Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor
Autor: | Erik W. Thompson, Mark Waltham, Mehrdad Nikfarjam, Christopher Christophi, Jurstine Daruwalla, Lie Sam Chan, Caterina Malcontenti-Wilson, Linh Nguyen, Vijayaragavan Muralidharan, Theodora Fifis, Patricia Luiza Nunes Costa |
---|---|
Rok vydání: | 2013 |
Předmět: |
Male
Cancer Research Pathology Neoplasm Residual medicine.medical_treatment Vimentin Apoptosis chemistry.chemical_compound Mice 0302 clinical medicine Stilbenes ZEB1 Angiogenic Proteins beta Catenin Cancer Biology 0303 health sciences Mice Inbred BALB C biology Liver Neoplasms EMT growth factor Cadherins Cell Hypoxia 3. Good health Neoplasm Proteins Up-Regulation Vascular endothelial growth factor Diphosphates Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Hepatocyte growth factor Female Colorectal Neoplasms medicine.drug medicine.medical_specialty Epithelial-Mesenchymal Transition vascular disruptive agent Down-Regulation Antineoplastic Agents 03 medical and health sciences Downregulation and upregulation OXi4503 medicine Animals Humans Radiology Nuclear Medicine and imaging Epithelial–mesenchymal transition 030304 developmental biology hypoxia Growth factor Mesenchymal stem cell Cancer Mammary Neoplasms Experimental medicine.disease chemistry biology.protein Mice Inbred CBA Neoplasm Transplantation |
Zdroj: | Cancer Medicine |
ISSN: | 2045-7634 |
Popis: | 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. Vascular disruptive treatments effectively destroy over 90% of solid tumors with minimal effects on host tissues but a viable rim of cells persists in the tumor periphery that leads to recurrence. An immediate and widespread epithelial to mesenchymal transition (EMT) occurs within the viable rim after treatment that may be responsible for this resistance to treatment. Targeting EMT in combination with vascular disruptive agents or other therapies in the clinic may improve treatment outcomes. |
Databáze: | OpenAIRE |
Externí odkaz: |