Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: MERTK (cancer-related)
Duan Y, Luo L, Qiao C, et al.A novel human anti-AXL monoclonal antibody attenuates tumour cell migration.
Scand J Immunol. 2019; 90(2):e12777 [PubMed
] Related Publications
TAM family members (TYRO3, AXL and MERTK) play essential roles in the resolution of inflammation and in infectious diseases and cancer. AXL, a tyrosine kinase receptor, is commonly overexpressed in several solid tumours and numerous hematopoietic malignancies including acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia, chronic lymphocytic leukaemia and multiple myeloma. AXL significantly promotes tumour cell migration, invasion and metastasis, as well as angiogenesis. AXL also plays an important role in inflammation and macrophage ontogeny. Recent studies have revealed that AXL contributes to leukaemic phenotypes through activation of oncogenic signalling pathways that lead to increased cell migration and proliferation. To evaluate the mechanisms underlying the role of AXL signalling in tumour metastasis, we screened a phage display library to generate a novel human monoclonal antibody, named DAXL-88, that recognizes both human and murine AXL. The concentrations of DAXL-88 required for 50% maximal binding to human and murine AXL were 0.118 and 0.164 μg/mL, respectively. Furthermore, DAXL-88 bound to human AXL with high affinity (K
Natural killer (NK) cells have increasingly become a target of interest for immunotherapies. NK cells express killer immunoglobulin-like receptors (KIRs), which play a vital role in immune response to tumors by detecting cellular abnormalities. The genomic region encoding the 16 KIR genes displays high polymorphic variability in human populations, making it difficult to resolve individual genotypes based on next generation sequencing data. As a result, the impact of polymorphic KIR variation on cancer phenotypes has been understudied. Currently, labor-intensive, experimental techniques are used to determine an individual's KIR gene copy number profile. Here, we develop an algorithm to determine the germline copy number of KIR genes from whole exome sequencing data and apply it to a cohort of nearly 5000 cancer patients. We use a k-mer based approach to capture sequences unique to specific genes, count their occurrences in the set of reads derived from an individual and compare the individual's k-mer distribution to that of the population. Copy number results demonstrate high concordance with population copy number expectations. Our method reveals that the burden of inhibitory KIR genes is associated with survival in two tumor types, highlighting the potential importance of KIR variation in understanding tumor development and response to immunotherapy.
Panossian A, Seo EJ, Efferth TNovel molecular mechanisms for the adaptogenic effects of herbal extracts on isolated brain cells using systems biology.
Phytomedicine. 2018; 50:257-284 [PubMed
] Related Publications
INTRODUCTION: Adaptogens are natural compounds or plant extracts that increase adaptability and survival of organisms under stress. Adaptogens stimulate cellular and organismal defense systems by activating intracellular and extracellular signaling pathways and expression of stress-activated proteins and neuropeptides. The effects adaptogens on mediators of adaptive stress response and longevity signaling pathways have been reported, but their stress-protective mechanisms are still not fully understood.
AIM OF THE STUDY: The aim of this study was to identify key molecular mechanisms of adaptogenic plants traditionally used to treat stress and aging-related disorders, i.e., Rhodiola rosea, Eleutherococcus senticosus, Withania somnifera, Rhaponticum carthamoides, and Bryonia alba.
MATERIALS AND METHODS: To investigate the underlying molecular mechanisms of adaptogens, we conducted RNA sequencing to profile gene expression alterations in T98G neuroglia cells upon treatment of adaptogens and analyzed the relevance of deregulated genes to adaptive stress-response signaling pathways using in silico pathway analysis software.
