Research IndicatorsGraph generated 11 March 2017 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 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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: SLC7A5 (cancer-related)
System l amino acid transporter 1 (LAT1) is highly expressed in various types of human cancer, and contributes to cancer growth and survival. Recently, we have shown that LAT1 expression is closely related to the growth and aggressiveness of esophageal cancer, and is an independent marker of poor prognosis. However, it remains unclear whether LAT1 inhibition could suppress esophageal cancer growth. In this study, we investigated the tumor-suppressive effects of the inhibition of LAT1. Both LAT1 and CD98, which covalently associates to LAT1 on the membrane, were expressed in human esophageal cancer cell lines KYSE30 and KYSE150. Quantitative PCR analysis showed that the expression of LAT1 was much higher than other subtypes of LAT. A selective inhibitor of LAT, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), suppressed cellular uptake of l-(14) C-leucine and cell proliferation in a dose-dependent manner. It also suppressed phosphorylation of mammalian target of rapamycin, 4E-BP1, and p70S6K protein, and induced cell cycle arrest at G1 phase. These results suggest that suppression of both mammalian target of rapamycin signaling and cell cycle progression is involved in BCH-induced growth inhibition. In tumor-bearing mice, daily treatment with BCH significantly delayed tumor growth and decreased glucose metabolism, indicating that LAT1 inhibition potentially suppresses esophageal cancer growth in vivo. Thus, our results suggest that LAT1 inhibition could be a promising molecular target for the esophageal cancer therapy.
BACKGROUND: Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.
METHODS: Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 'common Hispanic mutation' (CCM1-CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.
RESULTS: The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.
CONCLUSIONS: Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.
Despite progress in systemic small interfering RNA (siRNA) delivery to the liver and to solid tumors, systemic siRNA delivery to leukocytes remains challenging. The ability to silence gene expression in leukocytes has great potential for identifying drug targets and for RNAi-based therapy for leukocyte diseases. However, both normal and malignant leukocytes are among the most difficult targets for siRNA delivery as they are resistant to conventional transfection reagents and are dispersed in the body. We used mantle cell lymphoma (MCL) as a prototypic blood cancer for validating a novel siRNA delivery strategy. MCL is an aggressive B-cell lymphoma that overexpresses cyclin D1 with relatively poor prognosis. Down-regulation of cyclin D1 using RNA interference (RNAi) is a potential therapeutic approach to this malignancy. Here, we designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that are specifically taken up by human MCL cells in the bone marrow of xenografted mice. When loaded with siRNAs against cyclin D1, CD38-targeted LNPs induced gene silencing in MCL cells and prolonged survival of tumor-bearing mice with no observed adverse effects. These results highlight the therapeutic potential of cyclin D1 therapy in MCL and present a novel RNAi delivery system that opens new therapeutic opportunities for treating MCL and other B-cell malignancies.
Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.
Xu M, Sakamoto S, Matsushima J, et al.Up-Regulation of LAT1 during Antiandrogen Therapy Contributes to Progression in Prostate Cancer Cells.
J Urol. 2016; 195(5):1588-97 [PubMed
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PURPOSE: Cancer cells require massive amounts of amino acids for survival. LAT1 (L-type amino acid transporter 1) transports essential amino acids, including leucine, which trigger the downstream mTOR (mammalian target of rapamycin) pathway. We examined the association between androgen receptor and LAT1, and the association between LAT1 expression and the acquisition of castration resistance.
MATERIALS AND METHODS: Western blot and real-time polymerase chain reaction were performed to study protein and mRNA expression. siRNA was used to knock down target genes. A total of 92 prostate biopsy specimens of patients who underwent androgen deprivation therapy were used for immunohistochemical analyses. Cox hazard proportional models and the Kaplan-Meier method were used for statistical analyses.
