Current Signal Transduction Therapy - Volume 2, Issue 1, 2007

Despite recent advances in understanding the molecular biology of lung carcinoma and the introduction of multiple new chemotherapeutic agents for its treatment, its dismal five-year survival rate (<15%) has not changed substantially. The lack of advancements in this area reflects the limited knowledge available concerning the factors that promote oncogenic transformation and proliferation of carcinoma cells in the lung. Tumor growth and invasion are not only the result of malignant transformation, but also depend on environmental influences from their surrounding stroma, local growth factors, and systemic hormones. In particular, the composition of the extracellular matrix is believed to affect malignant behavior in vivo. This document reviews information that implicates the matrix glycoprotein fibronectin in regulation of lung carcinoma cell proliferation, apoptosis and resistance to therapy. Fibronectin is highly expressed in chronic lung disorders where most lung carcinomas are identified. Data available to date indicate that by binding to specific integrin receptors expressed on tumor cells, fibronectin stimulates a number of intracellular signals implicated in the pathobiology of lung carcinogenesis including GTPases, mitogen-activated protein kinases, and the PI3-Kinase/Akt/mTOR pathway. Targeting fibronectin and integrin-mediated signals in tumor cells represents a promising target for the development of effective anti-cancer strategies.

A crucial event in the inflammatory response is recruitment of polymorphonuclear leukocytes (PMNL) to a site of infection or injury. PMNL-epithelial interactions involve many fundamental cell processes, including adhesion, migration, secretion, phagocytosis and apoptosis. Thus, migration of PMNL across epithelial-lined organs is a primary event component of host defense. Moreover, PMNL transepithelial migration often results in disease symptoms. New insights into leukocyte-epithelial signalling mechanisms have emerged that are beginning to shed light on the role of many molecular interactions in regulating the rate of PMNL transepithelial migration. Knowledge of the basic mechanisms that control the activation of pro-inflammatory transcription factors, and how these innate immune signalling pathways lead to an activation of the adaptative immune response that maintains the chronically inflamed state, is essential for pharmacological manipulation of intestinal inflammation. This review highlights recent advances in our understanding of the different mechanisms of PMNL-epithelial cell adhesive interactions at the level of cell surface protein-protein binding events, and in intracellular signal transduction pathways that regulate the PMNL transepithelial migration. Finally, the potential modulation of these different signal pathways as possible therapeutic goals will be discussed.

The most important change that will emerge over the coming decade for management of cancer is the shift from conventional chemotherapy and radiotherapy to novel targeted therapies. The rapid expansion in the understanding of the molecular biological basis of cancer provides potential targets for novel therapies. Many molecules, with a variety of cellular targets are now entering the clinic with the emergence of some promising data. The key now is to define the patient population most likely to benefit from these agents through identification of clinical and biological markers indicating a sensitive tumour phenotype. The ongoing clinical development of signal transduction inhibitors presents several challenges to the existing dogma of clinical trial design. For example, in early phase trials the traditional endpoint of objective response rate may not be the most useful in selecting cytostatic agents, which nevertheless may possess clinically relevant activity. Rather, such trials should focus on the in vivo measurement of biological activity in order to define the optimum schedule of treatment that results in maximal inhibition of the therapeutic target. In later phase trials, endpoints such as progression free survival may be more useful than response rate, although of course there is no substitute for the endpoints of overall survival and quality of life, improvements in which these agents must demonstrate for them to be accepted into the cancer treatment armamentarium. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) that have entered clinical trials will be discussed and the successes and failures of these trials will be used to illustrate the obstacles that confront the assessment of the activity of these agents so that this may guide the future development of other new agents by optimising clinical trial design. Signal transduction inhibitors may allow us to overcome resistance or restore sensitivity to conventional chemotherapy. The integration of these molecules with existing therapies should be based on robust pre-clinical data indicating potentially beneficial additive or even synergistic interactions. The correct clinical management strategy can be guided by preclinical modelling but can only be validated by carefully designed clinical trials. These will at the very least need to be conducted with correlative translational research elements that will allow us to select the most appropriate treatment strategy for individual patients.

