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Molecular Cancer Research: MCR

Sayantan Maji, Pankaj Chaudhary, Irina Akopova, Phung M Nguyen, Richard J Hare, Ignacy Gryczynski, Jamboor K Vishwanatha
: Tumor-derived exosomes are emerging mediators of tumorigenesis and tissue-specific metastasis. Proteomic profiling has identified Annexin A2 as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal-AnnexinA2 (exo-AnxA2) are still lacking. In this study, mechanistic insight was sought regarding exo-AnxA2 and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-AnxA2 in angiogenesis...
October 19, 2016: Molecular Cancer Research: MCR
Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Aska Toda, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi, Ken-Ichirou Morishige, Hirohisa Kurachi, Ernst Lengyel, Tadashi Kimura
: Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMCs) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell-cell communications are exosomes, 30-100 nm membrane vesicles of endocytic origin, through the cell-cell transfer of proteins, mRNAs, or microRNAs...
October 6, 2016: Molecular Cancer Research: MCR
Masayoshi Miyawaki, Hiroyuki Yasuda, Tetsuo Tani, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Keiko Ohgino, Shigenari Nukaga, Toshiyuki Hirano, Ichiro Kawada, Katsuhiko Naoki, Yuichiro Hayashi, Tomoko Betsuyaku, Kenzo Soejima
: Activation of the epidermal growth factor receptor (EGFR) pathway is one of the mechanisms inducing acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) such as crizotinib and alectinib. Ceritinib is a highly selective ALK inhibitor and shows promising efficacy in non-small cell lung cancers (NSCLCs) harboring the ALK gene rearrangement. However, the precise mechanism underlying acquired resistance to ceritinib is not well defined. This study set out to clarify the mechanism in ALK-translocated lung cancer and to find the preclinical rationale overcoming EGFR pathway-induced acquired resistance to ALK-TKIs...
October 5, 2016: Molecular Cancer Research: MCR
Emily J Faivre, Denise Wilcox, Xiaoyu Lin, Paul Hessler, Maricel Torrent, Wei He, Tamar Uziel, Daniel H Albert, Keith McDaniel, Warren Kati, Yu Shen
: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075...
October 5, 2016: Molecular Cancer Research: MCR
Pegah Abdollahi, Esten Nymoen Vandsemb, Magnus Aassved Hjort, Kristine Misund, Toril Holien, Anne-Marit Sponaas, Torstein B Ro, Tobias S Slordahl, Magne Borset
: Phosphatase of regenerating liver-3 (PTP4A3/PRL-3) is a dual specificity phosphatase that is up-regulated in various types of cancers and is related to poor prognosis and aggressive tumor behavior. The expression level of PRL-3 is elevated in response to several anti-apoptotic cytokines, including interleukin-6 (IL6), in cancer cells from patients with multiple myeloma (MM) and can promote survival and migration. Here it is demonstrated that PRL-3 activates Src kinase in the IL6-dependent MM cell line INA-6...
October 3, 2016: Molecular Cancer Research: MCR
Tao Wang, Faiyaz Notta, Roya Navab, Joella Joseph, Emin Ibrahimov, Jing Xu, Chang-Qi Zhu, Ayelet Borgida, Steven Gallinger, Ming-Sound Tsao
: Carcinoma associated fibroblasts (CAFs) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumour progression. However, evidence of both cancer promoting and restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared to non-senescent control CAFs using in vitro transwell invasion models and in vivo xenograft mouse models...
September 27, 2016: Molecular Cancer Research: MCR
Yang Zhan, Guanyi Zhang, Xiaojie Wang, Yangfeng Qi, Dongyi Li, Shanshan Bai, Tianfang Ma, Erik K Flemington, Haitao Zhang, Oliver Sartor, Peng Lee, Yan Dong
: Androgen receptor splice variants (AR-Vs) are implicated in resistance of prostate cancer to androgen-directed therapies. When expressed alone in cells, some AR-Vs (e.g., AR-V7) localize primarily to the nucleus, whereas others (e.g., AR-V1, AR-V4, and AR-V6) localize mainly to the cytoplasm. Significantly, the latter are often co-expressed with the nucleus-predominant AR-Vs and the full-length AR (AR-FL). An important question to be addressed is whether the cytoplasmic-localized AR-Vs play a role in castration-resistant prostate cancer (CRPC) through interaction with the nucleus-predominant AR-Vs and AR-FL...