RESULTS: LAT1 was highly expressed in hormone resistant prostate cancer cell lines. Knockdown of LAT1 in LNCaP and C4-2 cells significantly suppressed cell proliferation, migration and invasion. Androgen receptor siRNA or androgen receptor blocking through bicalutamide (10 μM) or MDV3100 (10 μM) significantly increased LAT1 expression (p <0.01). Treatment with dihydrotestosterone (0.1 to 10 nM) reduced LAT1 expression in a dose dependent manner (p <0.01). Bicalutamide/MDV3100 plus siLAT1 synergistically suppressed prostate cancer cell proliferation compared to single inhibition by androgen receptor or LAT1 (p <0.01). High LAT1 expression correlated with significantly shorter prostate specific antigen recurrence-free survival in patients receiving androgen deprivation therapy (p <0.0001). LAT1 expression was an independent predictor of castration resistance on multivariate analysis (HR 3.56, p = 0.0133).
CONCLUSIONS: The current data may indicate a novel mechanism to acquire castration resistance through activation of the amino acid transporter LAT1.
OBJECTIVE: Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders characterized by increased risk of leukemic transformation. This study identifies microRNAs(miRNA) and miRNA targets that might represent leukemic transformation markers for MDS.
METHODS: Based on our previously established nested case-control study cohort of MDS patients, we chose paired patients to undergo Angilent 8 × 15K human miRNA microarrays. Target prediction analysis was administrated using targetscan 5.1 software. We further investigated the function of target gene in MDS cell line using siRNA method, including cell proliferation, cell apoptosis, cell cycle and electron microscope.
RESULTS: Finally we screened a subset of 7 miRNAs to be significantly differentially expressed between the case (at the end of follow up with leukemic transformation) and control group (at the end of follow up without leukemic transformation). Target prediction analysis revealed SLC7A5 was the common target gene of these 7 miRNAs. Further study on the function of SLC7A5 gene in SKM-1 cell line showed that downregulation of SLC7A5 inhibited SKM-1 cells proliferation, increased apoptosis and caused cell cycle arrest in the G0/G1 stage.
CONCLUSIONS: Our data indicate that SLC7A5 gene may act as a potential leukemic transformation target gene in MDS.
PURPOSE: The onset of drug resistance is a major cause of treatment failure in multiple myeloma. Although increasing evidence is defining the role of miRNAs in mediating drug resistance, their potential activity as drug-sensitizing agents has not yet been investigated in multiple myeloma.
EXPERIMENTAL DESIGN: Here we studied the potential utility of miR-221/222 inhibition in sensitizing refractory multiple myeloma cells to melphalan.
RESULTS: miR-221/222 expression inversely correlated with melphalan sensitivity of multiple myeloma cells. Inhibition of miR-221/222 overcame melphalan resistance and triggered apoptosis of multiple myeloma cells in vitro, in the presence or absence of human bone marrow (BM) stromal cells. Decreased multiple myeloma cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ABC transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory multiple myeloma xenografts with systemic locked nucleic acid (LNA) inhibitors of miR-221 (LNA-i-miR-221) plus melphalan overcame drug resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.
CONCLUSIONS: Taken together, our findings provide the proof of concept that LNA-i-miR-221 can reverse melphalan resistance in preclinical models of multiple myeloma, providing the framework for clinical trials to overcome drug resistance, and improve patient outcome in multiple myeloma.
Park YY, Sohn BH, Johnson RL, et al.Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma.
Hepatology. 2016; 63(1):159-72 [PubMed
] Free Access to Full Article Related Publications
UNLABELLED: Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism's potential clinical implications for treating hepatocellular carcinoma.
CONCLUSION: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets.
BACKGROUND: The establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, however the underlying molecular mechanisms remain unclear. Here, we identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis.
METHODS: To explore the role of Scrib during epidermal development, we compared the permeability of toluidine blue dye in wild-type, Scrib heterozygous and Scrib KO embryonic epidermis at E16.5, E17.5 and E18.5. Mouse embryos were stained with alcian blue and alizarin red for skeletal analysis. To establish whether Scrib plays a tumor suppressive role during skin tumorigenesis and/or progression, we evaluated an autochthonous mouse model of skin carcinogenesis in the context of Scrib loss. We utilised Cre-LoxP technology to conditionally deplete Scrib in adult epidermis, since Scrib KO embryos are neonatal lethal.