The incidence of allergic diseases has dramatically increased in recent decades, especially in urban and industrialized areas. It has been reported that, at present, one third of the population in Japan suffers from bronchial asthma, atopic dermatitis, or allergic rhinitis. The medical cost for treating such patients is huge and on the increase. Thus, it is important socially as well as medically to establish more useful strategies to overcome allergic disorders. Bronchial asthma is a complex disease characterized by airway inflammation involving a Th2-cytokine, interleukin (IL)-13. A substantial body of evidence has accumulated pointing to the pivotal role of IL-13 in the pathogenesis of bronchial asthma. Therefore, IL-13 and its signal pathway are thought to be promising targets to develop a therapeutic agent for bronchial asthma. In this article, we summarize the biological properties of IL-13 itself and its signal transduction pathway, the pathological roles of IL-13 in bronchial asthma, and the agents to inhibit the IL-13 signals that are now under development.

Osteoarthritis is a common disease in humans, which is caused by progressive degradation of articular cartilage and imbalance of extracellular matrix turnover. It usually causes pain and malfunction of the affected joints, and the incidence of this disease increases with aging. Classical treatment for osteoarthritis is pain alleviation and, in progressed disease, surgical operations. New surgical techniques include transplantation of autologous chondrocytes or osteochondral plugs to the lesion area. However, these techniques have the problem of limited cell and tissue sources available for transplantation. Therefore, cartilage engineering and use of mesenchymal stem cells have raised a lot of interest as therapeutic approaches. Various strategies are being tested for their ability to provide tissue constructs that could be used as a replacement for the damaged cartilage. Growth factors, cytokines and mechanical forces are known to direct chondrogenesis and the maintenance of chondrocytic phenotype, although the cellular signaling events involved are often poorly known. Yet, understanding of the signal transduction mechanisms involved in chondrogenesis and cartilage tissue engineering will be very important, especially to learn how to guide stem cells into the desired differentiation path. This review aims to summarize the known signal transduction pathways involved with osteoarthritis, cartilage mechanobiology and differentiation of mesenchymal stem cells to chondrocytes.

Gap junctional intercellular communication is a mechanism for direct cell-to-cell signaling and is mediated by gap junctions, which consist of transmembrane proteins called connexins. Many physiological roles have been proposed for gap junctions such as maintenance of tissue homeostasis, regulation of tissue development, electrical and metabolic coupling as well as regulation of cellular growth, differentiation and apoptosis. Signaling is especially altered via gap junctions in cancer. Furthermore, these membrane channels are believed to be engaged in metastasis. Involvement of aberrant gap junctional intercellular communication in carcinogenesis and tumor suppressing role of connexin genes has been well documented. However, clear explanation is required for the role of connexins that are localized in intracellular compartment of cancerous cells and participate in apoptosis and metastasis as well. The present review is confined to role of connexins in a cell signaling during carcinogenesis, regulation of apoptosis and involvement in metastasis. Potential role of gap junctions and connexins in therapy of cancers was analyzed, too.

Malignant gliomas remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of high-grade gliomas and identify oncogenic pathways that might be amenable to small molecule “targeted” therapy. Growth factor signaling pathways are often up-regulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include PI3K, Akt, and mTOR. In addition, function of the cell cycle and apoptotic pathways are often abnormal in malignant glial cells. “Targeted” therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (e.g., imatinib, erlotinib) and farnesyltransferase inhibitors (e.g., R115777). Molecular therapeutic small molecules specific to PI3K and mTOR include LY294002 and CCI-779, respectively. “Targeted” approaches to the apoptosis and cell cycle pathways include small molecular modulators, peptide CDK inhibitors, and proteasomal inhibitors. Further development of “targeted” therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with malignant gliomas.

Although the main cause of many neurodegenerative diseases is unknown, the glial reaction is considered to be a consequence of neuronal cell death in Alzheimer's disease, Parkinson's disease, and Huntington's disease. In Parkinson's disease, postmortem examination and experimental animal models exposed to neurotoxin reveals a dramatic loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. These glial cells can release deleterious compounds such as proinflammatory prostaglandins and cytokines, which may act by stimulating reactive oxygen species in glial cells, or which may exert a more direct effect on dopaminergic neurons by activating receptors that contain death domains involved in neuronal apoptosis. The anti-inflammatory drugs and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease. Elucidation of molecular mechanisms underlying intracellular signal transductions of glial activation will provide promising means of controlling neuroinflammation and the subsequent neurodegeneration.

Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. There is a growing body of evidence to conclude that intensive control of plasma glucose and blood pressure is crucial for effectively reducing diabetic vascular complication. So far, various molecular mechanisms have been proposed to play a role in the development and progression of diabetic vascular complication. In this paper, we review potential therapeutic strategies for the prevention of diabetic vascular complication, especially focusing on the signal transduction pathways activated under diabetes.