RESULTS AND DISCUSSION: At least 88 of the 3516 genes regulated by adaptogens were closely associated with adaptive stress response and adaptive stress-response signaling pathways (ASRSPs), including neuronal signaling related to corticotropin-releasing hormone, cAMP-mediated, protein kinase A, and CREB; pathways related to signaling involving CXCR4, melatonin, nitric oxide synthase, GP6, Gαs, MAPK, neuroinflammation, neuropathic pain, opioids, renin-angiotensin, AMPK, calcium, and synapses; and pathways associated with dendritic cell maturation and G-coupled protein receptor-mediated nutrient sensing in enteroendocrine cells. All samples tested showed significant effects on the expression of genes encoding neurohormones CRH, GNRH, UCN, G-protein-coupled and other transmembrane receptors TLR9, PRLR, CHRNE, GP1BA, PLXNA4, a ligand-dependent nuclear receptor RORA, transmembrane channels, transcription regulators FOS, FOXO6, SCX, STAT5A, ZFPM2, ZNF396, ZNF467, protein kinases MAPK10, MAPK13, MERTK, FLT1, PRKCH, ROS1, TTN), phosphatases PTPRD, PTPRR, peptidases, metabolic enzymes, a chaperone (HSPA6), and other proteins, all of which modulate numerous life processes, playing key roles in several canonical pathways involved in defense response and regulation of homeostasis in organisms. It is for the first time we report that the molecular mechanism of actions of melatonin and plant adaptogens are alike, all adaptogens tested activated the melatonin signaling pathway by acting through two G-protein-coupled membrane receptors MT1 and MT2 and upregulation of the ligand-specific nuclear receptor RORA, which plays a role in intellectual disability, neurological disorders, retinopathy, hypertension, dyslipidemia, and cancer, which are common in aging. Furthermore, melatonin activated adaptive signaling pathways and upregulated expression of UCN, GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2, RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10, MERTK, PRKCH, and TTN, which were commonly regulated by all adaptogens tested. We conclude that melatonin is an adaptation hormone playing an important role in regulation of homeostasis. Adaptogens presumably worked as eustressors ("stress-vaccines") to activate the cellular adaptive system by inducing the expression of ASRSPs, which then reciprocally protected cells from damage caused by distress. Functional investigation by interactive pathways analysis demonstrated that adaptogens activated ASRSPs associated with stress-induced and aging-related disorders such as chronic inflammation, cardiovascular health, neurodegenerative cognitive impairment, metabolic disorders, and cancer.
CONCLUSION: This study has elucidated the genome-wide effects of several adaptogenic herbal extracts in brain cells culture. These data highlight the consistent activation of ASRSPs by adaptogens in T98G neuroglia cells. The extracts affected many genes playing key roles in modulation of adaptive homeostasis, indicating their ability to modify gene expression to prevent stress-induced and aging-related disorders. Overall, this study provides a comprehensive look at the molecular mechanisms by which adaptogens exerts stress-protective effects.
Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35-60 years) carrying this mutation. The remaining four members (6-23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.
BACKGROUND: Although membrane-associated estrogen receptors (mERs) have been known to play important role in steroid-induced signal transmission, we still know little about their function in the estrogen-induced proliferation of breast cancer cells.
METHODS: In our current work we tried to separate membrane-initiated estrogen receptor signaling from the overall estrogenic effect in MCF-7 breast carcinoma cells. Re-analyzing expression data from multiple microarray experiments, we selected a set of key regulatory genes involved in proliferation regulation and estrogen signaling to monitor estrogen-induced transcription changes. We then compared these expression changes after 17β-estradiol and a membrane receptor selective estrogen-BSA treatment using quantitative real-time PCR. In order to follow receptor trafficking we used light and electron microscopy.
RESULTS: Our quantitative real-time PCR results confirmed that the selective membrane receptor agonist, estrogen-BSA induces similarly pronounced expression changes regarding these genes as 17β-estradiol. Morphological study revealed that the membrane-bound form of classical estrogen receptor alpha is internalized after ligand binding via dynamin-dependent, caveola-mediated endocytosis. Inhibition of this internalization with dynamin inhibitor, dynasore practically abolished the regulatory effect of E2-BSA, suggesting that interaction and internalization with the scaffold protein is necessary for effective signaling.
CONCLUSIONS: The physiological role of plasma membrane estrogen receptor alpha is intensively studied, yet there are still several aspects of it to be resolved. The dynamin-dependent, ligand-mediated internalization of mERs seems to play an important role in estrogen signaling. Our results may serve as another example of how membrane initiated estrogen signaling and nuclear receptor initiated signaling overlap and form an intertwined system.
VandenBoom T, Quan VL, Zhang B, et al.Genomic Fusions in Pigmented Spindle Cell Nevus of Reed.
