Hyaluronan and CD44: strategic players for cell-matrix interactions during chondrogenesis and matrix assembly

Embryonic induction, soluble and insoluble factors, receptors, and signal transduction are orchestrated for the morphogenesis of the cartilage elements. The interaction of cells with the extracellular matrix (ECM) may lead to altered cellular response to morphogens based on the formation of new adhesive contacts, or the uncoupling of cell-matrix interactions. Hyaluronan's influence on cell behavior, and its intimate association with cells are accomplished by a wide variety of specific binding proteins for hyaluronan. The temporal expression of the hyaluronan receptor CD44 (which is expressed as several alternatively spliced variants) may be strategic to many of these cell-matrix interactions during chondrogenesis. CD44 expression is temporally coincident with the reduction of intercellular spaces at the regions of future cartilage deposition. The spatial organization of CD44 at the cell surface may function to establish or regulate the structure of the pericellular matrix dependent on a hyaluronan scaffold. As the ECM is modified during embryogenesis, the cellular response to inductive signals may be altered. An uncoupling of chondrocyte-hyaluronan interaction leads to chondrocytic chondrolysis. Thus, consideration of cell-matrix interactions during chondrogenesis, in the light of our current understanding of the temporal and spatial expression of signaling morphogens, should become a promising focus of future research endeavors.     

支架蛋白Gab2信号调控与乳腺癌

Gab2是支架蛋白Gabs家族中的重要成员.该家族蛋白通过介导膜受体与信号转运蛋白间的偶联及各信号分子间的整合参与信号传导.作为支架蛋白,Gab2可被酪氨酸激酶磷酸化激活,接受胞外多种因子刺激,招募富含SH2结构域的信号转运分子,活化下游SHP2/Ras/ERK和PI3K/AKT等一系列信号传导途径,在细胞增殖、分化、...     

ILP-2-ECM1(P85)促进乳腺癌细胞的生长

凋亡抑制蛋白-2（inhibitor of apoptosis protein-like protein-2, ILP-2）是新发现的凋亡抑制蛋白质,其抑制肿瘤细胞凋亡促进其生长的分子机制有待阐明,而细胞外基质蛋白1(extracellular matrix protein 1, ECM1)所介导的信号通路与肿瘤细胞的生长密切相关。本研究通过免疫共沉淀法,检测到乳腺癌MCF-7细胞中ILP-2与ECM1（P85）存在相互作用。分别用化学合成的ILP-2-siRNA及ECM1-siRNA干扰处理MCF-7细胞。以未转染的MCF-7细胞和转染阴性对照siRNA的细胞分别作为空白和阴性对照,利用蛋白质印迹法,检测ILP-2-siRNA干扰后ECM1、FAK、Akt蛋白的表达,以及ECM1-siRNA干扰后ILP-2蛋白的表达。其结果显示,与空白对照组相比,ILP-2-siRNA-5 (0.32 ± 0.095)及ECM1-siRNA-1 (0.42 ± 0.024)干扰效率较高(均P<0.001);ILP-2-siRNA-5组待测蛋白质的相对表达量均显著下调 (ECM1, 0.19 ± 0.013, P<0.001), FAK (0.64 ± 0.069, P<0.01), Akt (0.35 ± 0.120, P<0.01)),ECM1-siRNA-1组ILP-2 (0.48 ± 0.060) 蛋白表达也显著下调,表明ILP-2与ECM1-mTOR信号通路联系密切。分别在ILP-2-siRNA和ECM1-siRNA转染24、48和72 h时,使用CCK-8法检测乳腺癌细胞的增殖,并用TUNEL标记荧光法和吖啶橙/溴化乙啶双荧光染色法(AO/EB)检测其凋亡。结果显示,与空白对照组相比,ILP-2-siRNA-5组和ECM1-siRNA-1组的存活率均显著下降（P<0.001）,凋亡率均明显升高（P<0.001）。利用共转染技术同时敲低ILP-2和ECM1表达,检测细胞的凋亡情况。结果显示,在干扰处理后24 h（0.55±0.122）,48 h（0.80 ± 0.107）和72h（0.73 ± 0.091）的凋亡率显著均高于阴性对照组（P＜0.05）。但与只敲低ILP-2或ECM1相比,无显著性差异（P＞0.05）。表明ILP-2可能是通过与ECM1作用激活FAK-mTOR信号通路,影响MCF-7细胞的增殖和凋亡,对乳腺癌细胞MCF-7的生长发挥了积极的作用。     

