Discovery Of Novel Molecular Targets Research Articles

Potato psyllids mount distinct gut responses against two different 'Candidatus Liberibacter solanacearum' haplotypes.

'Candidatus Liberibacter solanacearum' (Lso) is a bacterial pathogen infecting several crops and causing damaging diseases. Several Lso haplotypes have been identified. Among the seven haplotypes present in North America, LsoA and LsoB are transmitted by the potato psyllid, Bactericera cockerelli (Šulc), in a circulative and persistent manner. The gut, which is the first organ pathogen encounters, could be a barrier for Lso transmission. However, the molecular interactions between Lso and the psyllid vector at the gut interface remain largely unknown. In this study, we investigated the global transcriptional responses of the adult psyllid gut upon infection with two Lso haplotypes (LsoA and LsoB) using Illumina sequencing. The results showed that each haplotype triggers a unique transcriptional response, with most of the distinct genes elicited by the highly virulent LsoB. The differentially expressed genes were mainly associated with digestion and metabolism, stress response, immunity, detoxification as well as cell proliferation and epithelium renewal. Importantly, distinct immune pathways were triggered by LsoA and LsoB in the gut of the potato psyllid. The information in this study will provide an understanding of the molecular basis of the interactions between the potato psyllid gut and Lso, which may lead to the discovery of novel molecular targets for the control of these pathogens.

3D geometry orchestrates the transcriptional landscape of metastatic neuroblastoma cells in a multicellular in vitro bone model.

A key challenge for the discovery of novel molecular targets and therapeutics against pediatric bone metastatic disease is the lack of bona fide in vitro cell models. Here, we show that a beta-tricalcium phosphate (β-TCP) multicellular 3D in vitro bone microtissue model reconstitutes key phenotypic and transcriptional patterns of native metastatic tumor cells while promoting their stemness and proinvasive features. Comparing planar with interconnected channeled scaffolds, we identified geometry as a dominant orchestrator of proangiogenic traits in neuroblastoma tumor cells. On the other hand, the β-TCP-determined gene signature was DNA replication related. Jointly, the geometry and chemical impact of β-TCP revealed a prometastatic landscape of the engineered tumor microenvironment. The proposed 3D multicellular in vitro model of pediatric bone metastatic disease may advance further analysis of the molecular, genetic and metabolic bases of the disease and allow more efficient preclinical target validations.

A Review on Formulation and Evaluation of Nanoniosomal Topical gel of Paclitaxel for skin cancer

Cancer is the second leading cause of death in the world and one of the major public health problems. Despite the great advances in cancer therapy, the incidence and mortality rates of cancer remain high. Therefore, the goal for more efficient and less toxic cancer treatment strategies is still at the forefront of current research. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Paclitaxel (PCT) is a chemotherapeutic agent used as a first-line treatment for a wide range of cancers, such as lung, ovarian, breast, prostate, head, and neck cancers, and AIDS-related Kaposi sarcoma. Currently, the marketed forms of Paclitaxel are intravenous formulations. Oral administration of Paclitaxel is unfortunately hampered due to its low bioavailability. This is explained by its low aqueous solubility, low permeability, high affinity for cytochrome P450 and P-glycoprotein. As another approach, drug carrier systems are extensively studied to enhance oral Paclitaxel bioavailability and reduce side effects. The niosomes provides several important advantages over conventional drug therapy. Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non-ionic surface-active agents rather than phospholipids as seen in case of liposomes. Niosome nanoparticles are among these drug delivery systems, which have numerous applications in drug delivery and targeting. Niosomes are frequently used for loading drugs serving different purposes (e.g., anticancer, antiviral, and antibacterial agents). The aim of this review is to evaluate the extent of nanotherapeutics used in anti-cancer activity.

Cancer Recurrence and Omics: Metabolic Signatures of Cancer Dormancy Revealed by Transcriptome Mapping of Genome-Scale Networks.

A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular.

Monitoring Mitochondrial Morphology and Respiration in Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (DOX)-induced cardiomyopathy constitutes dose-dependent cardiac toxicity, culminating in fatal heart failure progression. Cardiac toxicity limits effective and subsequent use of DOX in chemotherapy regimens in pediatric, adult, and recurrent cancer patients. DOX-induced profound alterations in mitochondrial morphology, dynamics, and defects in mitochondrial energy metabolism in the heart comprise key stressors in DOX-induced cardiotoxicity. Hence, the discovery of novel molecular targets and therapeutics to mitigate DOX-induced mitochondrial dysfunctions are imperative. Herein, we provided two laboratory protocols to monitor DOX-induced alterations in mitochondrial morphology and respiration in isolated primary neonatal rat cardiomyocytes. Neonatal rat cardiomyocytes are extensively used to monitor signaling mechanisms regulating cardiomyopathy in vitro. Therefore, these protocols will help researchers study the effects of novel pharmacological and genetic manipulations against DOX-induced alterations in mitochondrial morphology and energy metabolism in cardiomyocytes.