RESULTS: We establish that Scrib perturbs keratinocyte maturation during embryonic development, causing impaired epidermal barrier formation, and that Scrib is required for skeletal morphogenesis in mice. Analysis of conditional transgenic mice deficient for Scrib specifically within the epidermis revealed no skin pathologies, indicating that Scrib is dispensable for normal adult epidermal homeostasis. Nevertheless, bi-allelic loss of Scrib significantly enhanced tumor multiplicity and progression in an autochthonous model of epidermal carcinogenesis in vivo, demonstrating Scrib is an epidermal tumor suppressor. Mechanistically, we show that apoptosis is the critical effector of Scrib tumor suppressor activity during skin carcinogenesis and provide new insight into the function of polarity proteins during DNA damage repair.
CONCLUSIONS: For the first time, we provide genetic evidence of a unique link between skin carcinogenesis and loss of the epithelial polarity regulator Scrib, emphasizing that Scrib exerts a wide-spread tumor suppressive function in epithelia.
BACKGROUND: Previous studies have shown that microRNAs are dysregulated in thyroid cancer and play important roles in the post-transcriptional regulation of target oncogenes and/or tumor suppressor genes.
METHODOLOGY/PRINCIPAL FINDINGS: We studied the function of miR-126-3p in thyroid cancer cells, and as a marker of disease aggressiveness. We found that miR-126-3p expression was significantly lower in larger tumors, in tumor samples with extrathyroidal invasion, and in higher risk group thyroid cancer in 496 papillary thyroid cancer samples from The Cancer Genome Atlas study cohort. In an independent sample set, lower miR-126-3p expression was observed in follicular thyroid cancers (which have capsular and angioinvasion) as compared to follicular adenomas. Mechanistically, ectopic overexpression of miR-126-3p significantly inhibited thyroid cancer cell proliferation, in vitro (p<0.01) and in vivo (p<0.01), colony formation (p<0.01), tumor spheroid formation (p<0.05), cellular migration (p<0.05), VEGF secretion and endothelial tube formation, and lung metastasis in vivo. We found 14 predicted target genes, which were significantly altered upon miR-126-3p transfection in thyroid cancer cells, and which are involved in cancer biology. Of these 14 genes, SLC7A5 and ADAM9 were confirmed to be inhibited by miR-126-3p overexpression and to be direct targets of miR-136-3p.
CONCLUSIONS/SIGNIFICANCE: To our knowledge, this is the first study to demonstrate that miR-126-3p has a tumor-suppressive function in thyroid cancer cells, and is associated with aggressive disease phenotype.
Wang J, Chen X, Su L, et al.MicroRNA-126 inhibits cell proliferation in gastric cancer by targeting LAT-1.
Biomed Pharmacother. 2015; 72:66-73 [PubMed
] Related Publications
MicroRNA-126 (miR-126) is a pivotal post-transcriptional regulator, which has been validated as a suppressor in gastric cancer (GC). However, the downstream of its tumor inhibiting function has not been totally clear. L-type amino-acid transporter 1 (LAT-1) is a novel member of system L-type transporters involving in cell proliferation, and we have previously validated that LAT-1 played a role of promotor in GC. In this study, we further detected and confirmed that LAT-1 was exactly targeted by miR-126 in GC. We found LAT-1 was significantly downregulated in GC MKN-45 cell lines by using miR-126 mimics, along with an impairment on cell proliferation and cell cycle. Additionally, by overexpressing LAT-1 in MKN-45 cells which was firstly treated with miR-126 mimics, the ability of cell proliferation in MKN-45 cells was definitely rescued. Thus, our results suggests and consolidates the standpoint that miR-126 plays a pivotal role in GC suppressing the process of GC cell, and this function is at least partly taken to implement by miR-126s's post-transcriptional effect on LAT-1. This might provide us likely potential biomarkers and targets for GC prevention, diagnosis and therapeutic treatment.
