-mediated signaling cascades. G-protein coupled receptor kinase, receptor tyrosine kinase, integrin and toll-like receptor pathways cover the most receptor-mediated signaling pathways. Apart from cell surface receptors-generated signaling pathways, intracellular receptor-mediated pathways also exist for which ligands such as thyroid hormones, steroid hormones etc need to cross the membrane and bind to its intracellular receptor. Under pathophysiological conditions, these signaling pathways are deregulated, resulting in intra- as well as intercellular miscommunication due to production of unwanted signals, leading to progression of the disease. Interruption of these signaling pathways using small molecules has emerged as a pivotal approach to treat a number of diseases. Unlike conventional approaches of blocking or activating a receptor, signaling inhibitors interfere in the intracellular signaling cascades either at upstream or downstream level. Blocking of an upstream signaling pathway may block a wide range of signals elicited by a receptor ligand. Inhibition of a downstream pathway provides relatively higher specificity to a therapy as only a specific transcriptional process will be affected. Most of the signaling inhibitors were developed for cancer treatment and named as “targeted therapies”. These therapies include small inhibitors of protein kinases that modify other proteins by adding phosphate groups to them (phosphorylation). Phosphorylation usually results in a functional change of the target protein by changing its activity, cellular location, or association with other proteins. Some protein kinases are mutated to be constitutively active in tumor cells and inhibitors of such kinases would be specific for cancer cells. Imatinib mesylate (Glivec®), an inhibitor of BCR-ABL (a cancer-related tyrosine kinase) and PDGF-R tyrosine kinases, was the first one to get approval by FDA in 2001 for the treatment of gastrointestinal stromal tumor and several types of leukemia. Its success started a new era in cancer therapy and since then many TKIs have made their way to the clinic including Gefitinib (Iressa®) and Lapatinib (Tykerb®) against EGF receptor, Sorafenib (Nexavar®) and Sunitinib (Sutent®) against many kinases including PDGF and VEGF receptors. Other dozens of kinase inhibitors are now in clinical trials. Apart from cancer, many other diseases are now potential targets for treatment using signaling inhibitors. However, signaling pathways are generally involved in the regulation of normal physiological functions and inhibition of these pathways ubiquitously would result in side effects in other organs. To make these therapies more specific to the affected organ, many new approaches have been applied. In this special issue, we aimed to provide instances of strategies used for organ-specific signaling inhibition. This issue encompasses review articles focused on the strategies used to target brain disorders, chronic kidney disease, liver disease (hepatocellular carcinoma), cancer, and inflammatory/autoimmune disorders. Wisler and co-authors review thoroughly the organ-specific therapies for autoimmune diseases such as Sjogren's syndrome, inflammatory bowel diseases or Crohn's disease and rheumatoid arthritis in their article [1]. These disorders are mainly characterized by deregulated innate and defective acquired cellular and humoral immune responses. As a result many proinflammatory cytokines (TNF-α, many interleukins and interferons) are induced systemically and in the affected organ where these cytokines activate many intracellular signaling pathways such as SAPK/MAPK, JAK/STAT and PI3K/PTEN/Akt/mTOR pathways. The authors have clearly described the disease mechanisms in detail including role of different cytokines and their signaling pathways in three disorders. To support the information, they have also reviewed the in vivo data. For Sjogren's syndrome, anti-TNF-α strategies mostly based on capturing TNF-α using monoclonal antibodies or soluble receptor have been covered. Similarly, monoclonal antibodies and small signaling inhibitors used experimentally or clinically have been discussed for inflammatory bowel disease and rheumatoid arthritis. Most interestingly, authors report literature on organ-specific drug delivery approaches to make these inhibitors selective to target organs. These approaches include drug targeting using immunoliposomes, humanized antibodies, aptamers, organ-specific peptides and the use of lectins and lectin-binding saccharides. Of interest, targeting of anti-inflammatory cytokines such as IL-10 to inflamed vasculature by coupling compounds to a fusion protein has also been addressed in this review. Together, this review provides a comprehensive overview of the interplay of various signaling pathways and newest targeted approaches to treat inflammatory/autoimmune diseases. As discussed above, signalling inhibitors have primarily been applied for cancer therapeutics but yet require more specificity to cancer tissue. Altintas and co-authors have elaborated this topic in their review reported in this issue [2]. They clearly explain why tumor-specific targeting of the so-called targeted therapies is essential. Some tyrosine kinases are selectively present in tumor cells but most of the others are also actively present in normal tissues. Inhibitors of EGF and VEGF receptor kinases, especially for cancer therapies, have been reported to display serious side effects such as cardiotoxicity in long-term use. Furthermore, the authors describe in detail several drug delivery tools such as liposomes, polymers, microspheres, and drug-protein conjugates. Targeting to tumors can be through Enhanced Permeability and Retention (EPR)- mediated effects which is mostly applicable to particulate system such as liposomes, nanoparticles, etc. In contrast, use of peptides, monoclonal antibodies and proteins to deliver signalling inhibitors into cells are active receptor-mediated endocytosis process. In addition, new linking technology to conjugate these inhibitors to different carriers has also been incorporated in this article. In addition, this review covers up the latest examples of targeted signalling inhibitors (chemical structures) examined in vivo. In continuation of the topic of tumor targeting, Farinati et al. have contributed a review on (targeting of) signalling inhibitors to hepatocellular carcinoma [3]. As the authors indicate, the diagnostics and therapy of early stages of hepatocellular carcinoma have tremendously improved, although for intermediate and advanced stages the therapeutic options are far from optimal. The authors will discuss in detail the role of growth factors and their receptors. Particular attention is given to vascular endothelial growth factor (VEGF), as this factor has been identified as a major factor involved in angiogenesis. Additionally, epidermal growth factor (receptor), insulin-like growth factor (receptor) and platelet-derived growth factor are discussed as targets for intervention in hepatocellular carcinoma. More downstream of these growth factor receptors, intracellular pathways play a role in hepatic carcinogenesis. Pathways that have been targeted include mitogen-activated protein kinases and PI3KAkt/ mTOR. In their review paper, Farinati et al. put an emphasis on recent developments from clinical trials in hepatocellular carcinoma, which are excellently summarized.....

