Vascular smooth muscle cell proliferation as a therapeutic target. Part 1: molecular targets and pathways

Cardiovascular diseases are a major cause of human death worldwide. Excessive proliferation of vascular smooth muscle cells contributes to the etiology of such diseases, including atherosclerosis, restenosis, and pulmonary hypertension. The control of vascular cell proliferation is complex and encompasses interactions of many regulatory molecules and signaling pathways. Herein, we recapitulated the importance of signaling cascades relevant for the regulation of vascular cell proliferation. Detailed understanding of the mechanism underlying this process is essential for the identification of new lead compounds (e.g., natural products) for vascular therapies.     

Tissue fibrosis and carcinogenesis: divergent or successive pathways dictate multiple molecular therapeutic targets for oligo decoy therapies

The extracellular matrix (ECM) is composed of several families of macromolecular components: fibrous proteins such as collagens, type I collagen (COL1), type III collagen (COL3), fibronectin, elastin, and glycoconjugates such as proteoglycans and matrix glycoproteins. Their receptors on the cell membrane, most of which in the case of the ECM belong to the integrins, which are heterodimeric proteins composed of α and β chains. COL1 is the major fibrous collagen of bone, tendon, and skin; while COL3 is the more pliable collagen of organs like liver. Focus will not only be given to the regulation of synthesis of several fibrogenic parameters but also modulation of their degradation during growth factor‐induced tissue fibrosis and cancer development. Evidence will be provided that certain tissues, which undergo fibrosis, also become cancerous. Why does there exist a divergency between tissues, which undergo frank fibrosis as an endpoint, and those tissues that undergo fibrosis and subsequently are susceptible to carcinogenicity; resulting from the etiological factor(s) causing the initial injury? For example, why does a polyvinyl alcohol (PVA) sponge implant become encapsulated and filled with fibrous tissue then fibrosis tissue growth stops? Why does the subcutaneous injection of a fibrogenic growth factor cause a benign growth and incisional wounding results in fibrosis and ultimately scarring? There are many examples of tissues, which undergo fibrosis as a prerequisite to carcinogenesis. Is there a cause‐effect relationship? If you block tissue fibrosis in these precancerous tissues, would you block cancer formation? What are the molecular targets for blocking fibrosis and ultimately carcinogenesis? How can oligo decoys may be used to attenuate carcinogenesis and which oligo decoys specifically attenuate fibrogenesis as a prelude to carcinogenesis? What are other molecular targets for oligo decoy therapy in carcinogenesis? J. Cell. Biochem. 97: 1161–1174, 2006. © 2006 Wiley‐Liss, Inc.     

Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis

Vascular integrins are essential regulators and mediators of physiological and pathological angiogenesis, including tumor angiogenesis. Integrins provide the physical interaction with the extracellular matrix (ECM) necessary for cell adhesion, migration and positioning, and induce signaling events essential for cell survival, proliferation and differentiation. Integrins preferentially expressed on neovascular endothelial cells, such as alphaVbeta3 and alpha5beta1, are considered as relevant targets for anti-angiogenic therapies. Anti-integrin antibodies and small molecular integrin inhibitors suppress angiogenesis and tumor progression in many animal models, and are currently tested in clinical trials as anti-angiogenic agents. Cyclooxygense-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxans, is highly up-regulated in tumor cells, stromal cells and angiogenic endothelial cells during tumor progression. Recent experiments have demonstrated that COX-2 promotes tumor angiogenesis. Chronic intake of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors significantly reduces the risk of cancer development, and this effect may be due, at least in part, to the inhibition of tumor angiogenesis. Endothelial cell COX-2 promotes integrin alphaVbeta3-mediated endothelial cell adhesion, spreading, migration and angiogenesis through the prostaglandin-cAMP-PKA-dependent activation of the small GTPase Rac. In this article, we review the role of integrins and COX-2 in angiogenesis, their cross talk, and discuss implications relevant to their targeting to suppress tumor angiogenesis.     

Tumor angiogenesis and molecular target therapy in ovarian carcinomas

Growth of solid tumors depends on angiogenesis, the process by which new blood vessels develop from the endothelium of a pre-existing vasculature. Tumors promote angiogenesis by secreting various angiogeneic factors, and newly formed blood vessels induce tumor cell proliferation and invasiveness. Ovarian carcinomas have a poor prognosis, often associated with multifocal intraperitoneal dissemination accompanied by intense neovascularization. The degree of angiogenesis of ovarian carcinomas may directly influence the clinical course of the disease. Although a growing body of evidence indicates that angiogenic intensity may play a prognostic role in gynecological malignancies including ovarian carcinomas, the related biological mechanisms remain to be further elucidated. In this review, we describe current knowledge pertaining to mechanisms and regulation of angiogenesis in ovarian carcinomas with special reference to our recent research results.     

