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Neoplasia: An International Journal for Oncology Research

Yunzhou Shi, Jason Oeh, Anna Hitz, Maj Hedehus, Jeffrey Eastham-Anderson, Franklin V Peale, Patricia Hamilton, Thomas O'Brien, Deepak Sampath, Richard A D Carano
The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment...
October 5, 2017: Neoplasia: An International Journal for Oncology Research
Xiquan Ke, Rong Yan, Zhenguo Sun, Yulan Cheng, Amy Meltzer, Nonghua Lu, Xu Shu, Zhe Wang, Binbin Huang, Xi Liu, Zhixiong Wang, Jee Hoon Song, Christopher K Ng, Sariat Ibrahim, John M Abraham, Eun Ji Shin, Shuixiang He, Stephen J Meltzer
There have been no reports describing the effects of cancer cell-derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)-derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying these effects. EVs were identified using PKH-67 staining. Morphologic changes, Ki-67 immunochemistry, cell viability, growth rates, and expression levels of miR-25 and miR-210, as well as of their target mRNAs, were determined in gastroids co-cultured with EAC-derived extracellular vesicles (c-EVs)...
September 29, 2017: Neoplasia: An International Journal for Oncology Research
Laura J Vella, Andreas Behren, Bradley Coleman, David W Greening, Andrew F Hill, Jonathan Cebon
Treatment of BRAF mutant melanoma with kinase inhibitors has been associated with rapid tumor regression; however, this clinical benefit is short-lived, and most patients relapse. A number of studies suggest that the extracellular environment promotes BRAF inhibitor resistance and tumor progression. Extracellular vesicles, such as exosomes, are functional mediators in the extracellular environment. They are small vesicles known to carry a concentrated group of functional cargo and serve as intercellular communicators not only locally but also systemically...
September 27, 2017: Neoplasia: An International Journal for Oncology Research
Ana E Paiva, Luiza Lousado, Viviani M Almeida, Julia P Andreotti, Gabryella S P Santos, Patrick O Azevedo, Isadora F G Sena, Pedro H D M Prazeres, Isabella T Borges, Vasco Azevedo, Akiva Mintz, Alexander Birbrair
Prostate cancer cells metastasize to the bones, causing ectopic bone formation, which results in fractures and pain. The cellular mechanisms underlying new bone production are unknown. In a recent study, Lin and colleagues, by using state-of-the-art techniques, including prostate cancer mouse models in combination with sophisticated in vivo lineage-tracing technologies, revealed that endothelial cells form osteoblasts induced by prostate cancer metastasis in the bone. Strikingly, genetic deletion of osteorix protein from endothelial cells affected prostate cancer-induced osteogenesis in vivo...
September 25, 2017: Neoplasia: An International Journal for Oncology Research
William L Harryman, Jaime M C Gard, Kelvin W Pond, Skyler J Simpson, Lucas H Heppner, Daniel Hernandez-Cortes, Andrew S Little, Jennifer M Eschbacher, Anne E Cress
Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis...
September 24, 2017: Neoplasia: An International Journal for Oncology Research
Lu Zhang, Yuan Wang, Xiaojie Li, Xin Xia, Na Li, Ruiping He, Hongtao He, Chuanchun Han, Wenzhi Zhao
Chemoresistance remains a major drawback to osteosarcoma treatment. ZBTB7A, a member of the POK transcription repressor family, was shown to play an important role in tumorigenesis. However, the effect of ZBTB7A on osteosarcoma chemoresistance is completely unknown. In this study, we found that ZBTB7A is increased in cisplatin-resistant osteosarcoma cells and that elevated ZBTB7A inhibits cisplatin-induced apoptosis by repressing LINC00473 expression. Further mechanistic studies revealed that ZBTB7A directly binds to the promoter and suppresses the transcription of LINC00473...
September 20, 2017: Neoplasia: An International Journal for Oncology Research
Sara Zafarnia, Jessica Bzyl-Ibach, Igor Spivak, Yongping Li, Susanne Koletnik, Dennis Doleschel, Anne Rix, Sibylle Pochon, Isabelle Tardy, Seena Koyadan, Marc van Zandvoort, Moritz Palmowski, Fabian Kiessling, Wiltrud Lederle
Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis...
September 19, 2017: Neoplasia: An International Journal for Oncology Research
Wen-Cheng Chung, Shubing Zhang, Lavanya Challagundla, Yunyun Zhou, Keli Xu
Claudin-low breast cancer (CLBC) is a poor prognosis molecular subtype showing stemness and mesenchymal features. We previously discovered that deletion of a Notch signaling modulator, Lunatic Fringe (Lfng), in the mouse mammary gland induced a subset of tumors resembling CLBC. Here we report that deletion of one copy of p53 on this background not only accelerated mammary tumor development but also led to a complete penetrance of the mesenchymal stem-like phenotype. All mammary tumors examined in the Lfng/p53 compound mutant mice displayed a mesenchymal/spindloid pathology...