Am J Surg Pathol. 2018; 42(8):1042-1051 [PubMed
] Related Publications
Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. However, to date, there is little data in the literature focused on the molecular characterization of PSCN of Reed with next-generation sequencing. We analyzed a total of 129 melanocytic neoplasms with RNA sequencing including 67 spitzoid neoplasms (10 Spitz nevi, 44 atypical Spitz tumors, 13 spitzoid melanomas) and 23 PSCN of Reed. Although only 2 of 67 (3.0%) of spitzoid lesions had NTRK3 fusions, 13 of 23 (57%) of PSCN of Reed harbored NTRK3 fusions with 5' partners ETV6 (12p13) in 2 cases and MYO5A (15q21) in 11 cases. NTRK3 fusions were confirmed with a fluorescent in situ hybridization break-apart probe. The presence of a NTRK3 fusion correlated with younger age (P=0.021) and adnexal extension (P=0.001). Other minor fusions identified in PSCN of Reed included MYO5A-MERTK (2), MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3 leading to a total of 78% with fusions. Our study suggests that the majority of PSCN of Reed are the result of genomic fusions, and the most frequent and characteristic genomic aberration is an NTRK3 fusion.
Berning P, Schaefer C, Clemens D, et al.The CXCR4 antagonist plerixafor (AMD3100) promotes proliferation of Ewing sarcoma cell lines in vitro and activates receptor tyrosine kinase signaling.
Cell Commun Signal. 2018; 16(1):21 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: The CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine - receptor interaction between neoplastic cells and their microenvironment in tumor progression and metastasis. Here, we investigated plerixafor for anti-cancer activity in Ewing sarcoma, a rare and aggressive cancer of bone and soft tissues.
METHODS: We used a variety of methods such as cell viability and migration assays, flow cytometry, phospho-tyrosine arrays and western blotting to determine plerixafor effects on five characterized Ewing sarcoma cell lines and a low-passage culture in vitro.
RESULTS: Unexpectedly, plerixafor led to an increase in cell viability and proliferation in standard cell growth conditions, and to chemotactic migration towards plerixafor. Exploring potential molecular mechanisms underlying this effect, we found that Ewing sarcoma cell lines divided into classes of high- and low-level CXCR4 surface expression. Proliferative plerixafor responses were observed in both groups, maintained despite significant CXCR4 down-regulation or inhibition of Gαi-protein signal transduction, and involved activation of multiple receptor tyrosine kinases (DDR2, MERTK, MST1R, NTRK1, RET), the most prominent being platelet-derived growth factor receptor beta (PDGFRB). PDGFRB was activated in response to inhibition of the CXCL12-CXCR4 axis by plerixafor and/or pertussis toxin (Gαi-protein inhibitor). Dasatinib, a multi-kinase inhibitor of both PDGFRB and the CXCR4 downstream kinase SRC, counteracted this activation in some but not all cell lines.
CONCLUSION: These data suggest a feedback interaction between the CXCR4 chemokine receptor and RTK signaling cascades that elicits compensatory cell survival signaling and can shift the net effect of plerixafor towards proliferation. PDGFRB was identified as a candidate driver RTK and potential therapeutic co-target for CXCR4 in Ewing sarcoma. Although as yet limited to in vitro studies, these findings call for further investigation in the cancer - microenvironment interplay in vivo.
The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a
Yeom S, Jeong H, Kim SS, Jang KLHepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication.
J Gen Virol. 2018; 99(5):655-666 [PubMed
] Related Publications
Proteasomal activator gamma (PA28γ), frequently overexpressed in hepatocellular carcinoma, is believed to play important roles in tumourigenesis. However, the underlying mechanism of PA28γ overexpression and its possible roles in hepatitis B virus (HBV) replication are largely unknown. In the present study, we found that hepatitis B virus X protein (HBx) activates PA28γ expression by upregulating p53 levels in human hepatoma cells. The elevated PA28γ levels in turn repressed seven in absentia homologue 1 expression via downregulation of p53 levels, thereby inhibiting ubiquitin-dependent proteasomal degradation of HBx, which ultimately led to upregulation of HBx levels. The correlation among HBx, p53 and PA28γ was exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, knockdown of either p53 or PA28γ in HepG2 cells downregulated HBx levels and thereby inhibited HBV replication, whereas overexpression of p53 or PA28γ in Hep3B cells upregulated HBx levels, which stimulated HBV replication, indicating that p53 and PA28γ act as activators of HBV replication. In conclusion, HBx levels are upregulated via a positive feedback loop involving p53 and PA28γ to stimulate HBV propagation.