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance.

To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of anti-tumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

Corn Stunt Disease: An Ideal Insect-Microbial-Plant Pathosystem for Comprehensive Studies of Vector-Borne Plant Diseases of Corn.

Over 700 plant diseases identified as vector-borne negatively impact plant health and food security globally. The pest control of vector-borne diseases in agricultural settings is in urgent need of more effective tools. Ongoing research in genetics, molecular biology, physiology, and vector behavior has begun to unravel new insights into the transmission of phytopathogens by their insect vectors. However, the intricate mechanisms involved in phytopathogen transmission for certain pathosystems warrant further investigation. In this review, we propose the corn stunt pathosystem (Zea mays–Spiroplasma kunkelii–Dalbulus maidis) as an ideal model for dissecting the molecular determinants and mechanisms underpinning the persistent transmission of a mollicute by its specialist insect vector to an economically important monocotyledonous crop. Corn stunt is the most important disease of corn in the Americas and the Caribbean, where it causes the severe stunting of corn plants and can result in up to 100% yield loss. A comprehensive study of the corn stunt disease system will pave the way for the discovery of novel molecular targets for genetic pest control targeting either the insect vector or the phytopathogen.

Mapping Keratoconus Molecular Substrates by Multiplexed High-Resolution Proteomics of Unpooled Corneas.

Keratoconus (KCN) is a leading cause for cornea grafting worldwide. Keratoconus is a multifactorial disease that causes progressive thinning of the cornea and whose etiology is poorly understood. Several studies have used proteomics on patient tear fluids to identify potential biomarkers. However, proteome of the cornea itself has not been investigated fully. We report here new findings from a case-control study using multiplexed mass spectrometry (MS) on individual (unpooled) corneas to gain deeper insights into proteins and biomarkers relevant to keratoconus. We employed a high-pressure approach to extract total protein from individual corneas from five cases and five controls, followed by trypsin digestion and tandem mass tag (TMT) labeling. The MS-derived data were searched using the Human NCBI RefSeq protein database v92, with peptides and proteins filtered at 1% false discovery rate. A total of 3132 proteins were detected, of which 627 were altered significantly (p ≤ 0.05) in keratoconus corneas. The increases were overwhelmingly in the mTOR/PI3/AKT signal-mediated regulations of cell survival and proliferation, nonsense-mediated decay of transcripts, and proteasomal pathways. The decreases were in several extracellular matrix proteins and in many members of the complement system. Importantly, this multiplexed proteomic study of keratoconus corneas identified, to our knowledge, the largest number of corneal proteins. The novel findings include changes in pathways that regulate transcript stability, proteasomal degradation, and the complement system in corneas with keratoconus. These observations offer new prospects toward future discovery of novel molecular targets for diagnostic and therapeutic innovations for patients with keratoconus.

Do Perineuronal Net Elements Contribute to Pathophysiology of Spinal Muscular Atrophy? In Vitro and Transcriptomics Insights.

Spinal muscular atrophy (SMA) is one of the most common childhood onset neurodegenerative disorders in global health whereby novel biomarkers and therapeutic targets are sorely needed. SMA is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons in the brain stem and spinal cord that leads to mortality in infants worldwide. In majority of the patients, SMA is caused by homozygous deletion of the SMN1 gene. The clinical spectrum of the SMA displays, however, large person-to-person variations where the underlying mechanisms are poorly understood. We report in this study transcriptomics insights gleaned from patients with the severe type I (GM03813 and GM09677) and the mild type III. Pathway enrichment and functional analysis showed that especially extracellular matrix (ECM), synapse organization, and ECM receptor interaction pathways were affected. Among the neural ECM components, hyaluronan and proteoglycan link protein (HAPLN1), which is a key triggering molecule of the perineuronal net (PNN), was significantly downregulated in type I fibroblasts compared to type III. PNN is a specialized form of neural ECM around the neuronal cell bodies and dendrites in the central nervous system. In addition, we evaluated the PNN expression in vitro in a model established by SMN silencing in the PC12 rat pheochromocytoma cell line which can be differentiated into neurons with nerve growth factor treatment. In this neuronal in vitro model, we found that HAPLN1 showed a significant 50% decrease. Our results describe the association between PNN elements, especially HAPLN1, and SMA pathophysiology for the first time. These observations collectively inform future translational research on SMA for discovery of novel molecular targets for diagnostics and precision medicine innovation.

