title: Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor.
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.
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia.
authors.forename: Theodora
authors.initials: T
authors.lastname: Fifis
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.forename: Cathy
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: Lie Sam
authors.initials: LS
authors.lastname: Chan
authors.forename: Patricia Luiza
authors.initials: PL
authors.lastname: Nunes Costa
authors.forename: Jurstine
authors.initials: J
authors.lastname: Daruwalla
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Nikfarjam
authors.forename: Vijayaragavan
authors.initials: V
authors.lastname: Muralidharan
authors.forename: Mark
authors.initials: M
authors.lastname: Waltham
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D015687:Cell Hypoxia / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D011756:Diphosphates / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D015820:Cadherins; D011756:Diphosphates; D009363:Neoplasm Proteins; C465018:Oxi 4503; D013267:Stilbenes; D051176:beta Catenin
keywords: EMT; OXi4503; ZEB1; growth factor; hypoxia; vascular disruptive agent