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Martin Böttcher, Kathrin Renner, Raffaela Berger, Kristin Mentz, Simone Thomas, Zugey Elizabeth Cardenas-Conejo, Katja Dettmer, Peter J Oefner, Andreas Mackensen, Marina Kreutz, Dimitrios Mougiakakos
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion...
2018: Oncoimmunology
Elizabeth J English, Sarah A Mahn, Adriano Marchese
Signaling activated by binding of the C-X-C motif chemokine ligand CXCL12 to its cognate G protein-coupled receptor (GPCR), chemokine C-X-C motif receptor 4 (CXCR4), is linked to metastatic disease. Yet the mechanisms governing CXCR4 signaling remain poorly understood. Here we show that endocytosis and early endosome antigen 1 (EEA1), which is part of the endosome fusion machinery, are required for CXCL12-mediated AKT Ser/Thr kinase (Akt) signaling selective for certain Akt substrates. Pharmacological inhibition of endocytosis partially attenuated CXCL12-induced phosphorylation of Akt, but not phosphorylation of ERK-1/2...
June 13, 2018: Journal of Biological Chemistry
David Carr, Rosanna Lau, Alexandra D Hnatykiw, Gwendoline C D Ward, Manijeh Daneshmand, Miguel A Cabrita, M A Christine Pratt
Cellular inhibitor of apoptosis proteins-1 and -2 (cIAP1/2) are integral to regulation of apoptosis and signaling by the tumor necrosis factor (TNF) and related family of receptors. The expression of cIAP2 in tissues is typically low and considered functionally redundant with cIAP1, however cIAP2 can be activated by a variety of cellular stresses. Members of the TNFR family and their ligands have essential roles in mammary gland biology. We have found that cIAP2-/- virgin mammary glands have reduced ductal branching and delayed lobuloalveogenesis in early pregnancy...
June 6, 2018: Journal of Mammary Gland Biology and Neoplasia
Zhenyu Zhong, Vaishali Pannu, Matthew Rosenow, Adam Stark, David Spetzler
The KIAA0100 gene was identified in the human immature myeloid cell line cDNA library. Recent studies have shown that its expression is elevated in breast cancer and associated with more aggressive cancer types as well as poor outcomes. However, its cellular and molecular function is yet to be understood. Here we show that silencing KIAA0100 by siRNA in the breast cancer cell line MDA-MB-231 significantly reduced the cancer cells' aggressive behavior, including cell aggregation, reattachment, cell metastasis and invasion...
June 4, 2018: Cancers
Christopher M Dower, Carson A Wills, Steven M Frisch, Hong-Gang Wang
Macroautophagy/autophagy is a fundamental cellular degradation mechanism that maintains cell homeostasis, regulates cell signaling, and promotes cell survival. Its role in promoting tumor cell survival in stress conditions is well characterized, and makes autophagy an attractive target for cancer therapy. Emerging research indicates that autophagy also influences cancer metastasis, which is the primary cause of cancer-associated mortality. However, data demonstrate that the regulatory role of autophagy in metastasis is multifaceted, and includes both metastasis-suppressing and -promoting functions...
June 4, 2018: Autophagy
Eva Rath, Antonio Moschetta, Dirk Haller
The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3-5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity...
May 29, 2018: Nature Reviews. Gastroenterology & Hepatology
Carrie D House, Valentina Grajales, Michelle Ozaki, Elizabeth Jordan, Helmae Wubneh, Danielle C Kimble, Jana M James, Marianne K Kim, Christina M Annunziata
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC...
May 25, 2018: BMC Cancer
Sara Al Habyan, Christina Kalos, Joseph Szymborski, Luke McCaffrey
Ovarian cancer is the most lethal gynecological cancer, where survival rates have had modest improvement over the last 30 years. Metastasis of cancer cells is a major clinical problem, and patient mortality occurs when ovarian cancer cells spread beyond the confinement of ovaries. Disseminated ovarian cancer cells typically spread within the abdomen, where ascites accumulation aids in their transit. Metastatic ascites contain multicellular spheroids, which promote chemo-resistance and recurrence. However, little is known about the origin and mechanisms through which spheroids arise...