September 26, 2016: Molecular Cancer Research: MCR
Luke B Hesson, Benedict Ng, Peter Zarzour, Sameer Srivastava, Chau-To Kwok, Deborah Packham, Andrea C Nunez, Dominik Beck, Regina Ryan, Ashraf Dower, Caroline E Ford, John Pimanda, Mathew A Sloane, Nicholas J Hawkins, Michael J Bourke, Jason W H Wong, Robyn L Ward
: Laterally spreading tumors (LSTs) are colorectal adenomas that develop into extremely large lesions with predominantly slow progression to cancer depending on lesion subtype. Comparing and contrasting the molecular profiles of LSTs and colorectal cancer (CRCs) offers an opportunity to delineate key molecular alterations that drive malignant transformation in the colorectum. In a discovery cohort of 11 LSTs and paired normal mucosa, we performed a comprehensive and unbiased screen of the genome, epigenome and transcriptome followed by bioinformatics integration of these data and validation in an additional 84 large benign colorectal lesions...
September 26, 2016: Molecular Cancer Research: MCR
Gwendolyn M Cramer, Dustin P Jones, Hamid El Hamidi, Jonathan P Celli
: Pancreatic ductal adenocarcinoma (PDAC) is characterized by prominent stromal involvement, which plays complex roles in regulating tumor growth and therapeutic response. The extracellular matrix (ECM)-rich PDAC stroma has been implicated as a barrier to drug penetration, though stromal depletion strategies have had mixed clinical success. It remains less clear how interactions with ECM, acting as a biophysical regulator of phenotype, not only a barrier to drug perfusion, regulate susceptibilities and resistance to specific therapies...
September 26, 2016: Molecular Cancer Research: MCR
Kavitha Balaji, Smruthi Vijayaraghavan, Lixia Diao, Pan Tong, Youhong Fan, Jason Pw Carey, Tuyen N Bui, Steven Warner, John V Heymach, Kelly K Hunt, Jing Wang, Lauren Averett Byers, Khandan Keyomarsi
: Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non-small cell lung cancers (NSCLCs) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBCs) and head and neck squamous cell carcinomas (HNSCCs) and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiation, and targeted therapy...
September 26, 2016: Molecular Cancer Research: MCR
Maroof Alam, Audrey Bouillez, Ashujit Tagde, Rehan Ahmad, Hasan Rajabi, Takahiro Maeda, Masayuki Hiraki, Yozo Suzuki, Donald Kufe
: Apical-basal polarity and epithelial integrity are maintained in part by the Crumbs (CRB) complex. The C-terminal subunit of MUC1 (MUC1-C) is a transmembrane protein that is expressed at the apical border of normal epithelial cells and aberrantly at high levels over the entire surface of their transformed counterparts. However, it is not known if MUC1-C contributes to this loss of polarity that is characteristic of carcinoma cells. Here it is demonstrated that MUC1-C downregulates expression of the Crumbs complex CRB3 protein in triple-negative breast cancer (TNBC) cells...
September 22, 2016: Molecular Cancer Research: MCR
Monika D Polewski, Rosyli F Reveron-Thornton, Gregory A Cherryholmes, Georgi K Marinov, Kaniel Cassady, Karen S Aboody
: Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells up-regulate the expression of xCT (SLC7A11), the catalytic subunit of system xc-, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc- in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc- with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing...
September 22, 2016: Molecular Cancer Research: MCR
Mujeeburahiman Cheerathodi, Naze G Avci, Paola A Guerrero, Leung K Tang, Julia Popp, John E Morales, Zhihua Chen, Amancio Carnero, Frederick F Lang, Bryan A Ballif, Gonzalo M Rivera, Joseph H McCarty
: Glioblastoma (GBM) is a primary brain cancer that is resistant to all treatment modalities. This resistance is due, in large part, to invasive cancer cells that disperse from the main tumor site, escape surgical resection, and contribute to recurrent secondary lesions. The adhesion and signaling mechanisms that drive GBM cell invasion remain enigmatic, and as a result there are no effective anti-invasive clinical therapies. Here we have characterized a novel adhesion and signaling pathway comprised of the integrin alphavbeta8 and its intracellular binding partner, Spinophilin (Spn), which regulates GBM cell invasion in the brain microenvironment...