Cognitive disorders in mice: cytokine signaling pathways as therapeutic targets

Surplus accumulation of regulatory T cells (Tregs) is known to be at the bottom of many morbid conditions, among them being neuropsychiatric diseases. In particular, Tregs may inhibit Th1 cells, including brain autoimmune lymphocytes, controlling the local microglial response and brain tissue homeostasis. The present study was undertaken in an attempt to suggest a novel approach for the treatment of maladaptation to mental stress associated with excessive Treg accumulation. Recently it was shown that alkylating drugs (ADs), such as melphalan and cyclophosphamide (Cy) in the dose 100-fold lower than cytostatic one are capable to disturb signal transduction by IL-2R. In this study we demonstrated that IL-2R is not a unique receptor, which may be blocked with ADs. Similar effect has been shown for two other surface receptors: TNFR and Fas. Molecular mechanisms of the receptor blockage were investigated on the model of TNF signaling. Study of NF-κB activity in nuclear extracts showed that alkylating agents act at the level of surface receptor or of the receptor platform. It was also shown that ADs administration in ultralow doses results in selective elimination of Tregs. In this study we used a new laboratory model of Treg accumulation in mice. Such Treg accumulation was associated with cognitive and behavioral abnormalities, which may be prevented by Cy administration.     

Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. III. Visceral afferent pathways: a source of new therapeutic targets for abdominal pain

Visceral pain is the major cause of consulting in gastroenterology and the principal symptom of functional bowel disorders. This symptom is often associated with gut hypersensitivity to distension. The use of animal models has recently permitted the identification of some mediators supposed to play a pivotal role in the genesis of visceral hypersensitivity. Serotonin, through different receptor subtypes, as well as kinins and calcitonin gene-related peptide, are known to be involved, but other putative transmitters arise and are new potential targets for the development of efficacious treatments. This themes article addresses both physiological and preclinical issues of interest for the selection of active new drugs in regard to the clinical pharmacology of visceral pain.     

Osteosarcoma and chondrosarcoma: new signaling pathways as targets for novel therapeutic interventions

Osteosarcomas and chondrosarcomas are the most common primary bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. Although the prognosis and quality of life have been improved during the last decades, the pathogenesis of these tumours remains elusive. Recent advances in molecular genetics and cytogenetics have brought a wealth of genes and molecular pathways that govern osteoblast and chondroblast differentiation and maturation, providing a better understanding of the biology of osteogenetic and cartilage tumours. In this review we describe the major tumour suppressor and oncogenic pathways, as well as the most important signal transduction cascades implicated in the development and progression of these malignancies. Furthermore, we discuss novel treatment regimens and future, patient-tailored strategies that will add significantly to the current therapeutic armamentarium.     

The HER family and cancer: emerging molecular mechanisms and therapeutic targets

The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases regulates diverse cellular functions in response to extracellular ligands. The deregulation of HER signaling through gene amplification or mutation is seen in many human tumors and an abundance of experimental evidence supports the etiological role of these events in cancer pathogenesis. In addition, the fact that they are feasible targets for both antibody and small-molecule therapeutics has made them highly pursued targets for the development of rationally designed anticancer drugs. Several HER-targeting agents have entered clinical practice and this has led to novel discoveries regarding the mechanisms of resistance, which has defined a new generation of challenges for targeted cancer therapies. Here, we review recent advances in our understanding of HER signaling and targeting in cancer.     

General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal

The mechanisms through which general anaesthetics, an extremely diverse group of drugs, cause reversible loss of consciousness have been a long-standing mystery. Gradually, a relatively small number of important molecular targets have emerged, and how these drugs act at the molecular level is becoming clearer. Finding the link between these molecular studies and anaesthetic-induced loss of consciousness presents an enormous challenge, but comparisons with the features of natural sleep are helping us to understand how these drugs work and the neuronal pathways that they affect. Recent work suggests that the thalamus and the neuronal networks that regulate its activity are the key to understanding how anaesthetics cause loss of consciousness.     

