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Title: Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor.
Austin Authors: Fifis, Theodora;Nguyen, Linh;Malcontenti-Wilson, Caterina;Chan, Lie Sam;Nunes Costa, Patricia Luiza;Daruwalla, Jurstine;Nikfarjam, Mehrdad ;Muralidharan, Vijayaragavan ;Waltham, Mark;Thompson, Erik W;Christophi, Christopher 
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia
Issue Date: 18-Aug-2013
Publication information: Cancer Medicine 2013; 2(5): 595-610
Abstract: Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of β-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.
Gov't Doc #: 24403226
DOI: 10.1002/cam4.109
Type: Journal Article
Subjects: EMT
growth factor
vascular disruptive agent
Angiogenic Proteins.biosynthesis
Antineoplastic Agents.pharmacology.therapeutic use
Apoptosis.drug effects
Cell Hypoxia.drug effects
Colorectal Neoplasms.pathology
Diphosphates.pharmacology.therapeutic use
Down-Regulation.drug effects
Epithelial-Mesenchymal Transition.drug effects
Gene Expression Regulation, Neoplastic.drug effects
Liver Neoplasms.drug therapy.metabolism.pathology.secondary
Mammary Neoplasms, Experimental.drug therapy.metabolism.pathology
Mice, Inbred BALB C
Mice, Inbred CBA
Neoplasm Proteins.biosynthesis
Neoplasm Transplantation
Neoplasm, Residual
Stilbenes.pharmacology.therapeutic use
Up-Regulation.drug effects
beta Catenin.biosynthesis
Appears in Collections:Journal articles

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