Lat1 (SLC7A5) is an amino acid transporter often required for tumor cell import of essential amino acids (AA) including Methionine (Met). Met is the obligate precursor of S-adenosylmethionine (SAM), the methyl donor utilized by all methyltransferases including the polycomb repressor complex (PRC2)-specific EZH2. Cell populations sorted for surface Lat1 exhibit activated EZH2, enrichment for Met-cycle intermediates, and aggressive tumor growth in mice. In agreement, EZH2 and Lat1 expression are co-regulated in models of cancer cell differentiation and co-expression is observed at the invasive front of human lung tumors. EZH2 knockdown or small-molecule inhibition leads to de-repression of RXRα resulting in reduced Lat1 expression. Our results describe a Lat1-EZH2 positive feedback loop illustrated by AA depletion or Lat1 knockdown resulting in SAM reduction and concomitant reduction in EZH2 activity. shRNA-mediated knockdown of Lat1 results in tumor growth inhibition and points to Lat1 as a potential therapeutic target.
Yanagisawa N, Satoh T, Hana K, et al.L-amino acid transporter 1 may be a prognostic marker for local progression of prostatic cancer under expectant management.
Cancer Biomark. 2015; 15(4):365-74 [PubMed
] Related Publications
BACKGROUND: Oncocytic L-amino acid transporter (LAT) 1 could be a target of new molecular therapy against malignancies.
OBJECTIVE: To assess the correlation between overexpression of LAT1 and local progression (LP) in prostatic carcinoma (PC) patients under expectant management (EM).
METHODS: This retrospective study analyzed 109 patients with PC who received EM from 1991 to 2006. The expression of LAT1, LAT2, and CD98, as well as Ki-67 labeling indices (LI), was analyzed immunohistochemically in first biopsy or TUR samples diagnosed as adenocarcinomas.
RESULTS: Of the 109 patients, 44 (40%) showed LP on clinical examinations, whereas 65 showed stable disease (SD). LAT1 score and intensity were significantly higher in the LP than in the SD group, as well as among Gleason score (GS)-low (GS < 7) patients who were associated with low-risk. When the LP group was subdivided by D'Amico risk category (low-, intermediate- and high-risk groups), each showed higher LAT1 expression than the SD group. LAT1 expression did not correlate with GS or Ki-67 LI.
CONCLUSIONS: Independently of GS, aberrant overexpression of LAT1 in prostatic adenocarcinoma could predict LP under EM. Although prostate biopsy samples are small, LAT1 may be a novel prognostic biomarker of LP.
Carneiro BA, Altman JK, Kaplan JB, et al.Targeted therapy of acute myeloid leukemia.
Expert Rev Anticancer Ther. 2015; 15(4):399-413 [PubMed
] Related Publications
Advances in the understanding of the genetic underpinnings of acute myeloid leukemia are rapidly being translated into novel treatment strategies. Genomic profiling has highlighted the importance of the epigenetic machinery for leukemogenesis by identifying recurrent somatic mutations involving chromatin-modifier proteins. These genetic alterations function as dynamic regulators of gene expression and involve DNA-methyltransferase 3A, methyltransferase DOT1L, enhancer of zeste homologue 2, isocitrate dehydrogenases 1 and 2 and bromodomain-containing proteins. New therapeutic targets are also emerging from further delineation of cell signaling networks in acute myeloid leukemia blasts mediated by PIM kinases, polo-like kinase 1, cell surface protein CD98 and nucleocytoplasmic shuttling receptors, among others. Early results of targeted therapies directed at these molecular mechanisms are discussed in this review and their potential to improve the outcomes of patients by allowing the use of more effective and less toxic treatments.
Rosilio C, Nebout M, Imbert V, et al.L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.
Leukemia. 2015; 29(6):1253-66 [PubMed
] Related Publications
The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.
BACKGROUND: Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits. Carriers of the same genetic mutation can present with variable symptoms and severity of disease, suggesting the influence of modifier factors. Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM. The purpose of this study was to investigate whether common variants in inflammatory and immune response genes influence the severity of familial CCM1 disease, as manifested by ICH and greater brain lesion count.
METHODS: Hispanic CCM1 patients (n=188) harboring the founder Q455X 'common Hispanic mutation' (CHM) in the KRIT1 gene were analyzed at baseline. Participants were enrolled between June 2010 and March 2014 either through the Brain Vascular Malformation Consortium (BVMC) study or through the Angioma Alliance organization. Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging were performed to determine ICH as well as total and large (≥5 mm in diameter) lesion counts. Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 830 variants in 56 inflammatory and immune response genes for association with ICH and residuals of log-transformed total or large lesion count adjusted for age at enrollment and gender. Variants were analyzed individually or grouped by sub-pathways or whole pathways.
