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Lauren B Manning, Yefu Li, Nithya S Chickmagalur, Xiaolong Li, Lin Xu
Osteoarthritis (OA) is the most common form of arthritis disorders, but the identification of therapeutic targets to effectively prevent OA has been increasingly difficult. The goal of this investigation is to provide experimental evidence that discoidin domain receptor 2 (DDR2) may be an ideal target for the development of disease-modifying OA drugs. Ddr2 was conditionally deleted from articular cartilage of adult mouse knee joints. Aggrecan-CreERT2;floxed Ddr2 mice, which were generated by crossing Aggrecan-CreERT2 mice with floxed Ddr2 mice, then received tamoxifen injections at the age of 8 weeks...
September 15, 2016: American Journal of Pathology
Qiang Gao, Zhi-Chao Wang, Meng Duan, Yi-Hui Lin, Xue-Ya Zhou, Daniel L Worthley, Xiao-Ying Wang, Gang Niu, Yuchao Xia, Minghua Deng, Long-Zi Liu, Jie-Yi Shi, Liu-Xiao Yang, Shu Zhang, Zhen-Bin Ding, Jian Zhou, Chun-Min Liang, Ya Cao, Lei Xiong, Ruibin Xi, Yong-Yong Shi, Jia Fan
BACKGROUND & AIMS: No targeted therapies have been found to be effective against hepatocellular carcinoma (HCC), possibly due to the large degree of intratumor heterogeneity. We performed genetic analyses of different regions of HCCs to evaluate levels of intratumor heterogeneity and associate alterations with responses to different pharmacologic agents. METHODS: We obtained samples of HCCs (associated with hepatitis B virus infection) from 10 patients undergoing curative resection, before adjuvant therapy, at hospitals in China...
September 14, 2016: Gastroenterology
Lu Liu, Muzammal Hussain, Jinfeng Luo, Anna Duan, Chaonan Chen, Zhengchao Tu, Jiancun Zhang
Novel dasatinib analogues as DDR1 and DDR2 inhibitors were designed and synthesized. The synthesized compounds were screened for DDR1 and DDR2 kinase inhibitory and cancer cell proliferation inhibitory activities. Some of the compounds showed the potent inhibitory activities against both DDR1 and DDR2, as well as anticancer activity in low nanomolar range against K562 cell line; especially, compound 3j demonstrated significantly better inhibitory potency than the parental dasatinib against both DDRs and also demonstrated the potent inhibitory activity against K562 cell lines (IC50 values of 2...
September 2, 2016: Chemical Biology & Drug Design
Heidi Bildsoe, Xiaochen Fan, Emilie E Wilkie, Ator Ashoti, Vanessa J Jones, Melinda Power, Jing Qin, Junwen Wang, Patrick P L Tam, David A F Loebel
TWIST1, a basic helix-loop-helix transcription factor is essential for the development of cranial mesoderm and cranial neural crest-derived craniofacial structures. We have previously shown that, in the absence of TWIST1, cells within the cranial mesoderm adopt an abnormal epithelial configuration via a process reminiscent of a mesenchymal to epithelial transition (MET). Here, we show by gene expression analysis that loss of TWIST1 in the cranial mesoderm is accompanied by a reduction in the expression of genes that are associated with cell-extracellular matrix interactions and the acquisition of mesenchymal characteristics...
October 1, 2016: Developmental Biology
Mousumi Sahu, Bibekanand Mallick
The differentiation of human Embryonic Stem Cells (hESCs) is accompanied by the formation of different intermediary cells, gradually losing its stemness and acquiring differentiation. The precise mechanisms underlying hESCs integrity and its differentiation into fibroblast (Fib) are still elusive. Here, we aimed to assess important genes and co-expression sub-networks responsible for stemness, early differentiation of hESCs into embryoid bodies (EBs) and its lineage specification into Fibs. To achieve this, we compared transcriptional profiles of hESCs-EBs and EBs-Fibs and obtained differentially expressed genes (DEGs) exclusive to hESCs-EBs (early differentiation), EBs-Fibs (late differentiation) and common DEGs in hESCs-EBs and EBs-Fibs...
July 18, 2016: Computational Biology and Chemistry
Anne von Mässenhausen, Christine Sanders, Johannes Brägelmann, Martina Konantz, Angela Queisser, Wenzel Vogel, Glen Kristiansen, Stefan Duensing, Andreas Schröck, Friedrich Bootz, Peter Brossart, Jutta Kirfel, Claudia Lengerke, Sven Perner
Squamous cell carcinoma of the head and neck (HNSCC) is the tenth most common tumor entity in men worldwide. Nevertheless therapeutic options are mostly limited to surgery and radio-chemotherapy resulting in 5-year survival rates of around 50%. Therefore new therapeutic options are urgently needed. During the last years, targeting of receptor tyrosine kinases has emerged as a promising strategy that can complement standard therapeutical approaches. Here, we aimed at investigating if the receptor tyrosine kinase DDR2 is a targetable structure in HNSCC...