Eom H, Kaushik N, Yoo KC, et al.MerTK mediates STAT3-KRAS/SRC-signaling axis for glioma stem cell maintenance.
Artif Cells Nanomed Biotechnol. 2018; 46(sup2):87-95 [PubMed
] Related Publications
Receptor tyrosine kinase Mer (MerTK) has been shown to be highly expressed in Glioblastoma multiforme (GBM) in comparison to its healthy counterpart and is implicated in brain tumorigenesis. Clarifying the underlying mechanism of MerTK induced invasiveness would result in novel strategies to improve patient's response to chemotherapeutics. In vitro and in vivo assays were performed to examine the functional role of cancer stem sell (CSC) maintenance in MerTK associated invasiveness. In this article, we demonstrate that apart from GBM cells, MerTK is also upregulated in GBM stem-like cells and associated with an increased infiltrative potential of brain tumors in vivo. Silencing of MerTK suppressed the self-renewal of patient-derived GBM stem-like cells. The signaling mechanisms by which MerTK contributes to CSC maintenance have largely been obscure. Molecular analyses revealed that high expression of the signal transducer and activator of transcription 3 (STAT3)- Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene tyrosine-protein kinase SRC axis supports MerTK-induced CSC maintenance in GBM spheroids. Furthermore, a short-hairpin RNA-mediated MerTK knockdown effectively blocked invasiveness and N-cadherin expression in mouse xenografts. Collectively, our results uncover a critical function of MerTK in CSC maintenance. Considering the low basal level of MerTK expression in healthy brain cells, evaluation of MerTK as a therapeutic target should advance the research into better therapeutics for GBM.
Shen Y, Chen X, He J, et al.Axl inhibitors as novel cancer therapeutic agents.
Life Sci. 2018; 198:99-111 [PubMed
] Related Publications
Overexpression and activation of Axl receptor tyrosine kinase have been widely accepted to promote cell proliferation, chemotherapy resistance, invasion, and metastasis in several human cancers, such as lung, breast, and pancreatic cancers. Axl, a member of the TAM (Tyro3, Axl, Mer) family, and its inhibitors can specifically break the kinase signaling nodes, allowing advanced patients to regain drug sensitivity with improved therapeutic efficacy. Therefore, the research on Axl is promising and it is worthy of further investigations. In this review, we present an update on the Axl inhibitors and provide new insights into their latent application.
Growth arrest-specific 6, also known as Gas6, is a human gene encoding the Gas6 protein, which was originally found to be upregulated in growth-arrested fibroblasts. Gas6 is a member of the vitamin K-dependent family of proteins expressed in many human tissues and regulates several biological processes in cells, including proliferation, survival and migration, by binding to its receptors Tyro3, Axl and Mer (TAM). In recent years, the roles of Gas6/TAM signalling in cancer cells and the tumour microenvironment have been studied, and some progress has made in targeted therapy, providing new potential directions for future investigations of cancer treatment. In this review, we introduce the Gas6 and TAM receptors and describe their involvement in different cancers and discuss the roles of Gas6 in cancer cells, the tumour microenvironment and metastasis. Finally, we introduce recent studies on Gas6/TAM targeting in cancer therapy, which will assist in the experimental design of future analyses and increase the potential use of Gas6 as a therapeutic target for cancer.
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models. CFI-402257 induced apoptosis and potentiated aneuploidy in TNBC lines by accelerating progression through mitosis and inducing mitotic segregation errors. We used genome-wide CRISPR/Cas9 screens in multiple TNBC cell lines to identify mechanisms of resistance to CFI-402257. Our functional genomic screens identified members of the anaphase-promoting complex/cyclosome (APC/C) complex, which promotes mitotic progression following inactivation of the SAC. Several screen candidates were validated to confer resistance to CFI-402257 and other TTKis using CRISPR/Cas9 and siRNA methods. These findings extend the observation that impairment of the APC/C enables cells to tolerate genomic instability caused by SAC inactivation, and support the notion that a measure of APC/C function could predict the response to TTK inhibition. Indeed, an APC/C gene expression signature is significantly associated with CFI-402257 response in breast and lung adenocarcinoma cell line panels. This expression signature, along with somatic alterations in genes involved in mitotic progression, represent potential biomarkers that could be evaluated in ongoing clinical trials of CFI-402257 or other TTKis.