Emerging Molecular Targets for Anti-Cancer Drug Design

Background: Interest in targeting metabolism as a viable cancer therapy has been revived in last decade. This has significantly contributed to the understanding of the altered metabolic profile of proliferating cancer cells. Clinically launched target specific drugs have shown encouraging results in terms of both efficacy and safety than conventional anticancer drugs. Objective: Targeted approaches have significantly changed the treatment of cancer and substantially improved life expectancy of cancer patients. Moreover, the continual discovery of novel molecular targets against various cancer subtypes (lung, breast, colon, prostate, pancreatic cancer etc.) has enabled early diagnosis and treatment of patients against this dreadful disease. Identification of novel cancer biomarkers may aid in the development of new anti-cancer therapies and treatment strategies. Conclusion: Molecular mechanism and clinical efficacy of some of the emerging molecular targets for cancer chemotherapy have been briefly reviewed in the present article. Keywords: Cancer therapy, molecular targets, anti-cancer agents, oncogenes, drug design, novel molecular target.

Recent Advances and Perspectives in Cancer Drug Design.

Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Several noteworthy advances have been made, among which the development of targeted therapies is the most significant. Monoclonal antibodies and antibody-small molecule conjugates have emerged as a worthwhile approach to improve drug selectivity and reduce adverse effects, which are the main challenges in cancer drug discovery. This review will examine the current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years. Breakthrough discoveries will be highlighted along with the medicinal chemistry strategies used throughout the discovery process. In addition, this review will provide perspectives and updates on the discovery of novel molecular targets as well as drugs with innovative mechanisms of action.

OMICS, Oral Cancer Molecular Landscapes, and Clinical Practice

Molecular pathogenesis of oral cancers continues to be researched by omics systems science biotechnologies. Oral cancers rank as the 13th most common cancer globally. Notably, the burden of oral cancers from the Asian continent is 56.21%, with 26% of the burden contributed by India. Despite easy accessibility of the oral cavity and hence early detection of oral cancers, majority are diagnosed in advanced stages in the Asian countries. Innovation in oral cancer diagnostics, as well as theranostics for precision medicine, would aid their early diagnosis, prognosis, and treatment, not to mention discovery of novel molecular targets for drug development. This expert review offers an analysis of oral cancer biomarkers, including somatic mutations, deregulated expression, epigenetic regulation, and genomic variants associated with oral cancer. We also discuss the implications of the current and emerging oral cancer biomarkers with a view to clinical practice, global health, and make suggestions for the ways forward.

Basal Tumor Cell Isolation and Patient-Derived Xenograft Engraftment Identify High-Risk Clinical Bladder Cancers.

Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy

Natural products and their derivatives represent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds (BA-TPQ, TBA-TPQ, and TCBA-TPQ) has been accomplished and the mechanisms of action (MOA) and structure-activity relationships (SAR) have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids (unrelated to inhibition of Topoisomerase II) warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of in vitro and in vivo anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

Emerging Microtubule Targets in Glioma Therapy

Major advances in the genomics and epigenomics of diffuse gliomas and glioblastoma to date have not been translated into effective therapy, necessitating pursuit of alternative treatment approaches for these therapeutically challenging tumors. Current knowledge of microtubules in cancer and the development of new microtubule-based treatment strategies for high-grade gliomas are the topic in this review article. Discussed are cellular, molecular, and pharmacologic aspects of the microtubule cytoskeleton underlying mitosis and interactions with other cellular partners involved in cell cycle progression, directional cell migration, and tumor invasion. Special focus is placed on (1) the aberrant overexpression of βIII-tubulin, a survival factor associated with hypoxic tumor microenvironment and dynamic instability of microtubules; (2) the ectopic overexpression of γ-tubulin, which in addition to its conventional role as a microtubule-nucleating protein has recently emerged as a transcription factor interacting with oncogenes and kinases; (3) the microtubule-severing ATPase spastin and its emerging role in cell motility of glioblastoma cells; and (4) the modulating role of posttranslational modifications of tubulin in the context of interaction of microtubules with motor proteins. Specific antineoplastic strategies discussed include downregulation of targeted molecules aimed at achieving a sensitization effect on currently used mainstay therapies. The potential role of new classes of tubulin-binding agents and ATPase inhibitors is also examined. Understanding the cellular and molecular mechanisms underpinning the distinct behaviors of microtubules in glioma tumorigenesis and drug resistance is key to the discovery of novel molecular targets that will fundamentally change the prognostic outlook of patients with diffuse high-grade gliomas.

