Deletion of tetraspanin CD151 alters the Wnt oncogene-induced mammary tumorigenesis: A cell type-linked function and signaling.
Abstract Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of cancer development and progression. Here we investigated the role of CD151 in breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated tumor growth and an increased number of Ki-67+ proliferative cells. Mechanistically, the CD151-deficient tumors were largely ER+, and exhibited ...
Source: Neoplasia - November 26, 2019 Category: Cancer & Oncology Authors: Li H, Li J, Han R, Deng X, Shi J, Huang H, Hamad N, McCaughley A, Liu J, Wang C, Chen K, Wei D, Qiang J, Thatcher S, Wu Y, Liu C, Thibault O, Wei X, Chen S, Qian H, Zhou BP, Xu P, Yang XH Tags: Neoplasia Source Type: research

Glutamine deprivation counteracts hypoxia-induced chemoresistance.
r T Abstract The microenvironment of solid tumors is a key determinant of therapy efficacy. The co-occurrence of oxygen and nutrient deprivation is a common phenomenon of the tumor microenvironment and associated with treatment resistance. Cholangiocarcinoma (CCA) is characterized by a very poor prognosis and pronounced chemoresistance. A better understanding of the underlying molecular mechanisms is urgently needed to improve therapy strategies against CCA. We sought to investigate the importance of the conditionally essential amino acid glutamine, a centrally important nutrient for a variety of solid tumors, for...
Source: Neoplasia - November 22, 2019 Category: Cancer & Oncology Authors: Wappler J, Arts M, Röth A, Heeren RMA, Peter Neumann U, Olde Damink SW, Soons Z, Cramer T Tags: Neoplasia Source Type: research

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma.
Abstract Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targe...
Source: Neoplasia - November 22, 2019 Category: Cancer & Oncology Authors: Sun J, Li G, Liu Y, Ma M, Song K, Li H, Zhu D, Tang X, Kong J, Yuan X Tags: Neoplasia Source Type: research

CDK5RAP3 is a co-factor for the oncogenic transcription factor STAT3.
nk DA Abstract The transcription factor STAT3 regulates genes governing critical cellular processes such as proliferation, survival, and self-renewal. While STAT3 transcriptional function is activated rapidly and transiently in response to physiologic signals, through a variety of mechanisms it can become constitutively activated in the pathogenesis of cancer. This leads to chronic expression of genes that underlie malignant cellular behavior. However, STAT3 is known to interact with other proteins, which may modulate its function. Understanding these interactions can provide insights into novel aspects of STAT3 f...
Source: Neoplasia - November 22, 2019 Category: Cancer & Oncology Authors: Egusquiaguirre SP, Liu S, Tošić I, Jiang K, Walker SR, Nicolais M, Saw TY, Xiang M, Bartel K, Nelson EA, Frank DA Tags: Neoplasia Source Type: research

PODXL1 promotes metastasis of the pancreatic ductal adenocarcinoma by activating the C5aR/C5a axis from the tumor microenvironment.
Abstract Pancreatic invasive ductal adenocarcinoma (PDAC) is a representative intractable malignancy under the current cancer therapies, and is considered a scirrhous carcinoma because it develops dense stroma. Both PODXL1, a member of CD34 family molecules, and C5aR, a critical cell motility inducer, have gained recent attention, as their expression was reported to correlate with poor prognosis for patients with diverse origins including PDAC; however, previous studies reported independently on their respective biological significance. Here we demonstrate that PODXL1 is essential for metastasis of PDAC cells thro...
Source: Neoplasia - November 20, 2019 Category: Cancer & Oncology Authors: Saito K, Iioka H, Maruyama S, Sumardika IW, Sakaguchi M, Kondo E Tags: Neoplasia Source Type: research

Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment.
Abstract Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibrobla...
Source: Neoplasia - November 20, 2019 Category: Cancer & Oncology Authors: Lin Y, Li B, Yang X, Cai Q, Liu W, Tian M, Luo H, Yin W, Song Y, Shi Y, He R Tags: Neoplasia Source Type: research

APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.
Abstract Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the ApcMin/+ mouse model crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased sensitivity ...
Source: Neoplasia - November 20, 2019 Category: Cancer & Oncology Authors: Stefanski CD, Keffler K, McClintock S, Milac L, Prosperi JR Tags: Neoplasia Source Type: research

Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR.
In this study, we found that the LXR agonist enhanced the anti-tumor activity of sorafenib in a subset of HCC cells with high LXR-β/α gene expression ratio. Mechanically, the activation of LXR suppressed sorafenib dependent recruitment of MET and epidermal growth factor receptor (EGFR) in lipid rafts through cholesterol efflux. Our findings imply that LXR agonist can serve as a potential sensitizer to enhance the anti-tumor effect of sorafenib. PMID: 31751859 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - November 18, 2019 Category: Cancer & Oncology Authors: Shao W, Zhu W, Lin J, Luo M, Lin Z, Lu L, Jia H, Qin L, Lu M, Chen J Tags: Neoplasia Source Type: research