Oji Y, Inoue M, Takeda Y, et al.WT1 peptide-based immunotherapy for advanced thymic epithelial malignancies.
Int J Cancer. 2018; 142(11):2375-2382 [PubMed
] Related Publications
Thymic epithelial tumors are rare malignancies, and no optimal therapeutic regimen has been defined for patients with advanced disease. Patients with advanced thymic epithelial tumors, which were resistant or intolerable to prior therapies, were eligible for this study. Patients received 9 mer-WT1-derived peptide emulsified with Montanide ISA51 adjuvant via intradermal administration once a week as a monotherapy. After the 3-month-protocol treatment, the treatment was continued mostly at intervals of 2-4 weeks until disease progression or intolerable adverse events occurred. Of the 15 patients enrolled, 11 had thymic carcinoma (TC) and 4 had invasive thymoma (IT). Median period from diagnosis to the start of treatment was 13.3 and 65.5 months for TC and IT, respectively. No patients achieved a complete or partial response. Of the 8 evaluable TC patients, 6 (75.0%) had stable disease (SD) and 2 had progressive disease (PD). Of the 4 evaluable IT patients, 3 (75.0%) had SD and 1 (25.0%) had PD. Median period of monotherapy treatment was 133 and 683 days in TC and IT patients, respectively. No severe adverse events occurred during the 3-month-protocol treatment. As adverse events in long responders, thymoma-related autoimmune complications, pure red cell aplasia and myasthenia gravis occurred in two IT patients. Cerebellar hemorrhage developed in a TC patient complicated with Von Willebrand disease. Induction of WT1-specific immune responses was observed in the majority of the patients. WT1 peptide vaccine immunotherapy may have antitumor potential against thymic malignancies.
Koda Y, Itoh M, Tohda SEffects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells.
Anticancer Res. 2018; 38(1):199-204 [PubMed
] Related Publications
BACKGROUND: MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase that affects cancer cell proliferation. This study evaluated the effects of the synthetic MERTK inhibitors UNC569 and UNC1062 on in vitro growth of acute myeloid leukaemia (AML) cells.
MATERIALS AND METHODS: Four AML cell lines expressing MERTK were treated with UNC569 and UNC1062 and analyzed for cell proliferation, immunoblotting, and gene expression. The effects of MERTK knockdown were also evaluated.
RESULTS: Treatment with the inhibitors suppressed cell growth and induced apoptosis in all cell lines. OCI/AML5 and TMD7 cells, in which MERTK was constitutively phosphorylated by autocrine mechanisms, were highly susceptible to these inhibitors. The treatment reduced the phosphorylation of MERTK and its down-stream signalling molecules, v-akt murine thymoma viral oncogene homolog 1 (AKT) and extracellular signal-regulated kinase (ERK). Similar effects were observed after MERTK knockdown. The inhibitors and the knockdown caused similar changes in mRNA expression.
CONCLUSION: These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK.
Ringleb J, Strack E, Angioni C, et al.Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages.
J Immunol. 2018; 200(2):857-868 [PubMed
] Related Publications
The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MΦ) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MΦ. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MΦ and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MΦ. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase-dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression.
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.
Duployez N, Abou Chahla W, Lejeune S, et al.Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia.
Eur J Haematol. 2018; 100(1):104-107 [PubMed
] Related Publications
ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia (ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH-ALL, we screened 81 unrelated subjects with HeH-ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL.
Luu TH, Bard JM, Carbonnelle D, et al.Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells.
Cell Oncol (Dordr). 2018; 41(1):13-24 [PubMed
] Related Publications
BACKGROUND: It has amply been documented that mammary tumor cells may exhibit an increased lipogenesis. Biliary acids are currently recognized as signaling molecules in the intestine, in addition to their classical roles in the digestion and absorption of lipids. The aim of our study was to evaluate the impact of lithocholic acid (LCA) on the lipogenesis of breast cancer cells. The putative cytotoxic effects of LCA on these cells were also examined.