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-XL is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-XL inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-XL. In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/slow-proliferating LCSC strongly depend on Bcl-XL for their survival and indicate Bcl-XL inhibition as a potential therapeutic avenue in NSCLC.

The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker.

Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited. Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n = 17) and non-healing (NH, n = 11) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out. Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of human SERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabetic mice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement. We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabetic patients.

Analysis of Molecular Networks Uncovers Potential Targets in Vestibular Schwannoma

Objective: Understanding molecular pathway mechanisms of the formation of vestibular schwannoma may lead to potential therapeutic targets. Study Design: We performed gene expression profiling of 49 schwannomas (36 sporadic and 13 NF2-associated cases) and 7 normal control vestibular nerves. Results: We identified over 4,000 differentially expressed genes between control and schwannoma with network analysis uncovering proliferation and antiapoptotic pathways previously not implicated in vestibular schwannomas. Using several distinct clustering technologies, we could not reproducibly identify subtypes of schwannomas suggesting that our schwannoma cohort was molecularly distinct from normal tissue yet highly similar among themselves. At the molecular level the PI3K/AKT/mTOR signaling network was overexpressed in our schwannoma cohort and evaluated for therapeutic targeting. Testing compounds BEZ235 and PKI-587 both novel dual inhibitors of PI3K and mTOR attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that ablation of the PI3K/AKT/mTOR pathway with next generation inhibitors lead to decreased cell viability and increased cell death. Conclusion: The discovery of novel molecular targets in vestibular schwannoma by transcriptional profiling as compared with appropriate controls may lead to effective therapeutic strategies and shed insight into the molecular ontogeny of this tumor.

Phage display discovery of novel molecular targets in glioblastoma-initiating cells.

Glioblastoma is the most common primary intrinsic brain tumor and remains incurable despite maximal therapy. Glioblastomas display cellular hierarchies with self-renewing glioma-initiating cells (GICs) at the apex. To discover new GIC targets, we used in vivo delivery of phage display technology to screen for molecules selectively binding GICs that may be amenable for targeting. Phage display leverages large, diverse peptide libraries to identify interactions with molecules in their native conformation. We delivered a bacteriophage peptide library intravenously to a glioblastoma xenograft in vivo then derived GICs. Phage peptides bound to GICs were analyzed for their corresponding proteins and ranked based on prognostic value, identifying VAV3, a Rho guanine exchange factor involved tumor invasion, and CD97 (cluster of differentiation marker 97), an adhesion G-protein-coupled-receptor upstream of Rho, as potentially enriched in GICs. We confirmed that both VAV3 and CD97 were preferentially expressed by tumor cells expressing GIC markers. VAV3 expression correlated with increased activity of its downstream mediator, Rac1 (ras-related C3 botulinum toxin substrate 1), in GICs. Furthermore, targeting VAV3 by ribonucleic acid interference decreased GIC growth, migration, invasion and in vivo tumorigenesis. As CD97 is a cell surface protein, CD97 selection enriched for sphere formation, a surrogate of self-renewal. In silico analysis demonstrated VAV3 and CD97 are highly expressed in tumors and inform poor survival and tumor grade, and more common with epidermal growth factor receptor mutations. Finally, a VAV3 peptide sequence identified on phage display specifically internalized into GICs. These results show a novel screening method for identifying oncogenic pathways preferentially activated within the tumor hierarchy, offering a new strategy for developing glioblastoma therapies.

Tumor microenviroment and hepatocellular carcinoma metastasis

The cross talk between tumor cells and the surrounding peritumoral stroma has been extensively studied as a dynamic system involving the processes of hepatocarcinogenesis, tumor invasion, and metastasis in recent few decades. Besides hepatocytes, liver tumor microenvironments are generally classified into cellular and noncellular components, including hepatic stellate cells, fibroblasts, immune, endothelial, mesenchymal stem cells, together with growth factors, cytokines, extracellular matrix, hormone as well as viruses et al. The noncellular components manipulate hepatocellular carcinoma invasion and metastasis by facilitating epithelial-mesenchymal transition, increasing proteolytic activity of matrix metalloproteinases, and regulating antitumor immunity, etc. Because the main cause of death in hepatocellular carcinoma patients is tumor progression with metastasis, a better understanding of the interplay between hepatocytes and their environment during tumor metastasis may be helpful for the discovery of novel molecular targets.