Browsing by Subject "secondary"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Development of a Research Agenda for the Management of Metastatic Colorectal Cancer: Proceedings from a Multidisciplinary Research Consensus Panel
    (Elsevier, 2012-02) d’Othée, Bertrand Janne; Sofocleous, Constantinos T.; Hanna, Nader; Lewandowski, Robert J.; Soulen, Michael C.; Vauthey, Jean-Nicolas; Cohen, Steven J.; Venook, Alan P.; Johnson, Matthew S.; Kennedy, Andrew S.; Murthy, Ravi; Geschwind, Jean-Francois; Kee, Stephen T.; Department of Radiology and Imaging Sciences, IU School of Medicine
  • Thumbnail Image
    Item
    DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer
    (Oxford University Press) Woditschka, Stephan; Evans, Lynda; Duchnowska, Renata; Reed, L. Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George; Gril, Brunilde; Aladjem, Mirit I.; Fu, Haiqing; Flores, Natasha M.; Gökmen-Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arlukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B.; Steeg, Patricia S.; Department of Medicine, IU School of Medicine
    Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic brain.
  • Thumbnail Image
    Item
    Epithelial Splicing Regulatory Protein 1 is a Favorable Prognostic Factor in Pancreatic Cancer that Attenuates Pancreatic Metastases
    (Nature Publishing Group, 2014-09-04) Ueda, Junji; Matsuda, Yoko; Yamahatsu, Kazuya; Uchida, Eiji; Naito, Zenya; Korc, Murray; Ishiwata, Toshiyuki; Department of Medicine, IU School of Medicine
    Epithelial splicing regulatory protein 1 (ESRP1) binds the FGFR-2 auxiliary cis-element ISE/ISS-3, located in the intron between exon IIIb and IIIc, and primarily promotes FGFR-2 IIIb expression. Here we assessed the role of ESRP1 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis was performed using anti-ESRP1, FGFR-2 IIIb and FGFR-2 IIIc antibodies in 123 PDAC cases. ESRP1-expression vector and small interference RNA (siRNA) targeting ESRP1 were transfected into human PDAC cells, and cell growth, migration and invasion were analyzed. In vivo heterotopic and orthotopic implantations using ESRP1 overexpression clones were performed and effects on pancreatic tumor volumes and hepatic and pulmonary metastases determined. ESRP1 immunoreactivity was strong in the nuclei of cancer cells in well-to-moderately differentiated PDACs, but weak in poorly-differentiated cancers. Well-to-moderately differentiated cancers also exhibited high FGFR-2 IIIb and low FGFR-2 IIIc expression, whereas this ratio was reversed in the poorly-differentiated cancers. Increased ESRP1 expression was associated with longer survival by comparison with low-ESRP1 expression, and PANC-1 cells engineered to express ESRP1 exhibited increased FGFR-2 IIIb expression and decreased migration and invasion in vitro, whereas ESRP1 siRNA-transfected KLM-1 cells exhibited increased FGFR-2 IIIc expression and increased cell growth, migration and invasion. In vivo, ESRP1-overexpressing clones formed significantly fewer liver metastases as compared with control clones. ESRP1 regulates the expression pattern of FGFR-2 isoforms, attenuates cell growth, migration, invasion, and metastasis, and is a favorable prognostic factor in PDAC. Therefore, devising mechanisms to up-regulate ESRP1 may exert a beneficial therapeutic effect in PDAC.
  • Thumbnail Image
    Item
    The microenvironment matters: estrogen deficiency fuels cancer bone metastases
    (American Association for Cancer Research, 2014-06-01) Wright, Laura E.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Factors released during osteoclastic bone resorption enhance disseminated breast cancer cell progression by stimulating invasiveness, growth, and a bone-resorptive phenotype in cancer cells. Postmenopausal bone loss may accelerate progression of breast cancer growth in bone, explaining the anticancer benefit of the bone-specific antiresorptive agent zoledronic acid in the postmenopausal setting. Clin Cancer Res; 20(11); 2817-9. ©2014 AACR.
  • Thumbnail Image
    Item
    Molecular mechanisms of bone metastasis and associated muscle weakness
    (American Association for Cancer Research, 2014-06-15) Waning, David L.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Bone is a preferred site for breast cancer metastasis and leads to pathologic bone loss due to increased osteoclast-induced bone resorption. The homing of tumor cells to the bone depends on the support of the bone microenvironment in which the tumor cells prime the premetastatic niche. The colonization and growth of tumor cells then depend on adaptations in the invading tumor cells to take advantage of normal physiologic responses by mimicking bone marrow cells. This concerted effort by tumor cells leads to uncoupled bone remodeling in which the balance of osteoclast-driven bone resorption and osteoblast-driven bone deposition is lost. Breast cancer bone metastases often lead to osteolytic lesions due to hyperactive bone resorption. Release of growth factors from bone matrix during resorption then feeds a "vicious cycle" of bone destruction leading to many skeletal-related events. In addition to activity in bone, some of the factors released during bone resorption are also known to be involved in skeletal muscle regeneration and contraction. In this review, we discuss the mechanisms that lead to osteolytic breast cancer bone metastases and the potential for cancer-induced bone-muscle cross-talk leading to skeletal muscle weakness.
  • Thumbnail Image
    Item
    The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone
    (Elsevier, 2015-06-08) Fournier, Pierrick GJ; Juárez, Patricia; Jiang, Guanglong; Clines, Gregory A.; Niewolna, Maria; Kim, Hun Soo; Walton, Holly W.; Peng, C. Xiang Hong; Liu, Yunlong; Mohammad, Khalid S.; Wells, Clark D.; Chirgwin, John M.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Transforming growth factor-β (TGF-β) regulates the expression of genes supporting breast cancer cells in bone, but little is known about prostate cancer bone metastases and TGF-β. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGF-β upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGF-β signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model.