METHODS: The effects of LCA on breast cancer-derived MCF-7 and MDA-MB-231 cells were studied using MTT viability assays, Annexin-FITC and Akt phosphorylation assays to evaluate anti-proliferative and pro-apoptotic properties, qRT-PCR and Western blotting assays to assess the expression of the bile acid receptor TGR5 and the estrogen receptor ERα, and genes and proteins involved in apoptosis (Bax, Bcl-2, p53) and lipogenesis (SREBP-1c, FASN, ACACA). Intracellular lipid droplets were visualized using Oil Red O staining.
RESULTS: We found that LCA induces TGR5 expression and exhibits anti-proliferative and pro-apoptotic effects in MCF-7 and MDA-MB-231 cells. Also, an increase in pro-apoptotic p53 protein expression and a decrease in anti-apoptotic Bcl-2 protein expression were observed after LCA treatment of MCF-7 cells. In addition, we found that LCA reduced Akt phosphorylation in MCF-7 cells, but not in MDA-MB-231 cells. We also noted that LCA reduced the expression of SREBP-1c, FASN and ACACA in both breast cancer-derived cell lines and that cells treated with LCA contained low numbers of lipid droplets compared to untreated control cells. Finally, a decrease in ERα expression was observed in MCF-7 cells treated with LCA.
CONCLUSIONS: Our data suggest a potential therapeutic role of lithocholic acid in breast cancer cells through a reversion of lipid metabolism deregulation.
Bobin-Dubigeon C, Chauvin A, Brillaud-Meflah V, et al.Liver X Receptor (LXR)-regulated Genes of Cholesterol Trafficking and Breast Cancer Severity.
Anticancer Res. 2017; 37(10):5495-5498 [PubMed
] Related Publications
BACKGROUND: Liver X receptor [LXR; nuclear receptor subfamily 1, group H, member 2 (NR1H2, alias LXRB)] can inhibit proliferation and induce apoptosis of cancer cells. Its relationship with disease severity is not known.
MATERIALS AND METHODS: Expression of LXRB, ATP binding cassette subfamily A member 1 (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), apolipoprotein E (APOE) and paraoxonase 2 (PON2) were determined in 69 breast tumors and were related to clinical stages of the disease and tumor characteristics, as well as time to recurrence.
RESULTS: ABCG1 expression differed with the tumor Scarff Bloom and Richardson (SBR) status (p=0.02), with a lower expression in SBRIII than in SBRII and SBRI. ABCG1 expression was significantly higher in estrogen receptor-positive tumors (N=63) (p=0.02). APOE expression was significantly lower in progesterone receptor-positive tumors (N=55) (p=0.03). No relationship with time to recurrence was observed.
CONCLUSION: Expression of some LXR-dependent genes is related to breast tumor characteristics, but not time to recurrence. This may be due to a lack of study power or too short a follow-up time.
Ruvolo PP, Ma H, Ruvolo VR, et al.Anexelekto/MER tyrosine kinase inhibitor ONO-7475 arrests growth and kills FMS-like tyrosine kinase 3-internal tandem duplication mutant acute myeloid leukemia cells by diverse mechanisms.
Haematologica. 2017; 102(12):2048-2057 [PubMed
] Free Access to Full Article Related Publications
Nearly one-third of patients with acute myeloid leukemia have FMS-like tyrosine kinase 3 mutations and thus have poor survival prospects. Receptor tyrosine kinase anexelekto is critical for FMS-like tyrosine kinase 3 signaling and participates in FMS-like tyrosine kinase 3 inhibitor resistance mechanisms. Thus, strategies targeting anexelekto could prove useful for acute myeloid leukemia therapy. ONO-7475 is an inhibitor with high specificity for anexelekto and MER tyrosine kinase. Herein, we report that ONO-7475 potently arrested growth and induced apoptosis in acute myeloid leukemia with internal tandem duplication mutation of FMS-like tyrosine kinase 3. MER tyrosine kinase-lacking MOLM13 cells were sensitive to ONO-7475, while MER tyrosine kinase expressing OCI-AML3 cells were resistant, suggesting that the drug acts
Kabir TD, Ganda C, Brown RM, et al.A microRNA-7/growth arrest specific 6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma.
