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Advanced Drug Delivery Reviews (v.63, #8)
Target cell movement in tumor and cardiovascular diseases based on the epithelial–mesenchymal transition concept
by Kian-Ngiap Chua; Kar Lai Poon; Jormay Lim; Wen-Jing Sim; Ruby Yun-Ju Huang; Jean Paul Thiery (pp. 558-567).
Epithelial–mesenchymal transition (EMT) is a fundamental mechanism in development driving body plan formation. EMT describes a transition process wherein polarized epithelial cells lose their characteristics and acquire a mesenchymal phenotype. The apico-basal polarity of epithelial cells is replaced by a front-rear polarity in mesenchymal cells which favor cell–extracellular matrix than intercellular adhesion. These events serve as a prerequisite to the context-dependent migratory and invasive functions of mesenchymal cells. In solid tumors, carcinoma cells undergoing EMT not only invade and metastasize but also exhibit cancer stem cell-like properties, providing resistance to conventional and targeted therapies. In cardiovascular systems, epicardial cells engaged in EMT contribute to myocardial regeneration. Conversely, cardiovascular endothelial cells undergoing EMT cause cardiac fibrosis. Growing evidence has shed light on the potential development of novel therapeutics that target cell movement by applying the EMT concept, and this may provide new therapeutic strategies for the treatment of cancer and heart diseases.Display Omitted
Keywords: Epithelial–mesenchymal transition; Carcinoma; Invasion; Metastasis; Heart; Fibrosis; Coronary disease; Regeneration
Targeting tumor cell motility to prevent metastasis
by Trenis D. Palmer; William J. Ashby; John D. Lewis; Andries Zijlstra (pp. 568-581).
Mortality and morbidity in patients with solid tumors invariably result from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited.In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell–cell adhesion, cell–matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities.Display Omitted
Keywords: Abbreviations; ALCAM; Activated Leukocyte Adhesion Molecule; EMT; Epithelial–Mesenchymal Transition; RGD; Arg–Gly–Asp amino acid sequence; TGFβ; Transforming Growth Factor beta; HGF; Hepatocyte Growth Factor; VEGF; Vascular Endothelial Growth Factor; EGF; Epidermal Growth Factor; SDF-1; Stromal cell Derived Factor-1; TNFα; Tumor Necrosis Factors alpha; EpCAM; Epithelial Cell Adhesion Molecule; EphA2; Ephrin A2; MMP; Matrix Metalloproteinase; FAK; Focal Adhesion Kinase; WAVE; Wiskott–Aldrich syndrome protein (WASP)-family protein, WASP family Verprolin-homologous proteinMigration; Metastasis; Motility; Therapy; Tumor; Adhesion; Invasion; Intravasation
Cancer Cell Invasion: Treatment and Monitoring Opportunities in Nanomedicine
by Omid Veiseh; Forrest M. Kievit; Richard G. Ellenbogen; Miqin Zhang (pp. 582-596).
Cell invasion is an intrinsic cellular pathway whereby cells respond to extracellular stimuli to migrate through and modulate the structure of their extracellular matrix (ECM) in order to develop, repair, and protect the body's tissues. In cancer cells this process can become aberrantly regulated and lead to cancer metastasis. This cellular pathway contributes to the vast majority of cancer related fatalities, and therefore has been identified as a critical therapeutic target. Researchers have identified numerous potential molecular therapeutic targets of cancer cell invasion, yet delivery of therapies remains a major hurdle. Nanomedicine is a rapidly emerging technology which may offer a potential solution for tackling cancer metastasis by improving the specificity and potency of therapeutics delivered to invasive cancer cells. In this review we examine the biology of cancer cell invasion, its role in cancer progression and metastasis, molecular targets of cell invasion, and therapeutic inhibitors of cell invasion. We then discuss how the field of nanomedicine can be applied to monitor and treat cancer cell invasion. We aim to provide a perspective on how the advances in cancer biology and the field of nanomedicine can be combined to offer new solutions for treating cancer metastasis.Display Omitted
Keywords: Nanoparticles; Nanotechnology; Molecular targets; Angiogenesis; Metastasis; Contrast agents; Gene therapy; Drug delivery; Imaging
The roles of CYP450 epoxygenases and metabolites, epoxyeicosatrienoic acids, in cardiovascular and malignant diseases
by Xizhen Xu; Xin A. Zhang; Dao Wen Wang (pp. 597-609).
Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active eicosanoids. The primary epoxidation products are four regioisomers of cis-epoxyeicosatrienoic acid (EET): 5,6-, 8,9-, 11,12-, and 14,15-EET. CYP2J2, CYP2C8, and CYP2C9 are the predominant epoxygenase isoforms involved in EET formation. CYP2J and CYP2C gene families in humans are abundantly expressed in the endothelium, myocardium, and kidney. The cardiovascular effects of CYP epoxygenases and EETs range from vasodilation, anti-hypertension, pro-angiogenesis, anti-atherosclerosis, and anti-inflammation to anti-injury caused by ischemia-reperfusion. Using transgenic animals for in vivo analyses of CYP epoxygenases revealed comprehensive and marked cardiovascular protective effects. In contrast, CYP epoxygenases and their metabolites, EETs, are upregulated in human tumors and promote tumor progression and metastasis. These biological effects result from the anti-apoptosis, pro-mitogenesis, and anti-migration roles of CYP epoxygenases and EETs at the cellular level. Importantly, soluble epoxide hydrolase (sEH) inhibitors are anti-hypertensive and anti-inflammatory and, therefore, protect the heart from damage, whereas the terfenadine-related, specific inhibitors of CYP2J2 exhibit strong anti-tumor activity in vitro and in vivo. Thus, CYP2J2 and arachidonic acid-derived metabolites likely play important roles in regulating cardiovascular functions and malignancy under physiological and/or pathological conditions. Moreover, although challenges remain to improving the drug-like properties of sEH inhibitors and identifying efficient ways to deliver sEH inhibitors, sEH will likely become an important therapeutic target for cardiovascular diseases. In addition, CYP2J2 may be a therapeutic target for treating human cancers and leukemia.Display Omitted
Keywords: Abbreviations; AA; arachidonic acid; CYP; cytochrome P450; EETs; epoxyeicosatrienoic acids; HETEs; hydroxyeicosatetraenoic acids; DHETs; dihydroxyeicosatrienoic acids; EDHF; endothelium-derived hyperpolarizing factor; tPA; tissue plasminogen activator; cAMP; cyclic AMP; PKA; protein kinase A; COX-2; cyclooxygenase-2; PPAR; peroxisome proliferator-activated receptors; PI3K; phosphatidylinositol 3-kinase; TNF-α; tumor necrosis factor-α; MAPK; mitogen-activated protein kinase; HCAECs; human coronary artery endothelial cells; HLMVECs; human lung microvascular endothelial cells; PASMC; pulmonary artery smooth muscle cells; PDGF; platelet-derived growth factor; HB-EGF; heparin binding epidermal growth factor (EGF)-like growth factor; MMPs; metalloproteinases; ROCK; rho-associated protein kinase; NO; nitric oxide; PGI2; prostacyclin; Trp; transient receptor potential; eNOS; endothelial NO synthase; PKC; protein kinase C; rAAV; Recombinant adeno-associated virus; sEH; soluble epoxide hydrolase; PAH; Pulmonary arterial hypertension; TGF beta; transforming growth factor; BMPRII; bone morphogenetic protein receptor II; VEGF; vascular endothelial growth factor; CREBP; cAMP response-element binding protein; JNK; c-Jun N-terminal kinase; NF-κB; nuclear factor-ΚB; VCAM-1; vascular cell adhesion molecule-1; HUVECs; human umbilical vein endothelial cells; ICAM-1; intercellular adhesion molecule-1; IKK; IκB kinase; IκB-α; inhibitor κB-α; HSVEC; human saphenous vein endothelial cells; Hcy; Homocysteine; GSK-3; β; glycogen synthase kinase-3; βArachidonic acid (AA); Cytochrome P450 (CYP) epoxygenase; Epoxyeicosatrienoic acid (EET); Cardiovascular disease; Cancer
Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis
by Xiaofeng Zhao; Jun-Lin Guan (pp. 610-615).
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays critical roles in integrin-mediated signal transductions and also participates in signaling by other cell surface receptors. In integrin-mediated cell adhesion, FAK is activated via disruption of an auto-inhibitory intra-molecular interaction between its amino terminal FERM domain and the central kinase domain. The activated FAK forms a complex with Src family kinases, which initiates multiple downstream signaling pathways through phosphorylation of other proteins to regulate different cellular functions. Multiple downstream signaling pathways are identified to mediate FAK regulation of migration of various normal and cancer cells. Extensive studies in cultured cells as well as conditional FAK knockout mouse models indicated a critical role of FAK in angiogenesis during embryonic development and cancer progression. More recent studies also revealed kinase-independent functions for FAK in endothelial cells and fibroblasts. Consistent with its roles in cell migration and angiogenesis, increased expression and/or activation of FAK are found in a variety of human cancers. Therefore, small molecular inhibitors for FAK kinase activity as well as future development of novel therapies targeting the potentially kinase-independent functions of FAK are promising treatments for metastatic cancer as well as other diseases.Display Omitted
Keywords: FAK; Cell migration; Angiogenesis; Signal transduction; Cancer
miRNA and vascular cell movement
by Junming Yue (pp. 616-622).