November 15, 2016: International Journal of Cancer. Journal International du Cancer
Yi Fan, Zhe Xu, Jin Fan, Liu Huang, Ming Ye, Kun Shi, Zheng Huang, Yaqiong Liu, Langchi He, Jiezhen Huang, Yibin Wang, Qiufeng Li
Increasing evidence has suggested that discoidin domain receptor 2 (DDR2) plays an important role in cancer development and metastasis. However, the correlation between DDR2 expression and clinical outcome in ovarian cancer has not been investigated. In this study, DDR2 expression was examined by Real-time PCR in surgically resected ovarian cancer and normal ovary tissues. Besides, DDR2 expression was analyzed immunohistochemically in 103 ovarian cancer patients, and the correlation between DDR2 expression with clinicopathologic factors was analyzed...
2016: American Journal of Translational Research
Hu Zhao, Huan Bian, Xin Bu, Shuya Zhang, Pan Zhang, Jiangtian Yu, Xiaofeng Lai, Di Li, Chuchao Zhu, Libo Yao, Jin Su
Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. Herein, we demonstrated that discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase that predominantly transduces signals from fibrillar collagens, plays a critical role in the induction of fibrosis and angiogenesis in the lung. In vitro cell studies showed that DDR2 can synergize the actions of both transforming growth factor (TGF)-β and fibrillar collagen to stimulate lung fibroblasts to undergo myofibroblastic changes and vascular endothelial growth factor (VEGF) expression...
June 28, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Chunxi Ge, Zhengyan Wang, Guisheng Zhao, Binbin Li, Jinhui Liao, Hanshi Sun, Renny T Franceschi
Cell-extracellular matrix interactions play major roles in controlling progenitor cell fate and differentiation. The receptor tyrosine kinase, discoidin receptor 2 (DDR2), is an important mediator of interactions between cells and fibrillar collagens. DDR2 signals through both ERK1/2 and p38 MAP kinase, which stimulate osteoblast differentiation and bone formation. Here we show that DDR2 is critical for skeletal development and differentiation of marrow progenitor cells to osteoblasts while suppressing marrow adipogenesis...
June 24, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Yuqiao Chang, Kang Guo, Qiong Li, Cixia Li, Zhikun Guo, He Li
BACKGROUND/AIMS: Fibroblasts are abundantly distributed throughout connective tissues in the body and are very important in maintaining the structural and functional integrity. Recent reports have proved that fibroblasts and mesenchymal stem cells share much more in common than previously recognized. The aim of this study was to investigate comparative studies in fibroblasts on the differences in the expression of molecular markers and differentiation capacity from different organs. METHODS: Combined trypsin/collagenase enzymes digestion method was used to isolate and culture the fibroblasts derived from heart, liver, spleen, lung, kidney and skin...
2016: Cellular Physiology and Biochemistry
Callie A S Corsa, Audrey Brenot, Whitney R Grither, Samantha Van Hove, Andrew J Loza, Kun Zhang, Suzanne M Ponik, Yuming Liu, David G DeNardo, Kevin W Eliceiri, Patricia J Keely, Gregory D Longmore
High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers...
June 14, 2016: Cell Reports
Raffaella Lombardi, Suet Nee Chen, Alessandra Ruggiero, Priyatansh Gurha, Grazyna Z Czernuszewicz, James T Willerson, Ali J Marian
RATIONALE: Mutations in desmosome proteins cause arrhythmogenic cardiomyopathy (AC), a disease characterized by excess myocardial fibroadipocytes. Cellular origin(s) of fibroadipocytes in AC is unknown. OBJECTIVE: To identify the cellular origin of adipocytes in AC. METHODS AND RESULTS: Human and mouse cardiac cells were depleted from myocytes and flow sorted to isolate cells expressing platelet-derived growth factor receptor-α and exclude those expressing other lineage and fibroblast markers (CD32, CD11B, CD45, Lys76, Ly(-6c) and Ly(6c), thymocyte differentiation antigen 1, and discoidin domain receptor 2)...
June 24, 2016: Circulation Research
Sun Min Lim, Hye Ryun Kim, Eun Kyung Cho, Young Joo Min, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Byoung Chul Cho, Ji-Hyun Lee, Hye Cheol Jeong, Eun Kyung Kim, Joo-Hang Kim
BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. METHODS: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies)...
