N-cadherin as a therapeutic target in cancer

During tumor progression, cancer cells undergo dramatic changes in the expression profile of adhesion molecules resulting in detachment from original tissue and acquisition of a highly motile and invasive phenotype. A hallmark of this change, also referred to as the epithelial-mesenchymal transition, is the loss of E- (epithelial) cadherin and the de novo expression of N- (neural) cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and a high level of its expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer. A peptidic N-cadherin antagonist (ADH-1) has been developed and has entered clinical testing. In this review, the authors discuss the biochemical and functional features of N-cadherin, its potential role in cancer and angiogenesis, and summarize the preclinical and clinical results achieved with ADH-1.     

RhoGDI2 as a therapeutic target in cancer

Importance of the field: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho GTPases that play important roles in the development of numerous aspects of the malignant phenotype, including cell cycle progression, resistance to apoptotic stimuli, neovascularization, tumor cell motility, invasiveness, and metastasis. Although RhoGDI2 has been known to be expressed only in hematopoietic tissues, recent studies suggest that this protein is also aberrantly expressed in several human cancers and contributes to aggressive phenotypes, such as invasion and metastasis. Hence, RhoGDI2 appears to be a target of interest for therapeutic manipulation.

Areas covered in this review: Here, we summarize the role of RhoGDI2 in human cancers, specifically metastasis-related processes, and discuss its potential as a therapeutic target.

What the reader will gain: RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity.

Take home message: RhoGDI2 may be a useful marker for tumor progression in human cancers, and interruption of the RhoGDI2-mediated cancer cell invasion and metastasis by an interfacial inhibitor may be a powerful therapeutic approach to cancer.     

LAMC2 as a therapeutic target for cancers

Cancer is the leading cause of morbidity and mortality in developed countries and the second major cause of death in developing countries. Laminins are crucial proteins in the basal lamina (one of the layers of the basement membrane), and these form a protein network that influences both normal and transformed cell differentiation, migration and adhesion, as well as phenotype and survival. The basement membranes act as a mechanical barrier to tumor growth, but these molecules, including laminins, are also important autocrine factors produced by cancers to promote tumorigenesis. Several studies in cancers have shown the importance of LAMC2, a laminin component. The elevated expression of LAMC2 on cancer cells appears to drive tumorigenesis through its interactions with several cell-surface receptors including α6β4 and α3β1 integrins and EGFRs. The accumulating evidence indicates that LAMC2-mediated signaling network plays an important role in the progression, migration and invasion of multiple types of cancer, suggesting that it might be a potential therapeutic anticancer target for inhibiting tumorigenesis. Furthermore, elevated serum levels of LAMC2 in cancer patients might be an attractive serum-based diagnostic biomarker.     

Osteopontin as a therapeutic target for cancer

Introduction: Cancer is a complex pathological disorder, established as a result of accumulation of genetic and epigenetic changes, which lead to adverse alterations in the cellular phenotype. Tumor progression involves intricate signaling mediated through crosstalk between various growth factors, cytokines and chemokines. Osteopontin (OPN), a chemokine-like protein, is involved in promotion of neoplastic cancer into higher grade malignancies by regulating various facets of tumor progression such as cell proliferation, angiogenesis and metastasis.

Areas covered: Tumors as well as stroma-derived OPN play key roles in various signaling pathways involved in tumor growth, angiogenesis and metastasis. OPN derived from tumor-activated macrophages modulates the tumor microenvironment and thereby regulate melanoma growth and angiogenesis. OPN also regulates hypoxia-inducible factor-1α-dependent VEGF expression leading to breast tumor growth and angiogenesis in response to hypoxia. Thus, a clear understanding of the molecular mechanism underlying OPN-mediated regulation will shed light on exciting avenues for further investigation of targeted therapies. Silencing of OPN using RNAi technology, blocking OPN activity using specific antibodies and small-molecule inhibitors might provide novel strategies, which would aid in developing effective therapeutics for the treatment of various types of cancer.

Expert opinion: This review focuses on new possibilities to exploit OPN as a tumor and stroma-derived therapeutic target to combat cancer.     

Adrenomedullin as a therapeutic target in angiogenesis

Importance of the field: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target.

Areas covered in this review: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models.

What the reader will gain: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target.

Take home message: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments.     