miRNAs are a new class of endogenous small RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating experimental evidence shows that miRNAs regulate cellular apoptosis, proliferation, differentiation, and migration. Dysregulation of miRNA expression leads to various human diseases including cancer and cardiovascular disease. miRNA maturation is regulated at multiple steps by different mechanisms, including miRNA editing, hairpin loop binding, self-regulation, and cross-talk with other signaling pathways. Vascular cell movement plays a pivotal role in the development of various cancers and cardiovascular diseases. miRNAs have been found to regulate vascular cell movement. Presently the chemically synthesized antagomir and miRNA mimics have been widely used in investigating the biological functions of miRNA genes. The viral vectors, including adenoviral, lentiviral, and adeno-associated viral vectors, have been used to efficiently overexpress or knockdown miRNAs in vitro and in vivo. Therefore, targeting vascular cell movement using miRNA-based drug or gene therapy would provide a novel therapeutic approach in the treatment of cancers and vascular diseases.Display Omitted
Keywords: miRNA; Vascular; Cell movement; Therapy
Extravasation of polymeric nanomedicines across tumor vasculature
by Michael K. Danquah; Xin A. Zhang; Ram I. Mahato (pp. 623-639).
Tumor microvasculature is fraught with numerous physiological barriers which hinder the efficacy of anticancer agents. These barriers include chaotic blood supply, poor tumor vasculature permeability, limited transport across the interstitium due to high interstitial pressure and absence of lymphatic network. Abnormal microvasculature also leads to hypoxia and acidosis which limits effectiveness of chemotherapy. These barriers restrict drug or drug carrier extravasation which hampers tumor regression. Targeting key features of the tumor microenvironment such as tumor microvessels, interstitial hypertension and tumor pH is a promising approach to improving the efficacy of anticancer drugs. This review highlights the current knowledge on the distinct tumor microenvironment generated barriers which limit extravasation of drugs and focuses on modalities for overcoming these barriers using multi-functional polymeric carriers. Special attention is given to utilizing polymeric nanomedicines to facilitate extravasation of anticancer drugs for future cancer therapy.Extravasation across tumor vasculature.Display Omitted
Keywords: Extravasation; Drug delivery; Nanomedicines; Tumor vasculature; Tumor targeting
Role of tumor vascular architecture in drug delivery
by Ajit S. Narang; Sailesh Varia (pp. 640-658).
Tumor targeted drug delivery has the potential to improve cancer care by reducing non-target toxicities and increasing the efficacy of a drug. Tumor targeted delivery of a drug from the systemic circulation, however, requires a thorough understanding of tumor pathophysiology. A growing or receding (under the impact of therapy) tumor represents a dynamic environment with changes in its angiogenic status, cell mass, and extracellular matrix composition. An appreciation of the salient characteristics of tumor vascular architecture and the unique biochemical markers that may be used for targeting drug therapy is important to overcome barriers to tumor drug therapy and to facilitate targeted drug delivery. This review discusses the unique aspects of tumor vascular architecture that need to be overcome or exploited for tumor targeted drug delivery.Display Omitted
Keywords: Abbreviations; ABC; ATP-binding cassette; ADCC; antibody-dependent cellular toxicity; APC; antigen presenting cell; bFGF; basic fibroblast growth factor; FGF-2; fibroblast growth factor-2; CRC; Cancer Research Campaign; DMXAA; 5,6-dimethylxanthenone-4-acetic acid; ECM; extra-cellular matrix; EORTC; European Organization for Research and Treatment of Cancer; EPR; enhanced permeation and retention; EGFR; epidermal growth factor receptor; FITC; fluorescein isothiocyanate; GAG; glycosaminoglycan; IFP; interstitial fluid pressure; IgG; immunoglobulin G; IV; intravenous; MDR; multi-drug resistance; MMP; matrix metalloproteinase; MRP; multidrug resistance related proteins; NCI; National Cancer Institute; NF-κB; nuclear factor-κB; PA; plasminogen activators; PEG; polyethylene glycol; PG; proteoglycan; PGP; P-glycoprotein; SCID; severe combined immunodeficient; SEM; scanning electron microscopy; TNF; tumor necrosis factor; TRAIL; TNF-related apoptosis inducing ligands; VCAM; vascular cell adhesion molecule; VEGF; vascular endothelial growth factorAngiogenesis; Vasculature; Drug therapy; Drug delivery; Targeting
Prodrugs for improving tumor targetability and efficiency
by Rubi Mahato; Wanyi Tai; Kun Cheng (pp. 659-670).