Somatic copy number alterations are associated with EGFR amplification and shortened survival in patients with primary glioblastoma.
;-Nicolás M, López-Ginés C Abstract Glioblastoma (GBM) is the most common malignant primary tumor of the central nervous system. With no effective therapy, the prognosis for patients is terrible poor. It is highly heterogeneous and EGFR amplification is its most frequent molecular alteration. In this light, we aimed to examine the genetic heterogeneity of GBM and to correlate it with the clinical characteristics of the patients. For that purpose, we analyzed the status of EGFR and the somatic copy number alterations (CNAs) of a set of tumor suppressor genes and oncogenes. Thus, we found GBMs w...
Source: Neoplasia - November 18, 2019 Category: Cancer & Oncology Authors: Muñoz-Hidalgo L, San-Miguel T, Megías J, Monleón D, Navarro L, Roldán P, Cerdá-Nicolás M, López-Ginés C Tags: Neoplasia Source Type: research

Prostaglandin F2 α-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity.
Prostaglandin F2α-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity. Neoplasia. 2019 Nov 14;21(11):1073-1084 Authors: Jiménez-Segovia A, Mota A, Rojo-Sebastián A, Barrocal B, Rynne-Vidal A, García-Bermejo ML, Gómez-Bris R, Hawinkels LJAC, Sandoval P, Garcia-Escudero R, López-Cabrera M, Moreno-Bueno G, Fresno M, Stamatakis K Abstract The role of prostaglandin (PG) F2α has been scarcely studied in cancer. We have identified a new function for PGF2α in ovarian cancer, stimula...
Source: Neoplasia - November 14, 2019 Category: Cancer & Oncology Authors: Jiménez-Segovia A, Mota A, Rojo-Sebastián A, Barrocal B, Rynne-Vidal A, García-Bermejo ML, Gómez-Bris R, Hawinkels LJAC, Sandoval P, Garcia-Escudero R, López-Cabrera M, Moreno-Bueno G, Fresno M, Stamatakis K Tags: Neoplasia Source Type: research

Extracellular acidosis differentiates pancreatitis and pancreatic cancer in mouse models using acidoCEST MRI.
Abstract Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model trea...
Source: Neoplasia - November 14, 2019 Category: Cancer & Oncology Authors: High RA, Randtke EA, Jones KM, Lindeman LR, Ma JC, Zhang S, LeRoux LG, Pagel MD Tags: Neoplasia Source Type: research

Fibrin Deposit on the Peritoneal Surface Serves as a Niche for Cancer Expansion in Carcinomatosis Patients.
Abstract Peritoneal metastasis (PM) is a very serious complication of gastrointestinal and gynecological malignancies which is poorly documented. Modified mesothelial cell layer and their microenvironments can favor fibrin deposition for cancer cell adhesion. Scanning and transmission electron microscopy of peritoneal surface and cancer cell clusters from cancer patients was done. Ascites and its impact on mesothelial cells were assessed by cytokine array. Neprilysin, matrix metalloprotease, epithelial mesenchymal transition (EMT) related molecules (E-cadherin, Snail, Slug, Twist, Vimentin and Fibronectin), tissue...
Source: Neoplasia - November 14, 2019 Category: Cancer & Oncology Authors: Shahid S, Iman A, Matti U, Rachid K, Assaf A, Eveno C, Marc P, Massoud M Tags: Neoplasia Source Type: research

Genome-Wide Profiling of Acquired Uniparental Disomy Reveals Prognostic Factors in Head and Neck Squamous Cell Carcinoma.
Abstract Acquired uniparental disomy (aUPD) leads to homozygosity facilitating identification of monoallelically expressed genes. We analyzed single-nucleotide polymorphism array-based genotyping data of 448 head and neck squamous cell carcinoma (HNSCC) samples from The Cancer Genome Atlas to determine the frequency and distribution of aUPD regions and their association with survival, as well as to gain a better understanding of their influence on the tumor genome. We used expression data from the same dataset to identify differentially expressed genes between groups with and without aUPD. Univariate and multivari...
Source: Neoplasia - November 14, 2019 Category: Cancer & Oncology Authors: Tuna M, Liu W, Amos CI, Mills GB Tags: Neoplasia Source Type: research

Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells.
g A Abstract The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was ...
Source: Neoplasia - November 14, 2019 Category: Cancer & Oncology Authors: Otto C, Schmidt S, Kastner C, Denk S, Kettler J, Müller N, Germer CT, Wolf E, Gallant P, Wiegering A Tags: Neoplasia Source Type: research