RESULTS: At baseline, 30.3% of CCM1-CHM subjects had ICH, with a mean ± standard deviation (SD) of 60.1±115.0 (range 0-713) for total lesions and 4.9±8.7 (range 0-104) for large lesions. The heritability estimates explained by all autosomal variants were 0.20 (SE=0.31), 0.81 (SE=0.17), and 0.48 (SE=0.19), for ICH, total lesion count, and large lesion count, respectively. TGFBR2 rs9823731 was significantly associated with ICH as well as with the total and large lesion counts (p≤0.017). Further, IL-4 rs9327638, CD14 rs778588, IL-6R rs114660934 and MSR1 rs62489577 were associated with two markers of disease severity. Finally, the whole pathway was associated with total lesion count (p=0.005) with TLR-4 rs10759930, CD14 rs778588, IL-6R rs114660934 and IGH rs57767447 mainly bearing this association. Eicosanoid signaling, extracellular pattern recognition, and immune response sub-pathways were also associated with the total lesion count.
CONCLUSIONS: These results suggest that polymorphisms in inflammatory and immune response pathways contribute to variability in CCM1 disease severity and might be used as predictors of disease severity. In particular, TGFBR2 rs9823731 was associated with all three markers of CCM1 disease severity tested, suggesting that TGFBR2 might be a key participant in the mechanism underlying CCM1 disease severity and phenotype variability. However, further longitudinal studies in larger sample sizes are needed to confirm these findings.
Interactions with the bone marrow microenvironment are essential for leukemia survival and disease progression. We developed an imaging-based RNAi platform to identify protective cues from bone marrow derived mesenchymal stromal cells (MSC) that promote survival of primary acute lymphoblastic leukemia (ALL) cells. Using a candidate gene approach, we detected distinct responses of individual ALL cases to RNA interference with stromal targets. The strongest effects were observed when interfering with solute carrier family 3 member 2 (SLC3A2) expression, which forms the cystine transporter xc- when associated with SLC7A11. Import of cystine and metabolism to cysteine by stromal cells provides the limiting substrate to generate and maintain glutathione in ALL. This metabolic interaction reduces oxidative stress in ALL cells that depend on stromal xc-. Indeed, cysteine depletion using cysteine dioxygenase resulted in leukemia cell death. Thus, functional evaluation of intercellular interactions between leukemia cells and their microenvironment identifies a selective dependency of ALL cells on stromal metabolism for a relevant subgroup of cases, providing new opportunities to develop more personalized approaches to leukemia treatment.
L-type amino-acid transporter 1 (LAT1) plays a key role in cell growth and survival. To determine the prognostic significance of LAT1 in multiple myeloma (MM), we investigated the expression of LAT1 and its functional subunit, 4Fc heavy chain (CD98), on myeloma cells by immunohistochemistry in 100 newly diagnosed MM patients. High expression (moderate or strong staining intensity) of LAT1 and CD98 was detected in 56% and 45% of patients, respectively. The LAT1 expression score was positively correlated with Ki-67 index (r = 0.631, P < 0.001), and there was a statistically significant difference in Durie-Salmon stage between patients with high and low LAT1 expression (P = 0.03). In 43 patients treated with melphalan and prednisolone, the overall response rate was significantly higher in the high LAT1 expression group (60.0%) than in the low LAT1 expression group (17.6%) (P = 0.03). Multivariate analysis confirmed that high expression of LAT1 was a significant prognostic factor for predicting poor overall survival independently from the International Staging System (both P = 0.01). Here, we show that the overexpression of LAT1 is significantly associated with high proliferation and poor prognosis in newly diagnosed MM patients. Thus, LAT1 may be a promising pathological marker for identifying high-risk MM.
Jalali S, Singh S, Agnihotri S, et al.A role for matrix remodelling proteins in invasive and malignant meningiomas.