May 23, 2018: Oncogene
Hao Liu, Wei Chen, Xiao Zhi, En-Jiang Chen, Tao Wei, Jian Zhang, Jian Shen, Li-Qiang Hu, Bin Zhao, Xin-Hua Feng, Xue-Li Bai, Ting-Bo Liang
Tumor self-seeding occurs when circulating malignant cells reinfiltrate the original tumor. The process may breed more aggressive tumor cells, which may contribute to cancer progression. In this study, we observed tumor self-seeding in mouse xenograft models of hepatocellular carcinoma (HCC) for the first time. We confirmed that circulating tumor cell uptake of tumor-derived exosomes, which are increasingly recognized as key instigators of cancer progression by facilitating cell-cell communication, promoted tumor self-seeding by enhancing the invasive and migration capability of recipient HCC cells...
May 22, 2018: Oncogene
Fatma Ashour, Mohammed H Awwad, Hayam E L Sharawy, Mohamed Kamal
BACKGROUND AND OBJECTIVES: Breast cancer (BC) is classified according to estrogen receptor (ER) status into ER+ and ER- tumors. ER+ tumors have a worse response to chemotherapy compared to ER- tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs) play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB...
May 17, 2018: Journal of the Egyptian National Cancer Institute
Jolien S de Groot, Max A K Rätze, Miranda van Amersfoort, Tanja Eisemann, Eva J Vlug, Mijanou T Niklaas, Suet-Feung Chin, Carlos Caldas, Paul J van Diest, Jos Jonkers, Johan de Rooij, Patrick W B Derksen
Mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), although approximately 10-15% of all ILCs retain membrane-localized E-cadherin, despite the presence of an apparent non-cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α-catenin (CTNNA1) loss in the regulation of anchorage independence of non-invasive breast carcinoma...
May 17, 2018: Journal of Pathology
Yoshinaga Okugawa, Yuji Toiyama, Takashi Ichikawa, Mikio Kawamura, Hiromi Yasuda, Hiroyuki Fujikawa, Susumu Saigusa, Masaki Ohi, Toshimitsu Araki, Koji Tanaka, Yasuhiro Inoue, Motoyoshi Tanaka, Chikao Miki, Masato Kusunoki
Colony‑stimulating‑factor‑1 (CSF‑1) is a hematopoietic growth factor that exerts its effects through the c‑fms/CSF‑1 receptor (CSF‑1R). The CSF‑1/CSF‑1R axis is thought to be involved in the development of several types of cancer. This study aimed to clarify the clinical and biological significance of the CSF‑1/CSF‑1R axis in gastric cancer (GC). For this purpose, we evaluated CSF‑1 and CSF‑1R expression in GC tissues from 148 patients by RT‑qPCR and immunohistochemistry. The biological roles of the CSF‑1/CSF‑1R axis were investigated by measuring the cell proliferation and migration, and anoikis resistance in a human GC cell line following treatment with recombinant human CSF‑1 and/or CSF‑1R inhibitor...
May 16, 2018: International Journal of Oncology
Juliette Sauveur, Eva-Laure Matera, Kamel Chettab, Philippe Valet, Jerome Guitton, Ariel Savina, Charles Dumontet
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged in vitro exposure of the gastroesophageal junction cancer cell line OE-19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells...