Rectal cancer sub-clones respond differentially to neoadjuvant therapy.
Abstract Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Locally advanced rectal cancer patients underwent pr...
Source: Neoplasia - September 12, 2019 Category: Cancer & Oncology Authors: Frydrych LM, Ulintz P, Bankhead A, Sifuentes C, Greenson J, Maguire L, Irwin R, Fearon ER, Hardiman KM Tags: Neoplasia Source Type: research

Microenvironmental Factors Drive Tenascin C and Src Cooperation to Promote Invadopodia Formation in Ewing Sarcoma.
Abstract Ewing sarcoma is a bone tumor most commonly diagnosed in adolescents and young adults. Survival for patients with recurrent or metastatic Ewing sarcoma is dismal and there is a dire need to better understand the mechanisms of cell metastasis specific to this disease. Our recent work demonstrated that microenvironmental stress leads to increased Ewing sarcoma cell invasion through Src activation. Additionally, we have shown that the matricellular protein tenascin C (TNC) promotes metastasis in Ewing sarcoma. A major role of both TNC and Src is mediation of cell-cell and cell-matrix interactions resulting i...
Source: Neoplasia - September 12, 2019 Category: Cancer & Oncology Authors: Hawkins AG, Julian CM, Konzen S, Treichel S, Lawlor ER, Bailey KM Tags: Neoplasia Source Type: research

VCAM-1 Density and Tumor Perfusion Predict T-cell Infiltration and Treatment Response in Preclinical Models.
Abstract Cancer immunotherapies have demonstrated durable responses in a range of different cancers. However, only a subset of patients responds to these therapies. We set out to test if non-invasive imaging of tumor perfusion and vascular inflammation may be able to explain differences in T-cell infiltration in pre-clinical tumor models, relevant for treatment outcomes. Tumor perfusion and vascular cell adhesion molecule (VCAM-1) density were quantified using magnetic resonance imaging (MRI) and correlated with infiltration of adoptively transferred and endogenous T-cells. MRI biomarkers were evaluated for their ...
Source: Neoplasia - September 11, 2019 Category: Cancer & Oncology Authors: Riegler J, Gill H, Ogasawara A, Hedehus M, Javinal V, Oeh J, Ferl GZ, Marik J, Williams S, Sampath D, Schartner J, Carano RAD Tags: Neoplasia Source Type: research

MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis.
This study has four aims: 1) to examine whether Minichromosome Maintenance (MCM)2, MCM4, and MCM6 can be used as markers to differentiate between luminal A and luminal B subtypes; 2) to study whether MCM2, MCM4, and MCM6 are highly expressed in triple-negative breast cancer, as there is an urgent need to search for surrogate markers in this aggressive subtype, for drug development purposes; 3) to compare the prognostic values of these markers in predicting relapse-free survival; and 4) to compare the three approaches used for scoring the protein expression of these markers by immunohistochemistry (IHC). MCM2, MCM4, MCM6, a...
Source: Neoplasia - August 30, 2019 Category: Cancer & Oncology Authors: Issac MSM, Yousef E, Tahir MR, Gaboury LA Tags: Neoplasia Source Type: research

Iroquois Homeobox 1 Acts as a True Tumor Suppressor in Multiple Organs by Regulating Cell Cycle Progression.
In conclusion, our in vivo and in vitro studies revealed that IRX1 gene functionally acts as a true tumor suppressor, inhibiting tumor cell growth by regulating cell cycle. PMID: 31450023 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - August 23, 2019 Category: Cancer & Oncology Authors: Jung IH, Jung DE, Chung YY, Kim KS, Park SW Tags: Neoplasia Source Type: research

Pseudogene Associated Recurrent Gene Fusion in Prostate Cancer.
We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, a...
Source: Neoplasia - August 22, 2019 Category: Cancer & Oncology Authors: Chakravarthi BV, Dedigama-Arachchige P, Carskadon S, Sundaram SK, Li J, Wu KH, Chandrashekar DS, Peabody JO, Stricker H, Hwang C, Chitale DA, Williamson SR, Gupta NS, Navone NM, Rogers C, Menon M, Varambally S, Palanisamy N Tags: Neoplasia Source Type: research

Targeting c-MYC through Interference with NAMPT and SIRT1 and Their Association to Oncogenic Drivers in Murine Serrated Intestinal Tumorigenesis.
In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC. PMID: 31442917 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - August 20, 2019 Category: Cancer & Oncology Authors: B L, Z Y, K N, S A, B SL, J P, G F, R R, M A Tags: Neoplasia Source Type: research