Neuropathol Appl Neurobiol. 2015; 41(2):e16-28 [PubMed
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AIMS: Meningiomas are one of the most common brain tumours in adults. Invasive and malignant meningiomas present a significant therapeutic challenge due to high recurrence rates and invasion into surrounding bone, brain, neural and soft tissues. Understanding the molecular mechanism of invasion could help in designing novel therapeutic approaches in order to prevent the need for repeat surgery, decrease morbidity and improve patient survival. The aim of this study was to identify the key factors and underlying mechanisms which govern invasive properties of meningiomas.
METHODS: Formalin-fixed paraffin-embedded (FFPE) as well as frozen tumour tissues from bone-invasive, non-invasive and malignant meningiomas were used for RNA microarray, quantitative real-time PCR or Western blot analyses. Malignant meningioma cell lines (F5) were subject to MMP16 downregulation or overexpression and used for in vitro and in vivo functional assays. Subdural xenograft meningioma tumours were generated to study the invasion of tumour cells into brain parenchyma using cell lines with altered MMP16 expression.
RESULTS: We establish that the expression level of MMP16 was significantly elevated in both bone-invasive and brain invasive meningiomas. Gain- and loss-of-function experiments indicated a role for MMP16 in meningioma cell movement, invasion and tumour cell growth. Furthermore, MMP16 was shown to positively regulate MMP2, suggesting this mechanism may modulate meningioma invasion in invasive meningiomas.
CONCLUSIONS: Overall, the results support a role for MMP16 in promoting invasive properties of the meningioma tumours. Further studies to explore the potential value for clinical use of matrix metalloproteinases inhibitors are warranted.
Nedergaard MK, Kristoffersen K, Michaelsen SR, et al.The use of longitudinal 18F-FET MicroPET imaging to evaluate response to irinotecan in orthotopic human glioblastoma multiforme xenografts.
PLoS One. 2014; 9(2):e100009 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVES: Brain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.
METHODS: Human GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.
RESULTS: The relative tumor-to-brain (T/B) ratio of SUV max was significantly lower after one week (123 ± 6%, n = 7 vs. 147 ± 6%, n = 7; p = 0.018) and after two weeks (142 ± 8%, n = 5 vs. 204 ± 27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUV max T/B ratio and LAT1 (r = -0.62, p = 0.04) and LAT2 (r = -0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.
CONCLUSIONS: 18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUV max T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.
Oncocytic L-type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki-67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki-67 labeling index (LI). Kaplan-Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1-high and -low scores, whereas LAT2 and CD98 expression and Ki-67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1-high/LAT2-low than LAT1-low/LAT2-high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy.
Smith IE, Yeo B, Schiavon GThe optimal duration and selection of adjuvant endocrine therapy for breast cancer: how long is enough?
Am Soc Clin Oncol Educ Book. 2014; :e16-24 [PubMed
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Women with estrogen receptor (ER)+ early breast cancer (BC) are at continuing risk of relapse up to at least 15 years after diagnosis, despite being on adjuvant endocrine therapy for approximately 5 years. Extended adjuvant endocrine therapy with an aromatase inhibitor (AI) after 5 years of tamoxifen further reduces the risk of recurrence in postmenopausal women. More recently, continuing tamoxifen for 10 years has also been shown to further reduce the risk of recurrence compared with 5 years. There are no direct comparative data on the relative merits of extended tamoxifen compared with an AI; indirect evidence suggests that an AI may have increased efficacy but a greater adverse effect on quality of life. Results are awaited on the need for continuing front-line adjuvant AIs for more than 5 years. The next challenge is to determine which patients will benefit from this long-term treatment. Currently, tumor size, nodal involvement, and gene expression profile as measured by the PAM50 Risk of Recurrence (ROR) score have all been shown to have prognostic significance for late recurrence beyond 5 years.
Guo X, Li H, Fei F, et al.Genetic variations in SLC3A2/CD98 gene as prognosis predictors in non-small cell lung cancer.