April 20, 2018: Oncotarget
Sarmistha Talukdar, Anjan K Pradhan, Praveen Bhoopathi, Xue-Ning Shen, Laura A August, Jolene J Windle, Devanand Sarkar, Frank B Furnari, Webster K Cavenee, Swadesh K Das, Luni Emdad, Paul B Fisher
Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP)...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Ke-di Sa, Xiang Zhang, Xiao-Fei Li, Zhong-Ping Gu, An-Gang Yang, Rui Zhang, Ji-Peng Li, Jian-Yong Sun
Metastasis is the major cause for the death of patients with colorectal cancer (CRC). Anoikis resistance enhances the survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs. miR-124 is a pleiotropically tumor suppressive small non-coding molecule. However, its role and mechanism in the regulation of cancer cell anoikis are still unknown. Here, we found that overexpression of miR-124 promotes anoikis of CRC cells in vitro and in vivo. In silico analysis and the experimental evidence supported that ITGA3 is a bona fide target of miR-124...
May 11, 2018: Biochemical and Biophysical Research Communications
Naoko Yoneura, Shigetsugu Takano, Hideyuki Yoshitomi, Yasuyuki Nakata, Reiri Shimazaki, Shingo Kagawa, Katsunori Furukawa, Tsukasa Takayashiki, Satoshi Kuboki, Masaru Miyazaki, Masayuki Ohtsuka
The interaction between cancer cells and stromal components contributes to cancer invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). The present study investigated the role of the correlation between annexin II (ANX2) and stromal tenascin C (TNC) with the progression of PDAC. The functions of the expression ANX2 and TNC were assessed in in vitro experiments using mouse and human PDAC cells, and the clinical effect was analyzed using immunohistochemistry with surgically resected PDAC tissues...
May 2, 2018: International Journal of Molecular Medicine
Rosa Fontana, Daniela Guidone, Felicia Sangermano, Viola Calabrò, Alessandra Pollice, Girolama La Mantia, Maria Vivo
ARF role as tumor suppressor has been challenged in the last years by several findings of different groups ultimately showing that its functions can be strictly context dependent. We previously showed that ARF loss in HeLa cells induces spreading defects, evident as rounded morphology of depleted cells, accompanied by a decrease of phosphorylated Focal Adhesion Kinase (FAK) protein levels and anoikis. These data, together with previous finding that a PKC dependent signalling pathway can lead to ARF stabilization, led us to the hypothesis that ARF functions in cell proliferation might be regulated by phosphorylation...
May 4, 2018: Scientific Reports
Rie Imamaki, Kazuko Ogawa, Yasuhiko Kizuka, Yusuke Komi, Soichi Kojima, Norihiro Kotani, Koichi Honke, Takashi Honda, Naoyuki Taniguchi, Shinobu Kitazume
Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation-dependent regulatory mechanism for tumor angiogenesis. St6gal1-/- mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis...
May 2, 2018: Oncogene
Madhura Patankar, Sara Väyrynen, Anne Tuomisto, Markus Mäkinen, Sinikka Eskelinen, Tuomo J Karttunen
BACKGROUND/AIM: Micropapillary structures (MIPs) are focal piles of columnar cells without extracellular matrix contact, and common in serrated colorectal carcinoma (CRC). In order to characterize biology of MIPs in colorectal cancer (CRC), the proliferation and apoptosis rates, and survivin expression were compared between MIPs and other cancer epithelial cells of CRC (non-MIPs). MATERIALS AND METHODS: We assessed 46 samples of normal colorectal mucosa, 62 carcinomas and 54 polyps for proliferation (Ki67), apoptosis (M30), and survivin expression by immunohistochemistry...
May 2018: Anticancer Research
Lin Yang, Zihao He, Jingyue Yao, Renxiang Tan, Yejin Zhu, Zhiyu Li, Qinglong Guo, Libin Wei
Breast cancer is one of the most lethal tumors in the world, among which 15% are triple-negative breast cancers (TNBCs) with higher metastasis and lower survival rate. Anoikis resistance is a key process during tumor metastasis, which is usually accompanied with metabolism reprogram. In this study, we established an anchorage independent growth model for MDA-MB-231 cells and investigated the changes in metabolism and redox homeostasis. Results showed that during detached-growth, MDA-MB-231 cells tend to generate ATP through fatty acid oxidation (FAO), instead of glycolysis...
April 18, 2018: Redox Biology
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