Depletion of the Transcriptional Coactivator Amplified in Breast Cancer 1 (AIB1) Uncovers Functionally Distinct Subpopulations in Triple-Negative Breast Cancer.
Abstract The transcriptional coactivator Amplified in Breast Cancer 1 (AIB1) plays a major role in the progression of hormone and HER2-dependent breast cancers but its role in triple negative breast cancer (TNBC) is undefined. Here, we report that established TNBC cell lines, as well as cells from a TNBC patient-derived xenograft (PDX) that survive chemotherapy treatment in vitro express lower levels of AIB1 protein. The surviving cell population has an impaired tube-formation phenotype when cultured onto basement membrane, a property shared with TNBC cells that survive shRNA-mediated depletion of AIB1 (AIB1LOW ce...
Source: Neoplasia - August 19, 2019 Category: Cancer & Oncology Authors: Saenz FR, Ory V, Schmidt MO, Kallakury BV, Mueller SC, Furth PA, Wellstein A, Riegel AT Tags: Neoplasia Source Type: research

SMAR1 favors immunosurveillance of cancer cells by modulating calnexin and MHC I expression.
Abstract Down-regulation or loss of MHC class I expression is a major mechanism used by cancer cells to evade immunosurveillance and increase their oncogenic potential. MHC I mediated antigen presentation is a complex regulatory process, controlled by antigen processing machinery (APM) dictating immune response. Transcriptional regulation of the APM that can modulate gene expression profile and their correlation to MHC I mediated antigen presentation in cancer cells remain enigmatic. Here, we reveal that Scaffold/Matrix-Associated Region 1- binding protein (SMAR1), positively regulates MHC I surface expression by ...
Source: Neoplasia - August 15, 2019 Category: Cancer & Oncology Authors: Alam A, Taye N, Patel S, Thube M, Mullick J, Shah VK, Pant R, Roychowdhury T, Banerjee N, Chatterjee S, Bhattacharya R, Roy R, Mukhopadhyay A, Mogare D, Chattopadhyay S Tags: Neoplasia Source Type: research

Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse Model of Colon Cancer.
In this study, the effects of sole and dual CTLA-4 and PD-L1 blockade were investigated in a microsatellite stable highly aggressive orthotopic mouse model of colon cancer. Dual CTLA-4 and PD-L1 inhibition resulted in tumor growth stagnation and completely blocked liver metastasis. Sole CTLA-4 and PD-L1 inhibition only moderately reduced metastatic spread of the colon cancer cells, though CTLA-4 blockade being superior to PD-L1 inhibition. Dual immune checkpoint blockade and sole CTLA-4 inhibition significantly increased intratumoral CD8+ and CD4+ T cells and reduced FOXP3+/CD4+ Treg cells. This was associated with increas...
Source: Neoplasia - August 11, 2019 Category: Cancer & Oncology Authors: Fiegle E, Doleschel D, Koletnik S, Rix A, Weiskirchen R, Borkham-Kamphorst E, Kiessling F, Lederle W Tags: Neoplasia Source Type: research

A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation.
We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure-activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortenin...
Source: Neoplasia - August 8, 2019 Category: Cancer & Oncology Authors: Bilsland AE, Liu Y, Turnbull A, Sumpton D, Stevenson K, Cairney CJ, Boyd SM, Roffey J, Jenkinson D, Keith WN Tags: Neoplasia Source Type: research

p85 α Inactivates MMP-2 and Suppresses Bladder Cancer Invasion by Inhibiting MMP-14 Transcription and TIMP-2 Degradation.
p85α Inactivates MMP-2 and Suppresses Bladder Cancer Invasion by Inhibiting MMP-14 Transcription and TIMP-2 Degradation. Neoplasia. 2019 Aug 08;21(9):908-920 Authors: Wang J, Zhang N, Peng M, Hua X, Huang C, Tian Z, Xie Q, Zhu J, Li J, Huang H, Huang C Abstract Recent studies show p85α up-regulates epidermal growth factor (EGF) receptor, thereby promoting malignant cell transformation and migration in normal mouse embryonic fibroblasts (MEFs). However, the potential role of p85α in human bladder cancer (BC) remains unknown. Here, we show that p85α is down-regulated in BC tumor ...
Source: Neoplasia - August 8, 2019 Category: Cancer & Oncology Authors: Wang J, Zhang N, Peng M, Hua X, Huang C, Tian Z, Xie Q, Zhu J, Li J, Huang H, Huang C Tags: Neoplasia Source Type: research