N-cadherin、E-cadherin及p63在宫颈癌中的表达及相关性

目的：研究N-cadherin、E-cadherin以及p63在宫颈癌中的表达及其与临床病理因素之间的相关性。方法采用免疫组化检测正常宫颈15例、宫颈上皮内瘤变(CIN)30例、50例宫颈癌组织中的N-cadherin、E-cadherin及p63的表达。结果 N-cadherin在正常宫颈组织、CIN以及宫颈癌中的阳性表达率逐渐升高,差异均有统计学意义(P<0.05)。而E-cadherin和p63在正常宫颈组织、CIN以及宫颈癌中的阳性表达率则逐渐降低差异均有统计学意义( P <0.05),N-cadherin的表达与肿瘤的分期、病理分级以及淋巴结转移等密切相关( P <0.05)。结论 N-cadherin的高表达及E-cadherin、p63的低表达与宫颈癌的发生、发展、侵袭、转移密切相关,对上述因子的调控有可能成为宫颈癌治疗的新的靶点。     

Akt as a therapeutic target in cancer

Background: The phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/v-akt murine thymoma viral oncogene homolog (Akt)/mammalian target of rapamycin (mTOR) pathway is central in the transmission of growth regulatory signals originating from cell surface receptors. Objective: This review discusses how mutations occur that result in elevated expression the PI3K/PTEN/Akt/mTOR pathway and lead to malignant transformation, and how effective targeting of this pathway may result in suppression of abnormal growth of cancer cells. Methods: We searched the literature for articles which dealt with altered expression of this pathway in various cancers including: hematopoietic, melanoma, non-small cell lung, pancreatic, endometrial and ovarian, breast, prostate and hepatocellular. Results/conclusions: The PI3K/PTEN/Akt/mTOR pathway is frequently aberrantly regulated in various cancers and targeting this pathway with small molecule inhibitors and may result in novel, more effective anticancer therapies.     

Therapeutic targets associated to E-cadherin dysfunction in gastric cancer

Introduction: Epithelial cadherin (E-cadherin) plays a key role in epithelial cell-cell adhesion, contributing to tissue differentiation and homeostasis. Throughout the past decades, research has shed light on the molecular mechanisms underlying E-cadherin's role in tumor progression, namely in invasion and metastization. Emerging evidence established E-cadherin as a tumor suppressor and suggests that targeting E-cadherin or downstream signaling molecules may constitute effective cancer therapeutics.

Areas covered: This review aims to cover E-cadherin-mediated signaling during cancer development and progression and highlight putative therapeutic targets.

Expert opinion: Reconstitution of E-cadherin expression or targeting of E-cadherin downstream molecules holds promise in cancer therapies. Considering the high frequency of CDH1 promoter hypermethylation as a second hit in malignant lesions from hereditary diffuse gastric cancer patients, histone deacetylase inhibitors are potential therapeutic agents in combination with conventional chemotherapy, specifically in initial tumor stages. Concerning E-cadherin-mediated signaling, we propose that HER receptors (as epidermal growth factor receptor) and Notch downstream targets are clinically relevant and should be considered in gastric cancer therapeutics and control.     

PAK as a therapeutic target in gastric cancer

Importance of the field: Gastric cancer is one of the most common causes of cancer death worldwide. P21-activated kinases (PAKs), regulators of cancer-cell signalling networks, play fundamental roles in a range of cellular processes through their binding partners or kinase substrates.

Areas covered in this review: The complex regulation of PAKs through their upstream or downstream effectors in human cancers, especially in gastric cancer, are described and the identified inhibitors of PAKs are summarized.

What the readers will gain: The structural differences and activation mechanisms between two subgroups of PAK are described. Both groups of PAKs play complicated and important roles in human gastric cancer, which indicated a possible way for us to identify the specific inhibitors targeting PAKs for gastric cancer.

Take home message: PAKs play important roles in progression of many cancer types, the full mechanisms of PAKs in gastric cancer are still unclear. It seems there are different roles for two groups of PAKs in cancers. Group I PAKs play their functions mostly through their specific substrates, however, many binding partners that are independent of phosphorylation by group II PAKs were identified. Finding specific inhibitors of PAKs will help us discover the roles of PAKs and target these kinases in human gastric cancer.     

CIAPIN1 as a therapeutic target in cancer

Importance of the field: Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a newly identified cytokine-induced apoptosis inhibitor, which has roles in cell division and angiogenesis. Owing to its prognostic value for human tumors and involvement in cancer progression and tumor cell resistance to anticancer agents, CIAPIN1 has been proposed as an attractive target for new anticancer interventions.