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

The age‐related senescence of adult tissues is associated with the decreased level of angiogenic capability and with the development of a degenerative disease such as atherosclerosis which thereafter result in the deteriorating function of multiple systems. Findings indicate that tissue senescence not only diminishes repair processes but also promotes atherogenesis, serving as a double‐edged sword in the development and prognosis of ischaemia‐associated diseases. Evidence evokes microRNAs (miRNAs) as molecular switchers that underlie cellular events in different tissues. Here, miRNAs would promote new potential targets for optimizing therapeutic methods in blood flow recovery to the ischaemic area. Effectively beginning an ischaemia therapy, a more characteristic of miRNA changes in adult tissues is prerequisite and in the forefront. It may also be a preliminary phase in treatment strategies by stem cell‐based therapy.     

Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer

The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl-2 family, cytochrome c, Apaf-1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross-talk between several caspases and autophagy-related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD-modulating agents that may target caspases-3, -8 and -9, and their substrates PARP-1 and Beclin-1, which may help us harness caspase-modulated PCD pathways for future drug discovery.     

Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets

Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.     

Eph receptors and their ligands: Promising molecular biomarkers and therapeutic targets in prostate cancer

Although at present, there is a high incidence of prostate cancer, particularly in the Western world, mortality from this disease is declining and occurs primarily only from clinically significant late stage tumors with a poor prognosis. A major current focus of this field is the identification of new biomarkers which can detect earlier, and more effectively, clinically significant tumors from those deemed “low risk”, as well as predict the prognostic course of a particular cancer. This strategy can in turn offer novel avenues for targeted therapies. The large family of Receptor Tyrosine Kinases, the Ephs, and their binding partners, the ephrins, has been implicated in many cancers of epithelial origin through stimulation of oncogenic transformation, tumor angiogenesis, and promotion of increased cell survival, invasion and migration. They also show promise as both biomarkers of diagnostic and prognostic value and as targeted therapies in cancer. This review will briefly discuss the complex roles and biological mechanisms of action of these receptors and ligands and, with regard to prostate cancer, highlight their potential as biomarkers for both diagnosis and prognosis, their application as imaging agents, and current approaches to assessing them as therapeutic targets. This review demonstrates the need for future studies into those particular family members that will prove helpful in understanding the biology and potential as targets for treatment of prostate cancer.     

Tumor angiogenesis inhibitors

Formation of the blood supply system is a critical step in malignant transformation of neoplasms which results in the penetration of tumor cells into neighboring tissues and metastatic growth. Significant progress in the elucidation of mechanisms underlying tumor angiogenesis and the discovery of a great diversity of biomolecules involved in its regulation have culminated in the development of a radically new approach to antitumor therapy based on the search for efficient inhibitors of tumor angiogenesis. This review is devoted to the analysis of action mechanisms and expression of the major endogenous inhibitors involved in regulation of tumor and physiological angiogenesis. The antiangiogenic effects of the majority of currently known synthetic inhibitors are considered in the context of their roles in the main steps of tumor angiogenesis. Possible applications of antiangiogenic therapy in the chemotherapy of cancer diseases are discussed.     

Screening for therapeutic targets of tumor angiogenesis signatures in 31 cancer types and potential insights

Tumor vessel normalization can increase pericyte coverage, perfusion efficiency and immune infiltration, while reducing hypoxia, vessel leakage, CTC and metastasis. In this study, we systemically presented the expression pattern of tumor angiogenesis gene signatures in 31 cancer types and its association with immune infiltration and cancer metastasis. Specifically, READ, COAD etc. have relatively similar expression patterns with low GPAGs and high PPAGs. Patients with this expression pattern may benefit from tumor vessel normalization. COAD was selected for further investigation and we found GPAG CXCL12 was downregulated while PPAG EPHB3 was overexpressed in COAD, which were further validated using two independent colon cancer dataset. Further study indicated that CXCL12 expression was positively correlated innate inflammation pathways such as NFκB and negatively correlated with metastasis, while EPHB3 had a reverse result. Moreover, CXCL12 was positively correlated with cancer immune infiltration while EPHB3 was negatively correlated with cancer immune infiltration. Besides, the association between CXCL12/EPHB3 and mutation/CNA landscape were also explored. We also discussed the potential application of gut microbiota in cancer treatment. In summary, blood vessel normalization could promote immune infiltration and repress cancer metastasis while immune cell infiltration can promote blood vessel normalization through a positive feedback loop.