The Adiponectin-AdipoR1 Axis Mediates Tumor Progression and Tyrosine Kinase Inhibitor Resistance in Metastatic Renal Cell Carcinoma.
Abstract The survival of patients diagnosed with metastatic renal cell carcinoma (RCC) is still limited and the current targeted therapies are only partially effective. Herein, we investigated the clinical value and functions of adiponectin receptors (AdipoR1 and AdipoR2) in metastatic renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs). A total of 127 mRCC patients treated with first-line TKIs between 2008 and 2017 at a single institution were collected. AdipoR1 and AdipoR2 expression was assessed by immunohistochemistry. AdipoR1 was positively expressed in 87.4% (111/127) of tumors...
Source: Neoplasia - August 8, 2019 Category: Cancer & Oncology Authors: Sun G, Zhang X, Liu Z, Zhu S, Shen P, Zhang H, Zhang M, Chen N, Zhao J, Chen J, Liu J, Dai J, Wang Z, Zhu X, Wang Y, Zeng H Tags: Neoplasia Source Type: research

Down-Regulation of S100A8 is an Independent Predictor of PSA Recurrence in Prostate Cancer Treated by Radical Prostatectomy.
raefen M, Heumann A Abstract Dysregulation of S100A8 is described in many different human tumor types, but its role in prostate cancer is unknown. To evaluate the clinical relevance of S100A8 expression in prostate cancer, a tissue microarray containing 13,665 tumors was analyzed by immunohistochemistry. Cytoplasmic S100A8 staining was compared to prostate cancer phenotype, patient prognosis and molecular features including TMPRSS2:ERG fusion status and deletions of PTEN, 3p, 5q and 6q. S100A8 immunostaining was typically seen in normal prostate tissue but lost in 60% of 9786 interpretable prostate cancers. In the...
Source: Neoplasia - August 2, 2019 Category: Cancer & Oncology Authors: Minner S, Hager D, Steurer S, Höflmayer D, Tsourlakis MC, Möller-Koop C, Clauditz TS, Hube-Magg C, Luebke AM, Simon R, Sauter G, Göbel C, Weidemann S, Lebok P, Dum D, Fraune C, Izbicki J, Burandt E, Schlomm T, Huland H, Heinzer H, Haese A, Graefen M, H Tags: Neoplasia Source Type: research

AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance.
We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of As...
Source: Neoplasia - July 27, 2019 Category: Cancer & Oncology Authors: Jdey W, Kozlak M, Alekseev S, Thierry S, Lascaux P, Girard PM, Bono F, Dutreix M Tags: Neoplasia Source Type: research

miR-125a-5p Functions as Tumor Suppressor microRNA And Is a Marker of Locoregional Recurrence And Poor prognosis in Head And Neck Cancer.
Abstract MicroRNAs (miRNAs) are short single-stranded RNAs, measuring 21 to 23 nucleotides in length and regulate gene expression at the post-transcriptional level through mRNA destabilization or repressing protein synthesis. Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis. miR-125a-5p has been implicated as a tumor suppressor miRNA in malignancies such as non-small cell lung cancer and colon cancer. However, the role of miR-125a-5p has not been fully investigated in head and neck squamous cell carcin...
Source: Neoplasia - July 17, 2019 Category: Cancer & Oncology Authors: Vo DT, Karanam NK, Ding L, Saha D, Yordy JS, Giri U, Heymach JV, Story MD Tags: Neoplasia Source Type: research

The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells.
Abstract Translocation of 78-kDa glucose-regulated protein (GRP78) from endoplasmic reticulum (ER) to plasma membrane represents a paradigm shift beyond its traditional function as an ER chaperone protein. Cell surface GRP78 (csGRP78) exerts novel signaling functions, and mechanisms underlying its cell surface expression are just emerging. Acquired tamoxifen resistance of breast cancer cells is accompanied with elevated level of csGRP78. Therefore, the tamoxifen-resistant MCF7 breast cancer cells (MCF7-LR) represents a clinically relevant model to study mechanisms of csGRP78 expression. We discovered that a prolin...
Source: Neoplasia - July 12, 2019 Category: Cancer & Oncology Authors: Tseng CC, Zhang P, Lee AS Tags: Neoplasia Source Type: research

Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance.
CONCLUSION: Our integrated approach illustrates the utility of the serial passage spheroid model for examining the emergence and development of chemoresistance in ovarian cancer in a controllable and reproducible format. PMID: 31299607 [PubMed - as supplied by publisher] (Source: Neoplasia)
Source: Neoplasia - July 9, 2019 Category: Cancer & Oncology Authors: Ward Rashidi MR, Mehta P, Bregenzer M, Raghavan S, Fleck EM, Horst EN, Harissa Z, Ravikumar V, Brady S, Bild A, Rao A, Buckanovich RJ, Mehta G Tags: Neoplasia Source Type: research