Ischemic stroke is a leading cause of morbidity and mortality worldwide which incidence is increasing with society aging. Unfortunately, despite intensive research in treatments to reduce mortality and the severity of the cerebrovascular injury, there are not effective therapies available. Hypoxia-Inducible Factor-1 (HIF-1) triggers the overexpression of genes coding for proteins involved in the adaptative response of the cell to oxygen deprivation. The functional HIF unit is a heterodimeric protein composed of the two subunits, HIF-1alpha and HIF-1beta. HIF-1alpha activity is regulated through different mechanisms involving post-transcriptional and post-translational modifications. During normoxia, prolyl hydroxylases modify HIF-1alpha and marks it for proteasomal degradation. Under hypoxia, reduced activity of prolyl hydroxylases allows stabilization of HIF-1alpha and increases protein levels. Also, several transduction pathways have been proposed to act downstream of putative oxygen sensors and lead to HIF-1alpha phosphorylation by kinases. Collectively, these modifications regulate HIF-1alpha activity inducing gene expression associated with brain protection after ischemia. In this review, we summarize some of the latest compounds that have shown to regulate HIF function and induce protection in brain cells subjected to ischemia. We focus on compounds that target HIF hydroxylases and the PI-3K/Akt and the MAPK/ERK pathways. Increased HIF-1alpha expression holds great promise for the treatment of cerebral ischemia and makes HIF hydroxylases and kinases attractive therapeutic targets. The reduced number of reports associated to the study of kinases and HIF-1alpha in brain, points out the need of further investigation.