Areas covered in this review: We define CIAPIN1's potential function as a new therapeutic target for anticancer interventions and this review covers all related literature on CIAPIN1 in cancer from the past 5 years

What the reader will gain: Several preclinical studies have demonstrated that CIAPIN1 is associated with chemotherapy resistance, increased tumor recurrence and shorter patient survival in different human tumor models, making anti-CIAPIN1 therapy an attractive cancer treatment strategy. Recent studies also suggest that CIAPIN1 is expressed at low levels in some types of malignant tumors and that its overexpression may inhibit their proliferation or tumorigenesis.

Take home message: Considering that the exact expression and function of CIAPIN1 are still not well characterized and understood, better knowledge of CIAPIN1 in normal versus tumor tissues will be instrumental for the design of optimal strategies to selectively disrupt CIAPIN1 in cancer.     

TGF-beta in cancer and as a therapeutic target

Cancer develops through a series of genetic changes leading to malignant transformation. Numerous gene and pathways involved in stages of progression to frank malignancy have been elucidated. These genetic changes result in aberrations in fundamental cellular processes controlling proliferation, apoptosis, differentiation and genomic stability. Metastasis is the hallmark of malignancy. The process of metastasis is extremely complex and involves steps including dissemination of tumor cells from the primary tumor through the vascular and lymphatic system and growth selectively in distant tissues and organs. Transforming growth factor-beta which is a growth suppressive cytokine in many normal situations becomes an active and important participant in malignant disease including angiogenesis, extracellular matrix deposition, immuno-suppression and metastasis growth promotion. Transforming growth factor-beta and its receptors are targets for antibody therapeutics and small molecule kinase inhibitors.     

Pigment epithelium-derived factor (PEDF) as a therapeutic target in cardiovascular disease

In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.     

Protein kinase G as a therapeutic target for the treatment of metastatic colorectal cancer

Colorectal cancer is a leading cause of cancer-related death in the world and there is an urgent need for new strategies to combat this disease. Findings from several independent laboratories have converged on cGMP signaling as an exciting new therapeutic target, but the mechanisms remain controversial. A key intracellular effector of cGMP is protein kinase G (PKG). This article reviews the scientific literature concerning PKG effects on tumor development and progression, and discusses possible strategies for its exploitation in future cancer therapies. Studies from several independent laboratories have described novel anti-tumor effects of PKG in colon cancer cells that include inhibition of tumor growth and angiogenesis. While more preclinical research is warranted to better understand signaling mechanisms, these properties support the notion that PKG is a novel cancer target.     

COX-2 as a target for cancer chemotherapy

Cyclooxygenase-1 and -2 (COX-1/2) catalyze the initial step in the formation of prostaglandins. Very recently their role in carcinogenesis has become more evident. They influence apoptosis, angiogenesis, and invasion, and play a key role in the production of carcinogens. Usually, a high level of COX-2 expression is found in cancer cells. Large epidemiological trials studying users and non-users of aspirin have shown that cyclooxygenase inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) could be of benefit against the development and growth of malignancies. Moreover, clinical trials in patients with familial adenomatosis polyposis syndrome have shown the efficacy of selective COX-2 inhibitors in the reduction of the number and size of colorectal polyps. Several preclinical studies show promising results with combinatorial treatments of either chemotherapy or radiotherapy with COX inhibitors. Preclinical studies with the simultaneous use of inhibitors of the epidermal growth factor receptor and COX-2 inhibitors have shown also promising results. Encouraging results from the first clinical trials combining chemotherapy with COX-2 inhibitors in patients with cancer in the advanced and neoadjuvant setting have recently been reported. Thus, it appears that targeting the COX-2 pathway is a promising strategy in the prevention and treatment of solid tumors.     

Is caveolin-1 a viable therapeutic target to reduce cancer metastasis?

Caveolin-1 is the major structural protein in caveolae; small Ω-shaped invaginations within the plasma membrane. Caveolae are involved in signal transduction, wherein caveolin-1 acts as a scaffold to organise multiple molecular complexes regulating a variety of cellular events. Caveolin-1 has both tumour suppressor and oncogenic activities. However, recent evidence suggests a role for caveolin-1 in promoting cancer cell migration and metastasis with both loss and overexpression of caveolin-1 being described as a marker for progression in a variety of tumour types. Further studies are beginning to determine the molecular mechanisms by which caveolin-1 acts in promoting a metastatic phenotype. Targeting caveolin-1 expression may present a novel means of preventing metastasis. The purpose of this review is twofold: firstly, to survey the current knowledge of the contribution of caveolin-1 in promoting a metastasis, and secondly, to explore the viability of targeting caveolin-1 with novel therapeutics.