Overcoming Tyrosine Kinase Inhibitor Resistance in Transformed Cell Harboring SEPT9-ABL1 Chimeric Fusion Protein.
Abstract Hematological malignancies harboring various ABL1 fusions are expected to be sensitive to tyrosine kinase inhibitors (TKIs), similar to those with BCR-ABL1. However, SEPT9-ABL1 exhibits TKI resistance both in vitro and in vivo. SEPT9-ABL1 has the same ABL1 region as seen in BCR-ABL1 but no point mutation in its kinase domain, which is one of the main mechanisms underlying TKI resistance in the leukemic cells harboring BCR-ABL1. The purpose of this study was to reveal the mechanism underlying TKI resistance induced by SEPT9-ABL1. We focused on the TP53 status because TKI-induced apoptosis in BCR-ABL1-posit...
Source: Neoplasia - July 2, 2019 Category: Cancer & Oncology Authors: Kawai H, Matsushita H, Suzuki R, Kitamura Y, Ogawa Y, Kawada H, Ando K Tags: Neoplasia Source Type: research

Circulating Tumor Cell-Based Molecular Classifier for Predicting Resistance to Abiraterone and Enzalutamide in Metastatic Castration-Resistant Prostate Cancer.
Abstract While circulating tumor cell (CTC)-based detection of AR-V7 has been demonstrated to predict patient response to second-generation androgen receptor therapies, the rarity of AR-V7 expression in metastatic castrate-resistant prostate cancer (mCRPC) suggests that other drivers of resistance exist. We sought to use a multiplex gene expression platform to interrogate CTCs and identify potential markers of resistance to abiraterone and enzalutamide. 37 patients with mCRPC initiating treatment with enzalutamide (n = 16) or abiraterone (n = 21) were prospectively enrolled for CTC collection and gene expr...
Source: Neoplasia - July 2, 2019 Category: Cancer & Oncology Authors: Chung JS, Wang Y, Henderson J, Singhal U, Qiao Y, Zaslavsky AB, Hovelson DH, Spratt DE, Reichert Z, Palapattu GS, Taichman RS, Tomlins SA, Morgan TM Tags: Neoplasia Source Type: research

Downregulation of Notch Signaling in Kras-Induced Gastric Metaplasia.
Abstract Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer. Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia. However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood. Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas. These mice exhibit ectopic cell prolife...
Source: Neoplasia - July 2, 2019 Category: Cancer & Oncology Authors: Chung WC, Zhou Y, Atfi A, Xu K Tags: Neoplasia Source Type: research

Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo.
In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169+ bone marrow-resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was...
Source: Neoplasia - June 24, 2019 Category: Cancer & Oncology Authors: Opperman KS, Vandyke K, Clark KC, Coulter EA, Hewett DR, Mrozik KM, Schwarz N, Evdokiou A, Croucher PI, Psaltis PJ, Noll JE, Zannettino AC Tags: Neoplasia Source Type: research

The SOX4/miR-17-92/RB1 Axis Promotes Prostate Cancer Progression.
In this study, we show that SOX4 expression is associated with PCa progression and the development of the NE phenotype in androgen deprivation conditions. High-throughput microRNA profiling and bioinformatics analyses suggest that SOX4 may target the miR-17-92 cluster. SOX4 transcriptionally upregulates miR-17-92 cluster expression in PCa cells. SOX4-induced PCa cell proliferation, migration, and invasion are also mediated by miR-17-92 cluster members. Furthermore, RB1 is a target gene of miR-17-92 cluster. We found that SOX4 downregulates RB1 protein expression by upregulating the miR-17-92 expression. In addition, SOX4-k...
Source: Neoplasia - June 22, 2019 Category: Cancer & Oncology Authors: Liu H, Wu Z, Zhou H, Cai W, Li X, Hu J, Gao L, Feng T, Wang L, Peng X, Qi M, Liu L, Han B Tags: Neoplasia Source Type: research

Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice.
Abstract ELL-associated factor 1 is a transcription elongation factor that shares significant homology and functional similarity to the androgen-responsive prostate tumor suppressor ELL-associated factor 2. EAF2 is frequently down-regulated in advanced prostate cancer and Eaf2 deletion in the mouse induced the development of murine prostatic intraepithelial neoplasia. Here we show that similar to EAF2, EAF1 is frequently down-regulated in advanced prostate cancer. Co-downregulation of EAF1 and EAF2 occurred in 40% of clinical specimens with Gleason score>7. We developed and characterized a murine model of prost...
Source: Neoplasia - June 20, 2019 Category: Cancer & Oncology Authors: Pascal LE, Su F, Wang D, Ai J, Song Q, Wang Y, O'Malley KJ, Cross B, Rigatti LH, Green A, Dhir R, Wang Z Tags: Neoplasia Source Type: research