As the mainstay in the treatment of various cancers for several decades, chemotherapy is successful but still faces challenges including non-selectivity and high toxicity. Improving the selectivity is therefore a critical step to improve the therapeutic efficacy of chemotherapy. Prodrug is one of the most promising approaches to increase the selectivity and efficacy of a chemotherapy drug. The classical prodrug approach is to improve the pharmaceutical properties (solubility, stability, permeability, irritation, distribution, etc.) via a simple chemical modification. This review will focus on various targeted prodrug designs that have been developed to increase the selectivity of chemotherapy drugs. Various tumor-targeting ligands, transporter-associated ligands, and polymers can be incorporated in a prodrug to enhance the tumor uptake. Prodrugs can also be activated by enzymes that are specifically expressed at a higher level in tumors, leading to a selective anti-tumor effect. This can be achieved by conjugating the enzyme to a tumor-specific antibody, or delivering a vector expressing the enzyme into tumor cells.Display Omitted
Keywords: Prodrug; Cancer therapy; Targeted delivery; Polymer; Transporter; ADEPT; GDEPT
Viral delivery for gene therapy against cell movement in cancer
by Te-Lang Wu; Dongming Zhou (pp. 671-677).
Viral delivery for cancer gene therapy is a promising approach, where traditional radiotherapy or chemotherapy to limit proliferation and movement of cancer cells has met resistance. Based on the new understanding of the biology of the viral vectors, therapeutic viral vectors for cancer gene therapy have been improved for greater safety and efficacy as well as transitioned from being non-replicating to replication-competent. Traditional oncolytic vectors have focused on eliminating tumor growth, while novel vectors simultaneously target epithelial-to-mesenchymal transition (EMT) in cancer cells, which could further prevent and reverse the aggressive tumor progression. In this review, we highlight the illustrative examples of cancer gene therapy in clinical trials as well as preclinical data and include proposals on methods to further enhance the safety and efficacy of oncolytic viral vectors in cancer gene therapy.Display Omitted
Keywords: Cancer gene therapy; Oncolytic viral vector; Cell movement; Metastasis; Epithelial-to-mesenchymal transition
Regulatory systems for hypoxia-inducible gene expression in ischemic heart disease gene therapy
by Hyun Ah Kim; Taiyoun Rhim; Minhyung Lee (pp. 678-687).
Ischemic heart diseases are caused by narrowed coronary arteries that decrease the blood supply to the myocardium. In the ischemic myocardium, hypoxia-responsive genes are up-regulated by hypoxia-inducible factor-1 (HIF-1). Gene therapy for ischemic heart diseases uses genes encoding angiogenic growth factors and anti-apoptotic proteins as therapeutic genes. These genes increase blood supply into the myocardium by angiogenesis and protect cardiomyocytes from cell death. However, non-specific expression of these genes in normal tissues may be harmful, since growth factors and anti-apoptotic proteins may induce tumor growth. Therefore, tight gene regulation is required to limit gene expression to ischemic tissues, to avoid unwanted side effects. For this purpose, various gene expression strategies have been developed for ischemic-specific gene expression. Transcriptional, post-transcriptional, and post-translational regulatory strategies have been developed and evaluated in ischemic heart disease animal models. The regulatory systems can limit therapeutic gene expression to ischemic tissues and increase the efficiency of gene therapy. In this review, recent progresses in ischemic-specific gene expression systems are presented, and their applications to ischemic heart diseases are discussed.Display Omitted
Keywords: Hypoxia; Gene therapy; Gene regulation; Ischemic heart disease
Myocardial regeneration: Roles of stem cells and hydrogels
by Zhaoyang Ye; Yan Zhou; Haibo Cai; Wensong Tan (pp. 688-697).
Heart failure remains the leading cause of morbidity and mortality. Recently, it was reported that the adult heart has intrinsic regenerative capabilities, prompting a great wave of research into applying cell-based therapies, especially with skeletal myoblasts and bone marrow-derived cells, to regenerate heart tissues. While the mechanism of action for the observed beneficial effects of bone marrow-derived cells remains unclear, new cell candidates are emerging, including embryonic stem (ES) and introduced pluripotent stem (iPS) cells, as well as cardiac stem cells (CSCs) from adult hearts. However, the very low engraftment efficiency and survival of implanted cells prevent cell therapy from turning into a clinical reality. Injectable hydrogel biomaterials based on hydrophilic, biocompatible polymers and peptides have great potential for addressing many of these issues by serving as cell/drug delivery vehicles and as a platform for cardiac tissue engineering. In this review, we will discuss the application of stem cells and hydrogels in myocardial regeneration.Display Omitted
Keywords: Myocardial regeneration; Cell therapy; Tissue engineering; Stem cells; Hydrogels
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