September 19, 2017: Neoplasia: An International Journal for Oncology Research
Xiang Yuan, Xinshuai Wang, Bianli Gu, Yingjian Ma, Yiwen Liu, Man Sun, Jinyu Kong, Wei Sun, Huizhi Wang, Fuyou Zhou, Shegan Gao
Directional cell migration is of fundamental importance to a variety of biological events, including metastasis of malignant cells. Herein, we specifically investigated SET oncoprotein, a subunit of the recently identified inhibitor of acetyltransferases (INHAT) complex and identified its role in the establishment of front-rear cell polarity and directional migration in Esophageal Squamous Cell Carcinoma (ESCC). We further define the molecular circuits that govern these processes by showing that SET modulated DOCK7/RAC1 and cofilin signaling events...
September 19, 2017: Neoplasia: An International Journal for Oncology Research
Xiaozeng Lin, Yan Gu, Anil Kapoor, Fengxiang Wei, Tariq Aziz, Diane Ojo, Yanzhi Jiang, Michael Bonert, Bobby Shayegan, Huixiang Yang, Khalid Al-Nedawi, Pierre Major, Damu Tang
We investigate the association of MUC1 with castration-resistant prostate cancer (CRPC), bone metastasis, and PC recurrence. MUC1 expression was studied in patient-derived bone metastasis and CRPCs produced by prostate-specific PTEN(-/-) mice and LNCaP xenografts. Elevations in MUC1 expression occur in CRPC. Among nine patients with hormone-naïve bone metastasis, eight express MUC1 in 61% to 100% of PC cells. Utilizing cBioPortal PC genomic data, we organized a training (n=300), testing (n=185), and validation (n=194) cohort...
September 17, 2017: Neoplasia: An International Journal for Oncology Research
Bryan Oronsky, Tony R Reid, Arnold Oronsky, Corey A Carter
A few years ago the answer to the question in the title of this review would have been, "unfortunately not much" or even "nothing", likely eliciting knowing nods of agreement from oncologists. For the last 3 decades, SCLC has been notorious for its lack of progress, as drug after drug, over 60 of them, in fact, including inhibitors of VEGF, IGFR, mTOR, EGFR and HGF has failed and fallen by the wayside due to little or no impact on PFS or OS, while SCLC's cousin, NSCLC, has notched success after success with a spate of targeted treatment and immunotherapy regulatory approvals...
September 6, 2017: Neoplasia: An International Journal for Oncology Research
Jarmila Herůdková, Kamil Paruch, Prashant Khirsariya, Karel Souček, Martin Krkoška, Olga Vondálová Blanářová, Petr Sova, Alois Kozubík, Alena Hyršlová Vaculová
Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes...
September 5, 2017: Neoplasia: An International Journal for Oncology Research
Jaeil Kim, Eun-Ju Do, Helen Moinova, Sang Mun Bae, Ja Young Kang, Seung-Mo Hong, Stephen P Fink, Jinmyoung Joo, Young-Ah Suh, Se Jin Jang, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Jaewon Choe, Suk-Kyun Yang, Sanford D Markowitz, Sang-Yeob Kim, Seung-Jae Myung
A versatile biomarker for detecting colonic adenoma and colon cancer has yet to be developed. Colon cancer secreted protein-2 (CCSP-2) is a protein specifically expressed and secreted in colon adenomas and cancers. We developed a fluorescent imaging method based on CCSP-2 targeting for a more sensitive and specific detection of colorectal tumors. CCSP-2 expression was evaluated in human colon adenoma and colorectal specimens. Anti-CCSP-2 antibody was labeled with a near-infrared fluorescent dye, FPR-675, and molecular imaging of surgical human colorectal tumors was performed...
September 4, 2017: Neoplasia: An International Journal for Oncology Research
Naseruddin Höti, Shuang Yang, Paul Aiyetan, Binod Kumar, Yingwei Hu, David Clark, Arife Unal Eroglu, Punit Shah, Tamara Johnson, Wasim H Chowdery, Hui Zhang, Ronald Rodriguez
Although XPO5 has been characterized to have tumor-suppressor features in the miRNA biogenesis pathway, the impact of altered expression of XPO5 in cancers is unexplored. Here we report a novel "oncogenic" role of XPO5 in advanced prostate cancer. Using prostate cancer models, we found that excess levels of XPO5 override the inhibitory effect of the canoncial miRNA-mRNA regulation, resulting in a global increase in proteins expression. Importantly, we found that decreased expression of XPO5 could promote an increase in proteasome degradation, whereas overexpression of XPO5 leads to altered protein posttranslational modification via hyperglycosylation, resulting in cellular protein stability...
September 4, 2017: Neoplasia: An International Journal for Oncology Research
Lukasz Turczyk, Kamila Kitowska, Magdalena Mieszkowska, Kamil Mieczkowski, Dominika Czaplinska, Dominika Piasecka, Radzisław Kordek, Andrzej C Skladanowski, Piotr Potemski, Hanna M Romanska, Rafal Sadej
Signaling mediated by growth factors receptors has long been suggested as one of the key factors responsible for failure of endocrine treatment in breast cancer (BCa). Herein we present that in the presence of tamoxifen, FGFs (Fibroblast Growth Factors) promote BCa cell growth with the strongest effect being produced by FGF7. FGFR2 was identified as a mediator of FGF7 action and the FGFR2-induced signaling was found to underlie cancer-associated fibroblasts-dependent resistance to tamoxifen. FGF7/FGFR2-triggered pathway was shown to induce ER phosphorylation, ubiquitination and subsequent ER proteasomal degradation which counteracted tamoxifen-promoted ER stabilization...