The FUS-DDIT3 Interactome in Myxoid Liposarcoma.
Abstract Myxoid liposarcoma is a malignant lipogenic tumor that develops in deep soft tissues. While local control rates are good, current chemotherapy options remain ineffective against metastatic disease. Myxoid liposarcoma is characterized by the FUS-DDIT3 fusion oncoprotein that is proposed to function as an aberrant transcription factor, but its exact mechanism of action has remained unclear. To identify the key functional interacting partners of FUS-DDIT3, this study utilized immunoprecipitation-mass spectrometry (IP-MS) to identify the FUS-DDIT3 interactome in whole cell lysates of myxoid liposarcoma cells,...
Source: Neoplasia - June 17, 2019 Category: Cancer & Oncology Authors: Yu JSE, Colborne S, Hughes CS, Morin GB, Nielsen TO Tags: Neoplasia Source Type: research

Allosteric and ATP-Competitive Inhibitors of mTOR Effectively Suppress Tumor Progression-Associated Epithelial-Mesenchymal Transition in the Kidneys of Tsc2+/- Mice.
In this study, we report hybrid cells with epithelial and mesenchymal features in angiomyolipomas and partial EMT in carcinomas from TSC patients and describe a new model of EMT activation during tumor progression from cyst to papillary adenoma to solid carcinoma in the kidneys of Tsc2+/- mice. Features of EMT occurred infrequently in TSC-associated cysts but increased as the lesions progressed through papillary adenoma to solid carcinoma where epithelial-mesenchymal hybrid cells were abundant, indicating partial EMT. We also compared the effects of the novel ATP-competitive mTOR inhibitor AZD2014 with the allosteric mTOR ...
Source: Neoplasia - June 14, 2019 Category: Cancer & Oncology Authors: Jones AT, Yang J, Narov K, Henske EP, Sampson JR, Shen MH Tags: Neoplasia Source Type: research

Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells.
ied T Abstract Chromosomal aneuploidy is a defining feature of epithelial cancers. The pattern of aneuploidies is cancer-type specific. For instance, the gain of chromosome 13 occurs almost exclusively in colorectal cancer. We used microcell-mediated chromosome transfer to generate gains of chromosome 13 in the diploid human colorectal cancer cell line DLD-1. Extra copies of chromosome 13 resulted in a significant and reproducible up-regulation of transcript levels of genes on chromosome 13 (P = .0004, FDR = 0.01) and a genome-wide transcriptional deregulation in all 8 independent clones generated. Genes c...
Source: Neoplasia - June 4, 2019 Category: Cancer & Oncology Authors: Wangsa D, Braun R, Stuelten CH, Brown M, Bauer KM, Emons G, Weston LA, Hu Y, Yang HH, Vila-Casadesús M, Lee MP, Brauer P, Warner L, Upender M, Hummon AB, Camps J, Ried T Tags: Neoplasia Source Type: research

CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation.
Abstract Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymeraseII, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induct...
Source: Neoplasia - May 28, 2019 Category: Cancer & Oncology Authors: Itkonen HM, Poulose N, Walker S, Mills IG Tags: Neoplasia Source Type: research

The Deubiquitinase Inhibitor b-AP15 and Its Effect on Phenotype and Function of Monocyte-Derived Dendritic Cells.
, Dörfel D Abstract The ubiquitin-proteasome system is elementary for cellular protein degradation and gained rising attention as a new target for cancer therapy due to promising clinical trials with bortezomib, the first-in class proteasome inhibitor meanwhile approved for multiple myeloma and mantle cell lymphoma. Both bortezomib and next-generation proteasome inhibitors mediate their effects by targeting the 20S core particle of the 26S proteasome. The novel small molecule inhibitor b-AP15 affects upstream elements of the ubiquitin-proteasome cascade by suppressing the deubiquitinase activity of both prote...
Source: Neoplasia - May 24, 2019 Category: Cancer & Oncology Authors: Schmidt M, Altdörfer V, Schnitte S, Fuchs AR, Kropp KN, Maurer S, Müller MR, Salih HR, Rittig SM, Grünebach F, Dörfel D Tags: Neoplasia Source Type: research

Notch and mTOR Signaling Pathways Promote Human Gastric Cancer Cell Proliferation.
Abstract Notch pathway signaling is known to promote gastric stem cell proliferation, and constitutive pathway activation induces gastric tumors via mTORC1 activation in mouse genetic models. The purpose of this study was to determine whether human gastric adenocarcinomas are similarly dependent on Notch and mTORC1 signaling for growth. Gene expression profiling of 415 human gastric adenocarcinomas in The Cancer Genome Atlas, and a small set of locally obtained gastric cancers showed enhanced expression of Notch pathway components, including Notch ligands, receptors and downstream target genes. Human gastric adeno...
Source: Neoplasia - May 23, 2019 Category: Cancer & Oncology Authors: Hibdon ES, Razumilava N, Keeley TM, Wong G, Solanki S, Shah YM, Samuelson LC Tags: Neoplasia Source Type: research