IL-8通过激活PKC/ERK信号通路促进肾癌细胞上皮细胞-间质细胞转化

上皮细胞-间质细胞转化(EMT)在肿瘤转移方面起着非常重要的作用．肾癌发生EMT的具体分子机制尚不清楚．IL-8是一个重要的炎症趋化因子,研究表明肾癌细胞可以分泌IL-8,但IL-8是否参与肾癌细胞EMT的调节目前尚无报道．我们研究发现,IL-8可以促进肾癌细胞形态发生间质化改变,IL-8刺激后E-钙黏蛋白表达水平下降, N-钙黏蛋白表达上调．另外,IL-8可以促进肾癌细胞侵袭,但对肾癌细胞增殖的影响并不明显．进一步研究显示,IL-8通过激活蛋白激酶C(PKC)引起细胞外调节性激酶(ERK)磷酸化．因此,我们认为IL-8可能通过PKC/ERK信号通路促进肾癌细胞发生EMT,这可能是肾癌转移的重要机制之一．     

1-硝基-2-酰基蒽醌-缬氨酸通过抑制ERK1/2激活和ERCC1表达诱导结肠癌细胞死亡

化学方法合成是新药研发的一种重要途径。结合抗肿瘤药物的作用机制以及蒽醌类衍生物的构效关系,设计合成了一类新的蒽醌类衍生物1-硝基-2-酰基蒽醌-缬氨酸(简称C3),发现其具有很好的抗肿瘤活性。为了确定蒽醌类衍生物C3对结肠癌HCT116和HT29细胞的作用及其分子机制,首先通过MTT比色法检测C3对结肠癌HCT116和HT29细胞活性的影响。结果显示,C3对这两种结肠癌细胞具有明显的抑制作用,呈时间和剂量依赖性。60μg/mL的C3处理HCT116和HT29细胞48 h,细胞活性分别是50.67%和59.77%,达到了半抑制浓度;同时,其细胞形态和细胞核发生明显变化。进一步采用Western印迹和qRT-PCR技术,检测C3对DNA切除修复交叉互补1(excision repair cross-complementation group 1,ERCC1)转录水平和蛋白质水平表达及其稳定性的影响。结果表明,C3降低了ERCC1转录水平和蛋白质水平的表达,并且减弱了ERCC1转录水平和蛋白质水平的稳定性。最后,用U0126(MEK1/2抑制剂)和C3联合作用结肠癌HCT116和HT29细胞,通过Western印迹检测ERCC1蛋白质水平的表达。结果表明,C3通过降低p-ERK1/2的蛋白质水平的表达,从而抑制ERCC1的表达。上述结果证明,C3通过细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)信号通路,降低了ERCC1转录水平和蛋白质水平的稳定性,使ERCC1转录水平和蛋白质水平表达发生下调,进而抑制结肠癌HCT116和HT29细胞的活性。     

Decellularized breast matrix as bioactive microenvironment for in vitro three-dimensional cancer culture

Breast cancer (BC) is a leading cause of cancer-related death in women with unsatisfactory survival rates. Advances in the understanding of the genetic basis of BC provide the opportunity to develop gene-based medicines capable of treating metastatic diseases. Here, we first demonstrated efficient tissue engineering approaches applied to normal breast and BC extracellular matrix (ECM) starting from decellularized human biopsies to generate a three-dimensional (3D) bioactive model with the sodium lauryl ether sulfate solution. The decellularized tissues maximized the genetic component removal from tissues and minimally injured ECM structures and native compositions by histology and ECM compositions analyses. Importantly, we proved that the 3D ECM retained tissues biological properties. We demonstrated that after 30 days of recellularization with MCF-7 cell (human breast adenocarcinoma cell line), the 3D cancer ECM induced an overexpression of epithelial–mesenchymal transition (EMT) and cancer proliferation. Meanwhile, normal ECM from the breast inhibited EMT and cell growth with the inducement of apoptosis. Given the biological activity preserved in the ECM after decellularization, we believe these approaches are powerful tools for future preclinical research for BC and breast development.     

