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
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