Telomere Trimming and DNA Damage as Signatures of High Risk Neuroblastoma.
Abstract Telomeres play important roles in genome stability and cell proliferation. High risk neuroblastoma (HRNB), an aggressive childhood cancer, is especially reliant on telomere maintenance. Three recurrent genetic aberrations in HRNB (MYCN amplification, TERT re-arrangements, and ATRX mutations) are mutually exclusive and each capable of promoting telomere maintenance mechanisms (i.e., through telomerase or ALT). We analyzed a panel of 5 representative HRNB cell lines and 30 HRNB surgical samples using assays that assess average telomere lengths, length distribution patterns, single-stranded DNA on the G- and...
Source: Neoplasia - May 22, 2019 Category: Cancer & Oncology Authors: Yu EY, Cheung IY, Feng Y, Rabie MO, Roboz GJ, Guzman ML, Cheung NV, Lue NF Tags: Neoplasia Source Type: research

SUMOylation of Csk Negatively Modulates its Tumor Suppressor Function.
Abstract Csk, a non-receptor tyrosine kinase, serves as an indispensable negative regulator of the Src family kinases (SFKs). However, little is known about regulation of Csk expression so far. SUMOylation, a reversible post-translational modification, has been shown to regulate many biological processes especially in tumor progression. Here we report that Csk is covalently modified by SUMO1 at lysine 53 (K53) both in vitro and in vivo. Treatment with hydrogen peroxide inhibited this modification to a certain extent, but PIAS3, identified as the main specific SUMO E3 ligase for Csk, could significantly enhance SUM...
Source: Neoplasia - May 21, 2019 Category: Cancer & Oncology Authors: Cui N, Liu T, Guo Y, Dou J, Yang Q, Zhang H, Chen R, Wang Y, Zhao X, Yu J, Huang J Tags: Neoplasia Source Type: research

SIRT3 regulates cancer cell proliferation through deacetylation of PYCR1 in proline metabolism.
Abstract SIRT3 is a major mitochondrial deacetylase, which regulates various metabolic pathways by deacetylation; however, the effect of SIRT3 on proline metabolism is not reported. Pyrroline-5-carboxylate reductase 1 (PYCR1) participates in proline synthesis process by catalyzing the reduction of P5C to proline with concomitant generation of NAD+ and NADP+. PYCR1 is highly expressed in various cancers, and it can promote the growth of tumor cells. Here, through immunoprecipitation and mass spectrometry, we found that PYCR1 is in SIRT3's interacting network. PYCR1 directly binds to SIRT3 both in vivo and in vitro....
Source: Neoplasia - May 17, 2019 Category: Cancer & Oncology Authors: Chen S, Yang X, Yu M, Wang Z, Liu B, Liu M, Liu L, Ren M, Qi H, Zou J, Vucenik I, Zhu WG, Luo J Tags: Neoplasia Source Type: research

Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness.
In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulate...
Source: Neoplasia - May 14, 2019 Category: Cancer & Oncology Authors: Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E Tags: Neoplasia Source Type: research

Determination of Pyruvate Metabolic Fates Modulates Head and Neck Tumorigenesis.
Abstract Even with increasing evidence for roles of glycolytic enzymes in controlling cancerous characteristics, the best target of candidate metabolic enzymes for lessening malignancy remains under debate. Pyruvate is a main glycolytic metabolite that could be mainly converted into either lactate by Lactate Dehydrogenase A (LDHA) or acetyl-CoA by Pyruvate Dehydrogenase E1 component α subunit (PDHA1) catalytic complex. In tumor cells, accumulating lactate is produced whereas the conversion of pyruvate into mitochondrial acetyl-CoA is less active compared with their normal counterparts. This reciprocal molecu...
Source: Neoplasia - May 14, 2019 Category: Cancer & Oncology Authors: Chen TY, Hsieh YT, Huang JM, Liu CJ, Chuang LT, Huang PC, Kuo TY, Chia HY, Chou CY, Chang CW, Chen YF, Chen HM, Lo JF, Li WC Tags: Neoplasia Source Type: research

Cellular Metabolic Heterogeneity In Vivo Is Recapitulated in Tumor Organoids.
Abstract Heterogeneous populations within a tumor have varying metabolic profiles, which can muddle the interpretation of bulk tumor imaging studies of treatment response. Although methods to study tumor metabolism at the cellular level are emerging, these methods provide a single time point "snapshot" of tumor metabolism and require a significant time and animal burden while failing to capture the longitudinal metabolic response of a single tumor to treatment. Here, we investigated a novel method for longitudinal, single-cell tracking of metabolism across heterogeneous tumor cell populations using optic...
Source: Neoplasia - May 8, 2019 Category: Cancer & Oncology Authors: Sharick JT, Jeffery JJ, Karim MR, Walsh CM, Esbona K, Cook RS, Skala MC Tags: Neoplasia Source Type: research