April 21, 2016: Oncotarget
Charles Saby, Emilie Buache, Sylvie Brassart-Pasco, Hassan El Btaouri, Marie-Pierre Courageot, Laurence Van Gulick, Roselyne Garnotel, Pierre Jeannesson, Hamid Morjani
Tumor cells are confronted to a type I collagen rich environment which regulates cell proliferation and invasion. Biological aging has been associated with structural changes of type I collagen. Here, we address the effect of collagen aging on cell proliferation in a three-dimensional context (3D).We provide evidence for an inhibitory effect of adult collagen, but not of the old one, on proliferation of human fibrosarcoma HT-1080 cells. This effect involves both the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP-2...
May 3, 2016: Oncotarget
Maria Rosaria Raspollini, Francesca Castiglione, Guido Martignoni, Alberto Lapini, Liang Cheng, Rodolfo Montironi, Antonio Lopez-Beltran
We describe a rare multicentric neoplastic disease arising bilteraly in the kidney. The patient was a 70-year-old man, who, during a period of 3 years, was treated for five independent tumors of three histotypes (three multilocular cystic clear cell renal cell neoplasms of low malignant potential, one clear cell renal cell carcinoma, and one clear cell papillary renal cell carcinoma, respectively). Pathologic diagnosis of the reported tumors was confirmed by immunohistochemical analyses, including CD10, CA IX, CK7, AMACR/RACEMASE, and 34 beta E12...
April 7, 2016: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
Hassan Rammal, Charles Saby, Kevin Magnien, Laurence Van-Gulick, Roselyne Garnotel, Emilie Buache, Hassan El Btaouri, Pierre Jeannesson, Hamid Morjani
The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered...
2016: Frontiers in Pharmacology
Yu-Gang Wang, Ling Xu, Rong-Rong Jia, Qiong Wu, Ting Wang, Jue Wei, Jia-Li Ma, Min Shi, Zhao-Shen Li
BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) plays a role in cancer progression. Previous studies have suggested that discoidin domain receptor 2 (DDR2) is related to tumor progression and EMT. However, the role of DDR2 in regulating gastric cancer (GC) metastasis and in EMT has not been elucidated. In this study, we aimed to determine DDR2 expression and its clinical relation in GC and to investigate the effects of DDR2 on EMT and its underlying mechanisms. METHODS: DDR2 expression and the relation to patients' clinicopathological features were assayed by Western blot or immunohistochemical staining...
August 2016: Digestive Diseases and Sciences
Maria Rosaria Raspollini, Francesca Castiglione, Liang Cheng, Rodolfo Montironi, Antonio Lopez-Beltran
Clear cell papillary renal cell carcinoma (CCPRCC) cases were evaluated for mutations on the following genes: KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR. Four male and three female patients of age 42-74 years were evaluated. All cases were incidentally detected by ultrasound and ranged 1.8-3.5 cm. Microscopic examination showed variably tubulopapillary, tubular acinar, cystic architecture and the characteristic linear arrangement of nuclei. The cells were reactive with CK7 (strong), CA IX (cup-shape) and 34 β E12...
June 2016: Journal of Clinical Pathology
Junji Kurashige, Takanori Hasegawa, Atsushi Niida, Keishi Sugimachi, Niantao Deng, Kosuke Mima, Ryutaro Uchi, Genta Sawada, Yusuke Takahashi, Hidetoshi Eguchi, Masashi Inomata, Seigo Kitano, Takeo Fukagawa, Mitsuru Sasako, Hiroki Sasaki, Shin Sasaki, Masaki Mori, Kazuyoshi Yanagihara, Hideo Baba, Satoru Miyano, Patrick Tan, Koshi Mimori
Peritoneal dissemination is the most frequent, incurable metastasis occurring in patients with advanced gastric cancer (GC). However, molecular mechanisms driving peritoneal dissemination still remain poorly understood. Here, we aimed to provide novel insights into the molecular mechanisms that drive the peritoneal dissemination of GC. We performed combined expression analysis with in vivo-selected metastatic cell lines and samples from 200 GC patients to identify driver genes of peritoneal dissemination. The driver-gene functions associated with GC dissemination were examined using a mouse xenograft model...
2016: Scientific Reports
Xiaohua Shi, Huanwen Wu, Junliang Lu, Huanli Duan, Xuguang Liu, Zhiyong Liang
We investigated the frequency of major driver oncogenes in lung adenosquamous cell carcinoma (ASC) cases. Frequency of EGFR, K-Ras, B-Raf, PIK3CA, DDR2, ALK, and PDGFRA gene mutations was examined in 56 patients using next-generation sequencing, polymerase chain reaction, and Sanger sequencing. Macrodissection or microdissection was performed in 37 cases to separate the adenomatous and squamous components of ASC. The overall mutation rate was 64.29%, including 55.36%, 7.14%, and 1.79% for EGFR, K-Ras, and B-Raf mutations, respectively...
2016: Scientific Reports
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