Cancer stem cells: implications for the progression and treatment of metastatic disease

Metastasis is the major cause of death for cancer patients with solid tumours, due mainly to the ineffectiveness of current therapies once metastases begin to form. Further insight into the biology of metastasis is therefore essential in order to gain a greater understanding of this process and ultimately to develop better cancer therapies. Metastasis is an inefficient process, such that very few cells that leave a tumour successfully form macrometastases in distant sites. This suggests that only a small subset of cells can successfully navigate the metastatic cascade and eventually re-initiate tumour growth to form life-threatening metastases. Recently, there has been growing support for the cancer stem cell (CSC) hypothesis which stipulates that primary tumours are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. Classical properties of normal stem cells are strikingly reminiscent of the observed experimental and clinical behaviour of metastatic cancer cells, including an unlimited capacity for self renewal; the requirement for a specific 'niche' or microenvironment to grow; use of the stromal cell-derived factor 1 (SDF-1)/chemokine receptor 4 (CXCR4) axis for migration; enhanced resistance to apoptosis and an increased capacity for drug resistance. Therefore, in addition to playing a role in primary tumour formation, we believe that CSCs are also key players in the metastatic process. We will review the current evidence supporting this idea and discuss the potential implications of the CSC hypothesis with regards to experimental investigation and treatment of metastatic disease.     

Hyaluronan in part mediates IL-1beta-induced inflammation in mouse chondrocytes by up-regulating CD44 receptors

Interleukin-1beta (IL-1beta) elicits the expression of inflammatory mediators through a mechanism involving the CD44 receptor. Hyaluronan (HA) depolymerization also contributes to CD44 activation. This study investigated the potential of HA fragments, obtained by hyaluronidase (HYAL) treatment, as mediators of CD44 activation on IL-1beta-induced inflammation in mouse chondrocytes.mRNA and related protein levels were measured for CD44, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in chondrocytes, treated or untreated with IL-1beta, either with or without the addition of HYAL. The level of NF-kB activation was also assayed.CD44 mRNA expression was higher than controls in chondrocytes treated with IL-1beta. IL-1beta also induced NF-kB up-regulation and increased TNF-alpha, IL-6, MMP-13 and iNOS expression. Different effects resulted from HYAL treatment. Treatment of chondrocytes exposed to IL-1beta with HYAL synergistically increased the same parameters up-regulated by IL-1beta, while the same parameters were increased by HYAL in chondrocytes not exposed to IL-1beta but to a lesser extent. Specific CD44 blocking antibody and hyaluronan binding protein (HABP), which inhibit HA activity, were used to confirm CD44 to be the target of IL-1beta action through HA mediation. HA levels and molecular size further confirm the role of degraded HA.These findings suggest that IL-1beta exerts inflammatory activity via CD44 by the mediation of HA fragments derived from HA depolymerization.     

Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting

Maintenance of cell and tissue homeostasis is dependent upon the dynamic balance of cell proliferation, differentiation, and apoptosis through interactions between cells and their microenvironment. The unique prostatic cellular phenotypes are induced and maintained by interaction between epithelium and adjacent stroma through intimate intercellular signaling pathways. In this article, we summarize current advances in the tumor-stroma interaction and its biologic and therapeutic implications. We specifically emphasize current studies of the possible factors driving the "vicious cycle" between stroma and emerging prostate tumor epithelial cells that may be responsible for carcinogenesis and metastasis to bone. Stroma responds both genotypically and phenotypically to tumor epithelium upon co-culture under 3-D conditions. Likewise, the emerging carcinoma responds to stromal signals that drive progression to malignancy. A vicious cycle mediated by soluble and insoluble molecules secreted by tumor cells and stroma appear be the critical factors supporting and sustaining tumor colonization in bone. Co-targeting tumor and stroma with therapeutic agents has yielded promising results both in pre-clinical models of prostate cancer and bony metastasis and in clinical trials of patients treated with a dual tumor and stroma targeting strategies. In conclusion, understanding and targeting the interaction of the tumor and its stromal microenvironmant may improve the prognosis, reduce the suffering and increase the survival of patients with advanced cancer metastasis.     

Regulation of nitric oxide production in snail (Lymnaea stagnalis) defence cells: a role for PKC and ERK signalling pathways

Background information. Nitric oxide (NO) is an important molecule in innate immune responses. In molluscs NO is produced by mobile defence cells called haemocytes; however, the molecular mechanisms that regulate NO production in these cells is poorly understood. The present study focused on the role of cell signalling pathways in NO production by primary haemocytes from the snail Lymnaea stagnalis. Results. When haemocytes were challenged with PMA (10 μM) or the β‐1,3‐glucan laminarin (10 mg/ml), an 8‐fold and 4‐fold increase in NO production were observed after 60 min respectively. Moreover, the NOS (NO synthase) inhibitors L‐NAME (N^G‐nitro‐L‐arginine methyl ester) and L‐NMMA (N^G‐monomethyl‐L‐arginine) were found to block laminarin‐ and PMA‐induced NO synthesis. Treatment of haemocytes with PMA or laminarin also increased the phosphorylation (activation) status of PKC (protein kinase C). When haemocytes were preincubated with PKC inhibitors (calphostin C or GF109203X) or inhibitors of the ERK (extracellular‐signal‐regulated kinase) pathway (PD98059 or U0126) prior to challenge, significant reductions in PKC and ERK phosphorylation and NO production were observed following exposure to laminarin or PMA. The greatest effect on NO production was seen with GF109203X and U0126, with PMA‐induced NO production inhibited by 94% and 87% and laminarin‐induced NO production by 50% and 91% respectively. Conclusions. These data suggest that ERK and PKC comprise part of the signalling machinery that regulates NOS activation and subsequent production of NO in molluscan haemocytes. To our knowledge, this is the first report that shows a role for these signalling proteins in the generation of NO in invertebrate defence cells.     

A Decade of Progress in Targeted Therapy for Advanced Thyroid Cancer: An Overview

A better understanding of the molecular aberrations prevalent in thyroid cancers had led to significant advances in the management of advanced thyroid cancer. The landscape of thyroid cancer treatment has grown rapidly. Molecular profiling is the key to identify actionable targets for treatment of advanced disease. In the past decade, there have been regulatory approvals of 9 kinase inhibitors or kinase inhibitor combinations. There are now drugs approved for all of the different types of thyroid cancers, including anaplastic thyroid cancer. However, these drugs are not curative and therefore new strategies and treatments continue to be sought.     

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Mitogen‐activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal–epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular‐signal‐regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross‐talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase‐2, transforming growth factor‐β, NOTCH and (in particular) with phosphatidylinositol 3‐kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK‐targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre‐evaluation of cancer‐type‐specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.     

AD-1, a novel ginsenoside derivative,shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species

Background

Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug.

Methods

The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice.

Results

AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G₀/G₁ cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger — N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10–40 mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index.

Conclusions and general significance

These data support development of AD-1 as a potential agent for lung cancer therapy.     