Mol Carcinog. 2015; 54 Suppl 1:E52-60 [PubMed
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Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the risk of progression. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in the CD98 gene on prognosis of NSCLC patients. We genotyped three potential functional SNPs in CD98 gene using Sequenom iPLEX genotyping system in a cohort of 482 NSCLC patients. Multivariate cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis. The variant-containing genotypes of rs1059292 in 5'-flanking region of CD98 gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 1.49; 95% confidence interval [95% CI]: 1.04-2.14 in a dominant model). In stratified analysis, the association remained significant in patients with poor differentiation (HR=1.81, 95% CI=1.01-3.25). In addition, rs1059292 also showed a borderline significant association with T stage (OR=1.49; 95% CI: 0.96-2.35) and N stage (OR=1.53; 95% CI: 0.98-2.39). Functional analysis demonstrated that variant genotype of SNP rs1059292 significantly enhanced the transcription activity of CD98 gene promoter. Our data suggest that genetic variation of rs1059292 in CD98 gene may affect clinical outcome of NSCLC in Chinese population.
Janpipatkul K, Suksen K, Borwornpinyo S, et al.Downregulation of LAT1 expression suppresses cholangiocarcinoma cell invasion and migration.
Cell Signal. 2014; 26(8):1668-79 [PubMed
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Currently, there is no effective treatment for cholangiocarcinoma (CCA), which is the most prevalent in the northeastern part of Thailand. A new molecular target for the treatment of CCA is, therefore, urgently needed. Although L-type amino acid transporter 1 (LAT1) is highly expressed in CCA cells, its role in malignant phenotypes of CCA cells remains unclear. This study aimed to investigate the impact of LAT1 on proliferation, migration, and invasion of KKU-M213 cells, the CCA cells derived from Thai patients with intrahepatic cholangiocarcinoma. Results showed that KKU-M213 cells expressed all LAT isoforms (LAT1, LAT2, LAT3 and LAT4). The expressions of LAT1 and its associated protein 4F2hc were highest whereas those of LAT2 and LAT4 were extremely low. Treatment with 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) reduced L-leucine uptake concomitant with an inhibition of cell motility and, to a lesser extent, on cell proliferation. It also induced a time dependent up-regulation of LAT1 and 4F2hc expressions. Similarly, cell migration and invasion, but not proliferation, were reduced in LAT1 knockdown KKU-M213 cells. In addition, silencing of LAT1 inhibited the expressions of 4F2hc mRNA and protein whereas the expression of microRNA-7, the 4F2hc down-regulator, was increased. Furthermore, the phosphorylation levels of ERK1/2 and p70S6K were reduced after LAT1 knockdown. Collectively, these results suggest that suppression of cell invasion and migration in LAT1 knockdown KKU-M213 cells may be partly mediated through the inhibition of the 4F2hc-signaling pathway by the up-regulation of microRNA-7. Based on this finding, LAT1 may be a potential therapeutic target for treating CCA.
Giglia JL, White MJ, Hart AJ, et al.A single nucleotide polymorphism in SLC7A5 is associated with gastrointestinal toxicity after high-dose melphalan and autologous stem cell transplantation for multiple myeloma.
Biol Blood Marrow Transplant. 2014; 20(7):1014-20 [PubMed
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Multiple myeloma is the most frequent indication for high-dose melphalan (HDM) chemotherapy with autologous stem cell transplantation (ASCT). Gastrointestinal symptoms represent the most significant nonhematological toxicity of HDM. However, specific, especially genetic, predictors of their incidence or clinical severity are lacking. The amino acid transporters LAT1 and LAT2 encoded by the SLC7A5 and SLC7A8 genes, respectively, are the principal mediators of melphalan uptake into cells. To determine whether genetic variability at these loci contributed to interindividual differences in the development of gastrointestinal complications of HDM, we analyzed single nucleotide polymorphisms (SNPs) in these genes in 135 patients with multiple myeloma treated with HDM and ASCT and correlated these with the need for total parenteral nutrition (TPN). Seven SNPs in SLC7A5 and 20 in SLC7A8 were genotyped. Multiple analyses indicated that 1 SNP in the first intron of SLC7A5, rs4240803, was significantly associated with TPN use (odds ratio = .45, 95% confidence interval, .25 to .79; P = .007). Further, every haplotype that correlated with TPN requirement included this SNP. These results suggest that variability in melphalan transport affects mucosal injury after HDM. This finding could help in individualizing the dose of this effective and widely used chemotherapeutic agent for multiple myeloma.