The increasing prevalence of end-stage renal disease urges novel therapeutic strategies for the treatment of chronic kidney disease. As protein kinases play a pivotal role in renal inflammation and fibrosis, specific protein kinase inhibitors have been demonstrated to be renoprotective in experimental studies. However, since protein kinases are also involved in key physiological mechanisms such as cell differentiation, cell growth and proliferation, these beneficial effects have been associated with serious side effects, limiting their clinical applicability. However, the possibility to selectively deliver a drug to cells with a particular phenotype (i.e. cells expressing a cellspecific protein to which drugs can be targeted) has increased the potential of protein kinase inhibitors in chronic kidney disease. Several studies have reported renoprotective effects of protein kinase inhibitors specifically delivered to fibrotic cells, or to specific cell types such as proximal tubular epithelial cells or mesangial cells. An overview of these studies will be provided, as well as future directions in this exciting field of research that may lead to novel highly specific pharmacological intervention strategies.

Despite the advancements in diagnosis and therapy for hepatocellular carcinoma (HCC) that currently permit to treat with tailored strategies the disease in early stages, for intermediate and advanced stages the therapeutic options are far from optimal. In recent years, new targets have been searched by exploring the molecular pathways involved in hepatocarcinogenesis, leading to multiple trials on new agents interfering in these mechanisms. In this article we revised the principal agents that raised major interest, from the one already established as gold standard for advanced HCC (sorafenib) to the new molecules still in preclinical or early clinical studies. The extensive investigation on the field will identify the best agents and the subsets of patients that will benefit most from their application.

Conventional treatment of cancer is accompanied by severe systemic side effects. As an alternative, targeting only deregulated intracellular pathways that cause proliferation, migration and metastasis are emerging in the field of cancer therapy. Kinase inhibitors are one appealing class of drugs that target specific intracellular pathways. However, kinase inhibitors are not specific in terms of tissue or cellular distribution, and kinase inhibitor therapy can cause serious side effects that are dose-limiting or reason to withdraw the compound from clinical testing. This review will highlight how the selectivity of kinase inhibitors can be improved via a different type of targeted therapy, i.e. by using drug delivery systems that are capable of directing kinase inhibitors specifically to tumor cells. We will explain how so-called nanomedicines obtain specificity for tumor cells and how other mechanisms can contribute to the guiding of the drug delivery system into the tumor tissue. EGFR and VEGFR are two classes of receptor tyrosine kinases that are highly deregulated in almost all cancers, and several effective kinase inhibitors targeted to these pathways have entered the clinic. We will focus on the inhibition of these pathways by analyzing the strategies that combine these kinase inhibitors with drug delivery systems to obtain enhanced tumor-selective effects.

Pro-inflammatory cytokine and anabolic growth factor-mediated activation of the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-activated protein kinase/Mitogen-activated protein kinase (SAPK/MAPK) and Phosphatidylinositide-3-kinase/Phosphatase and TENsin homolog/Akt/mammalian Target Of Rapamycin (PI3K/PTEN/Akt/mTOR) pathways occurs in several autoimmune-mediated inflammatory disorders, such as primary Sjogren's syndrome, inflammatory bowel diseases, Crohn's disease and ulcerative colitis and rheumatoid arthritis. JAK/STAT pathway activation has been implicated in maintaining the high level of pro-inflammatory cytokine gene transcription in these disease states. Furthermore, activation of JAK/STAT can result in the ‘cross-talk’ activation of SAPK/MAPK and PI3K/PTEN/Akt/mTOR leading to the destruction of tissues and organs as well as the abnormal level of survival of immune cells which perpetuates the inflammatory response. Small molecule inhibitors (SMIs) of these intracellular signaling pathways are now being tested in animal models and in clinical trials with the view that SMIs will join the armamentarium of disease-modifying drugs that have shown clinical efficacy by virtue of their ability to neutralize pro-inflammatory cytokine/cytokine receptor binding. Although systemic administration of SMIs have long been considered the benchmark for predicting successful use in medical therapy, novel organ-specific drug delivery systems have now been shown to deliver drugs only to tissues and organs affected in these disease processes.