September 21, 2016: Molecular Cancer Research: MCR
Thomas Mandel Clausen, Marina Ayres Pereira, Nader Al Nakouzi, Htoo Zarni Oo, Mette Orskov Agerbæk, Sherry Lee, Maj Sofie Orum-Madsen, Anders Riis Kristensen, Amal El-Naggar, Paul M Grandgenett, Jean L Grem, Michael A Hollingsworth, Peter J Holst, Thor G Theander, Poul Hb Sorensen, Mads Daugaard, Ali Salanti
: Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways...
September 21, 2016: Molecular Cancer Research: MCR
Kelsey L McNew, Wiliam J Whipple, Anita K Mehta, Trevor J Grant, Leah Ray, Connor Kenny, Anurag Singh
: MEK inhibitors have limited efficacy in treating RAS-RAF-MEK pathway-dependent cancers due to feedback pathway compensation and dose-limiting toxicities. Combining MEK inhibitors with other targeted agents may enhance efficacy. Here, co-dependencies of MEK, TAK1 and KRAS in colon cancer were investigated. Combined inhibition of MEK and TAK1 potentiates apoptosis in KRAS-dependent cells. Pharmacological studies and cell cycle analyses on a large panel of colon cancer cell lines demonstrate that MEK/TAK1 inhibition induces cell death, as assessed by sub-G1 accumulation, in a distinct subset of cell lines...
September 21, 2016: Molecular Cancer Research: MCR
Stavros Kopsiaftis, Katie L Sullivan, Isha Garg, John A Taylor, Kevin P Claffey
: AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, AICAR. AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism...
September 16, 2016: Molecular Cancer Research: MCR
Hardik Mody, Sau Wai Hung, Mohammad Al-Saggar, Jazmine Griffin, Rajgopal Govindarajan
: Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects...
September 13, 2016: Molecular Cancer Research: MCR
Shelly Loewenstein, Nir Lubezky, Eran Nizri, Meir Zemel, Yishai Levin, Alon Savidor, Osnat Sher, Joseph M Klausner, Guy Lahat
: Previous data demonstrated that high retroperitoneal visceral fat (VF) content increases retroperitoneal soft-tissue sarcoma (RSTS) local recurrence and patients mortality. Most RSTS tumors initiate and recur within VF. The objective of the current study was to evaluate potential paracrine effects of VF on RSTS. A xenograft model was used to evaluate in vivo effects of human VF on STS growth. Tissue explants were prepared from VF, and their conditioned medium (CM) was utilized for various in vitro experiments designed to evaluate growth, survival, migration and invasion of STS and endothelial cells...
September 12, 2016: Molecular Cancer Research: MCR
Antonia A Nemec, Korie B Bush, Jamie B Towle-Weicksel, B Frazier Taylor, Vincent Schulz, Joanne Weidhaas, David P Tuck, Joann B Sweasy
: Repair of DNA damage is critical for maintaining the genomic integrity of cells. DNA polymerase lambda (POLL/Pol lambda) is suggested to function in base excision repair (BER) and non-homologous end-joining (NHEJ), and is likely to play a role in damage tolerance at the replication fork. Here, using next-generation sequencing, it was discovered that the POLL rs3730477 single nucleotide polymorphism (SNP) encoding R438W Pol lambda was significantly enriched in the germlines of breast cancer patients...
September 12, 2016: Molecular Cancer Research: MCR
Michael McMahon, Tania G Frangova, Colin J Henderson, C Roland Wolf
: Many drugs targeting the DNA damage response are being developed as anti-cancer therapies, either as single agents or in combination with ionizing radiation (IR) or other cytotoxic agents. Numerous clinical trials in this area are either in progress or planned. However, concerns remain about the potential of such treatments to increase toxicity to normal tissues. In order to address this issue, a novel reporter mouse line was created through the simultaneous incorporation of multiple reporters, b-galactosidase and firefly luciferase, into the DNA damage-inducible p21 (CDKN1A) locus...
September 7, 2016: Molecular Cancer Research: MCR
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