PURPOSE: (18)F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. (18)F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of (18)F-FAMT uptake in patients with oesophageal cancer.
METHODS: From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both (18)F-FAMT PET/CT and (18)F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of (18)F-FAMT uptake.
RESULTS: High uptake of (18)F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that (18)F-FAMT was specifically transported by LAT1.
CONCLUSIONS: The uptake of (18)F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of (18)F-FAMT accumulation.
Wang T, Chu Z, Lin H, et al.Galectin-3 contributes to cisplatin-induced myeloid derived suppressor cells (MDSCs) recruitment in Lewis lung cancer-bearing mice.
Mol Biol Rep. 2014; 41(6):4069-76 [PubMed
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Recently the recruitment/migration of myeloid derived suppressor cells (MDSCs) to tumor microenvironment after chemotherapy has attracted much attention. To determine the detailed mechanism for the responses of MDSCs to these chemotherapies, we investigated the changes of galectin-3 and MDSCs in response to cisplatin(0.4 mg/kg, 4 mg/kg) treatment both in vivo and ex vivo. In the process of cisplatin, we assessed levels of galectin-3 and MDSCs in the Lewis lung cancer (LLC) bearing mice using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), immunofluorence and flow cytometry (FCM). The expression and changes of galectin-3 in the LLC cell line were detected by western blot, immunofluorence and ELISA. The ligand for galectin-3 on MDSCs and the chemotaxis of galectin-3 to MDSCs were confirmed using FCM and transwell. Parallel increased level of galectin-3 with the number of MDSCs in vivo was detected after cisplatin treatment. LLC cells expressed galectin-3 and cisplatin increased galectin-3 level in the culture medium. Furthermore, MDSCs were detected to express CD98, the ligand of galectin-3, and could be recruited by galectin-3. Our results suggested that the elevated expression of gelectin-3 in LLC tumor cells may contribute to the migration of MDSCs to the tumor microenvironment in response to cisplatin.
BACKGROUND: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.
METHODS: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.
RESULTS: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.
CONCLUSIONS: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.
Wang Q, Beaumont KA, Otte NJ, et al.Targeting glutamine transport to suppress melanoma cell growth.
Int J Cancer. 2014; 135(5):1060-71 [PubMed
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Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF(WT) (C8161 and WM852) and BRAF(V600E) mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAF(WT) and BRAF(V600E) melanoma.
Ebrahimi F, Gopalan V, Smith RA, Lam AKmiR-126 in human cancers: clinical roles and current perspectives.
Exp Mol Pathol. 2014; 96(1):98-107 [PubMed
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miR-126 has been implicated in the processes of inflammation and angiogenesis. Through these processes, miR-126 is implicated in cancer biology, but its role there has not been well reviewed. The aim of this review is to examine the molecular mechanisms and clinicopathological significance of miR-126 in human cancers. miR-126 was shown to have roles in cancers of the gastrointestinal tract, genital tracts, breast, thyroid, lung and some other cancers. Its expression was suppressed in most of the cancers studied. The molecular mechanisms that are known to cause aberrant expression of miR-126 include alterations in gene sequence, epigenetic modification and alteration of dicer abundance. miR-126 can inhibit progression of some cancers via negative control of proliferation, migration, invasion, and cell survival. In some instances, however, miR-126 supports cancer progression via promotion of blood vessel formation. Downregulation of miR-126 induces cancer cell proliferation, migration, and invasion via targeting specific oncogenes. Also, reduced levels of miR-126 are a significant predictor of poor survival of patients in many cancers. In addition, miR-126 can alter a multitude of cellular mechanisms in cancer pathogenesis via suppressing gene translation of numerous validated targets such as PI3K, KRAS, EGFL7, CRK, ADAM9, HOXA9, IRS-1, SOX-2, SLC7A5 and VEGF. To conclude, miR-126 is commonly down-regulated in cancer, most likely due to its ability to inhibit cancer cell growth, adhesion, migration, and invasion through suppressing a range of important gene targets. Understanding these mechanisms by which miR-126 is involved with cancer pathogenesis will be useful in the development of therapeutic targets for the management of patients with cancer.