Hepatology. 2018; 67(1):216-231 [PubMed
] Related Publications
Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient, and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TYRO3-AXL-MER family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC; however, its role in SR is unknown. In this study, we generated two functionally distinct sorafenib-resistant human Huh-7 HCC cell lines in order to identify new mechanisms to abrogate acquired SR as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA (miR), miR-7-5p (miR-7), in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumor suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration, and invasion of Huh-7 cells through the phosphoinositide 3-kinase/protein kinase B pathway and is markedly elevated with acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib-resistant Huh-7 cells, inhibiting TYRO3/growth arrest specific 6-mediated cancer cell migration and invasion.
CONCLUSION: We identified a mechanism for acquiring SR in HCC that is through the aberrant expression of the TYRO3/phosphoinositide 3-kinase/protein kinase B signal transduction pathway, and that can be overcome by miR-7 overexpression. Taken together, these data suggest a potential role for miR-7 as an RNA-based therapeutic to treat refractory and drug-resistant HCC. (Hepatology 2018;67:216-231).
Kappelhoff R, Puente XS, Wilson CH, et al.Overview of transcriptomic analysis of all human proteases, non-proteolytic homologs and inhibitors: Organ, tissue and ovarian cancer cell line expression profiling of the human protease degradome by the CLIP-CHIP™ DNA microarray.
Biochim Biophys Acta Mol Cell Res. 2017; 1864(11 Pt B):2210-2219 [PubMed
] Related Publications
The protease degradome is defined as the complete repertoire of proteases and inhibitors, and their nonfunctional homologs present in a cell, tissue or organism at any given time. We review the tissue distribution of virtually the entire degradome in 23 different human tissues and 6 ovarian cancer cell lines. To do so, we developed the CLIP-CHIP™, a custom microarray based on a 70-mer oligonucleotide platform, to specifically profile the transcripts of the entire repertoire of 473 active human proteases, 156 protease inhibitors and 92 non-proteolytically active homologs known at the design date using one specific 70-mer oligonucleotide per transcript. Using the CLIP-CHIP™ we mapped the expression profile of proteases and their inhibitors in 23 different human tissues and 6 ovarian cancer cell lines in 104 sample datasets. Hierarchical cluster analysis showed that expression profiles clustered according to their anatomic locations, cellular composition, physiologic functions, and the germ layer from which they are derived. The human ovarian cancer cell lines cluster according to malignant grade. 110 proteases and 42 inhibitors were tissue specific (1 to 3 tissues). Of these 110 proteases 69% (74) are mainly extracellular, 30% (34) intracellular and 1% intramembrane. Notably, 35% (197/565) of human proteases and 30% (47/156) of inhibitors were ubiquitously expressed in all 23 tissues; 27% (155) of proteases and 21% (32) of inhibitors were broadly expressed in 4-20 tissues. Our datasets provide a valuable resource for the community of baseline protease and inhibitor relative expression in normal human tissues and can be used for comparison with diseased tissue, e.g. ovarian cancer, to decipher pathogenesis, and to aid drug development. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
Carbonnelle D, Luu TH, Chaillou C, et al.LXR Activation Down-regulates Lipid Raft Markers FLOT2 and DHHC5 in MCF-7 Breast Cancer Cells.
Anticancer Res. 2017; 37(8):4067-4073 [PubMed
] Related Publications
BACKGROUND/AIM: Lipid rafts are cholesterol-enriched microdomains of the plasma membrane. Recent studies have underlined that their integrity is critical for cancer cell survival. Liver X receptor (LXR) has a central role in cellular cholesterol homeostasis and its stimulation inhibits proliferation of several cancer cell lines. This study investigated whether LXR could modulate lipid rafts integrity and consequently alter proliferation of the MCF-7 breast cancer cell line.
MATERIALS AND METHODS: Effect of LXR agonist T0901317 on integrity of MCF-7 lipid rafts was examined by studying the expression of rafts marker flotillin-2 (FLOT2) and DHHC5, which palmitoylates FLOT2, and by studying the expression of phospho-Akt.
RESULTS: We demonstrated that LXR stimulation decreases mRNA and protein expression of FLOT2 and DHHC5 in MCF-7 cells. LXR stimulation also reduces Akt phosphorylation and its localization at the plasma membrane.