August 31, 2017: Neoplasia: An International Journal for Oncology Research
Nicola Alessio, Stefania Capasso, Angela Ferone, Giovanni Di Bernardo, Marilena Cipollaro, Fiorina Casale, Gianfranco Peluso, Antonio Giordano, Umberto Galderisi
Although mice models rank among the most widely used tools for understanding human genetics, biology, and diseases, differences between orthologous genes among species as close as mammals are possible, particularly in orthologous gene pairs in which one or more paralogous (i.e., duplicated) genes appear in the genomes of the species. Duplicated genes can possess overlapping functions and compensate for each other. The retinoblastoma gene family demonstrates typical composite functionality in its three member genes (i...
August 30, 2017: Neoplasia: An International Journal for Oncology Research
Yong-Sheng Tu, Jin He, Huan Liu, Hans C Lee, Hua Wang, Jo Ishizawa, Joshua E Allen, Michael Andreeff, Robert Z Orlowski, Richard E Davis, Jing Yang
In multiple myeloma, despite recent improvements offered by new therapies, disease relapse and drug resistance still occur in the majority of patients. Therefore, there is an urgent need for new drugs that can overcome drug resistance and prolong patient survival after failure of standard therapies. The imipridone ONC201 causes downstream inactivation of ERK1/2 signaling and has tumoricidal activity against a variety of tumor types, while its efficacy in preclinical models of myeloma remains unclear. In this study, we treated human myeloma cell lines and patient-derived tumor cells with ONC201...
August 29, 2017: Neoplasia: An International Journal for Oncology Research
Hima V Vangapandu, Mary L Ayres, Christopher A Bristow, William G Wierda, Michael J Keating, Kumudha Balakrishnan, Christine M Stellrecht, Varsha Gandhi
Peripheral blood chronic lymphocytic leukemia (CLL) cells are replicationally quiescent mature B-cells. In short-term cultures, supporting stromal cells provide a survival advantage to CLL cells by inducing transcription and translation without promoting proliferation. We hypothesized that the stromal microenvironment augments malignant B cells' metabolism to enable the cells to cope with their energy demands for transcription and translation. We used extracellular flux analysis to assess the two major energy-generating pathways, mitochondrial oxidative phosphorylation (OxPhos) and glycolysis, in primary CLL cells in the presence of three different stromal cell lines...
August 29, 2017: Neoplasia: An International Journal for Oncology Research
Nirmal Rajasekaran, Hun Soon Jung, Soo Hyeon Bae, Chaithanya Chelakkot, Sungyoul Hong, Jong-Sun Choi, Dong-Seok Yim, Yu-Kyoung Oh, Yoon-La Choi, Young Kee Shin
Toxicity and resistance remain major challenges for advanced or recurrent cervical cancer therapies, as treatment requires high doses of chemotherapeutic agents. Restoration of TP53 and hypophosphorylated-retinoblastoma (pRB) proteins by human papillomavirus (HPV) E6/E7 siRNA sensitizes HPV-positive cervical cancer cells toward chemotherapeutic agents. Here, we investigated the therapeutic effects of E6/E7 siRNA on the dynamic behavior of TP53 and RB/E2F signaling networks in deciding the cell fate. The synergistic effect of HPV E6/E7 siRNA pool (SP) with chemotherapeutic agents on TP53 and RB/E2F signaling, proliferation, and apoptosis was analyzed in vitro and in vivo...
August 23, 2017: Neoplasia: An International Journal for Oncology Research
Swetha Tati, John C Fisk, Julia Abdullah, Loukia Karacosta, Taylor Chrisikos, Padraic Philbin, Susan Morey, Diala Ghazal, Fatma Zazala, Joseph Jessee, Sally Quataert, Stephen Koury, David Moreno, Jing Ying Eng, Vladislav V Glinsky, Olga V Glinskii, Muctarr Sesay, Anthony W Gebhard, Karamveer Birthare, James R Olson, Kate Rittenhouse-Olson
JAA-F11 is a highly specific mouse monoclonal to the Thomsen-Friedenreich Antigen (TF-Ag) which is an alpha-O-linked disaccharide antigen on the surface of ~80% of human carcinomas, including breast, lung, colon, bladder, ovarian, and prostate cancers, and is cryptic on normal cells. JAA-F11 has potential, when humanized, for cancer immunotherapy for multiple cancer types. Humanization of JAA-F11, was performed utilizing complementarity determining regions grafting on a homology framework. The objective herein is to test the specificity, affinity and biology efficacy of the humanized JAA-F11 (hJAA-F11)...
August 19, 2017: Neoplasia: An International Journal for Oncology Research
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