Candidate tumour suppressor Fau regulates apoptosis in human cells: An essential role for Bcl-G

FAU, which encodes a ubiquitin-like protein (termed FUBI) with ribosomal protein S30 as a carboxy-terminal extension, has recently been identified as a pro-apoptotic regulatory gene. This activity may be mediated by Bcl-G (a pro-apoptotic member of the Bcl-2 family) which can be covalently modified by FUBI. FAU gene expression has been shown to be down-regulated in human breast, prostate and ovarian tumours, and this down-regulation is strongly associated with poor prognosis in breast cancer. We demonstrate here that ectopic FAU expression increases basal apoptosis in human T-cell lines and 293T/17 cells, whereas it has only a transient stimulatory effect on ultraviolet-C (UVC)-induced apoptosis. Conversely, siRNA-mediated silencing of FAU gene expression has no effect on basal apoptosis, but attenuates UV-induced apoptosis. Importantly, prior knockdown of Bcl-G expression ablates the stimulation of basal apoptosis by FAU, consistent with an essential downstream role for Bcl-G, itself a candidate tumour suppressor, in mediating the apoptosis regulatory role of FAU. In 293T/17 cells, Bcl-G knockdown also attenuates UV-induced apoptosis, so that Bcl-G may constitute a common factor in the pathways by which both FAU and UV-irradiation induce apoptosis. UV irradiation increases Bcl-G mRNA levels, providing an explanation for the transient nature of the effect of ectopic FAU expression on UV-induced apoptosis. Since failure of apoptosis is fundamental to the development of many cancers, the pro-apoptotic activity of the Fau/Bcl-G pathway offers an attractive explanation for the putative tumour suppressor role of FAU.     

Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches

The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed.     

Cartilage tissue engineering: Molecular control of chondrocyte differentiation for proper cartilage matrix reconstruction

Background

Articular cartilage defects are a veritable therapeutic problem because therapeutic options are very scarce. Due to the poor self-regeneration capacity of cartilage, minor cartilage defects often lead to osteoarthritis. Several surgical strategies have been developed to repair damaged cartilage. Autologous chondrocyte implantation (ACI) gives encouraging results, but this cell-based therapy involves a step of chondrocyte expansion in a monolayer, which results in the loss in the differentiated phenotype. Thus, despite improvement in the quality of life for patients, reconstructed cartilage is in fact fibrocartilage. Successful ACI, according to the particular physiology of chondrocytes in vitro, requires active and phenotypically stabilized chondrocytes.

Scope of review

This review describes the unique physiology of cartilage, with the factors involved in its formation, stabilization and degradation. Then, we focus on some of the most recent advances in cell therapy and tissue engineering that open up interesting perspectives for maintaining or obtaining the chondrogenic character of cells in order to treat cartilage lesions.

Major conclusions

Current research involves the use of chondrocytes or progenitor stem cells, associated with “smart” biomaterials and growth factors. Other influential factors, such as cell sources, oxygen pressure and mechanical strain are considered, as are recent developments in gene therapy to control the chondrocyte differentiation/dedifferentiation process.

General significance

This review provides new information on the mechanisms regulating the state of differentiation of chondrocytes and the chondrogenesis of mesenchymal stem cells that will lead to the development of new restorative cell therapy approaches in humans. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.     

Cell polarization: From epithelial cells to odontoblasts

Cell polarity identifies the asymmetry of a cell. Various types of cells, including odontoblasts and epithelial cells, polarize to fulfil their destined functions. Odontoblast polarization is a prerequisite and fundamental step for tooth development and tubular dentin formation. Current knowledge of odontoblast polarization, however, is very limited, which greatly impedes the development of novel approaches for regenerative endodontics. Compared to odontoblasts, epithelial cell polarization has been extensively studied over the last several decades. The knowledge obtained from epithelia polarization has been found applicable to other cell types, which is particularly useful considering the remarkable similarities of the morphological and compositional features between polarized odontoblasts and epithelia. In this review, we first discuss the characteristics, the key regulatory factors, and the process of epithelial polarity. Next, we compare the known facts of odontoblast polarization with epithelial cells. Lastly, we clarify knowledge gaps in odontoblast polarization and propose the directions for future research to fill the gaps, leading to the advancement of regenerative endodontics.     

Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy

Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis.     

Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway?

The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.