CONCLUSION: We showed, for the first time, that LXR regulates transcription of specific proteins of lipid rafts in a breast cancer model.
The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that AXL, but not MERTK or TYRO3 expression is enhanced in late stage colorectal cancer (CRC) and AXL expression associates with a cell migration gene signature. Silencing AXL or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs.
Background: Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025.
Methods: We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo.
Results: MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples.
Conclusions: These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.
Tumor exomes provide comprehensive information on mutated, overexpressed genes and aberrant splicing, which can be exploited for personalized cancer immunotherapy. Of particular interest are mutated tumor antigen T-cell epitopes, because neoepitope-specific T cells often are tumoricidal. However, identifying tumor-specific T-cell epitopes is a major challenge. A widely used strategy relies on initial prediction of human leukocyte antigen-binding peptides by
Toledo RAGenetics of Pheochromocytomas and Paragangliomas: An Overview on the Recently Implicated Genes MERTK, MET, Fibroblast Growth Factor Receptor 1, and H3F3A.
Endocrinol Metab Clin North Am. 2017; 46(2):459-489 [PubMed
] Related Publications
Genomic studies conducted by different centers have uncovered various new genes mutated in pheochromocytomas and paragangliomas (PPGLs) at germline, mosaic, and/or somatic levels, greatly expanding our knowledge of the genetic events occurring in these tumors. The current review focuses on very new findings and discusses the previously not recognized role of MERTK, MET, fibroblast growth factor receptor 1, and H3F3A genes in syndromic and nonsyndromic PPGLs. These 4 new genes were selected because although their association with PPGLs is very recent, mounting evidence was generated that rapidly consolidated the prominence of these genes in the molecular pathogenesis of PPGLs.
Shamsipur M, Nasirian V, Barati A, et al.Determination of cDNA encoding BCR/ABL fusion gene in patients with chronic myelogenous leukemia using a novel FRET-based quantum dots-DNA nanosensor.
Anal Chim Acta. 2017; 966:62-70 [PubMed
] Related Publications
In the present study, we developed a sensitive method based on fluorescence resonance energy transfer (FRET) for the determination of the BCR/ABL fusion gene, which is used as a biomarker to confirm the clinical diagnosis of both chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). For this purpose, CdTe quantum dots (QDs) were conjugated to amino-modified 18-mer oligonucleotide ((N)DNA) to form the QDs-(N)DNA nanosensor. In the presence of methylene blue (MB) as an intercalator, the hybridization of QDs-(N)DNA with the target BCR/ABL fusion gene (complementary DNA), brings the MB (acceptor) at close proximity of the QDs (donor), leading to FRET upon photoexcitation of the QDs. The enhancement in the emission intensity of MB was used to follow up the hybridization, which was linearly proportional to concentration of the target complementary DNA in a range from 1.0 × 10
Since growth arrest-specific gene 6 (Gas6) was discovered in 1988, numerous studies have highlighted the role of the Gas6 protein and its receptors Tyro3, Axl and Mer (collectively referred to as TAM), in proliferation, apoptosis, efferocytosis, leukocyte migration, sequestration and platelet aggregation. Gas6 has a critical role in the development of multiple types of cancers, including pancreatic, prostate, oral, ovarian and renal cancers. Acute myelocytic leukaemia (AML) is a Gas6-dependent cancer, and Gas6 expression predicts poor prognosis in AML. Interestingly, Gas6 also has a role in establishing tumour dormancy in the bone marrow microenvironment and in suppressing intestinal tumorigenesis. Numerous studies regarding cancer therapy have targeted Gas6 and TAM receptors with good results. However, some findings have suggested that Gas6 is associated with the development of resistance to cancer therapies. Concerning these significant effects of Gas6 in numerous cancers, we discuss the roles of Gas6 in cancer development in this review. First, we introduce basic knowledge on Gas6 and TAM receptors. Next, we describe and discuss the involvement of Gas6 and TAM receptors in cancers from different organ systems. Finally, we highlight the progress in therapies targeting Gas6 and TAM receptors. This review presents the significant roles of Gas6 in cancers from different systems and may contribute to the continued promotion of Gas6 as a therapeutic target.