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Title: Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.
Austin Authors: Nguyen, Linh;Fifis, Theodora;Malcontenti-Wilson, Caterina;Chan, Lie Sam;Costa, Patricia Nunes Luiza;Nikfarjam, Mehrdad ;Muralidharan, Vijayaragavan ;Christophi, Christopher 
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia
Issue Date: 15-Nov-2012
Publication information: Bmc Cancer 2012; 12(): 522
Abstract: Treatment of solid tumors with vascular disrupting agent OXi4503 results in over 90% tumor destruction. However, a thin rim of viable cells persists in the tumor periphery following treatment, contributing to subsequent recurrence. This study investigates inherent differences in the microenvironment of the tumor periphery that contribute to treatment resistance.Using a murine colorectal liver metastases model, spatial morphological and molecular differences within the periphery and the center of the tumor that may account for differences in resistance to OXi4503 treatment were investigated. H&E staining and immunostaining were used to examine vessel maturity and stability, hypoxia and HIF1α levels, accumulation of immune cells, expression of proangiogenic factors/receptors (VEGF, TGF-β, b-FGF, and AT1R) and expression of EMT markers (ZEB1, vimentin, E-cadherin and β-catenin) in the periphery and center of established tumors. The effects of OXi4503 on tumor vessels and cell kinetics were also investigated.Significant differences were found between tumor periphery and central regions, including association of the periphery with mature vessels, higher accumulation of immune cells, increased growth factor expression, minimal levels of hypoxia and increased evidence of EMT. OXi4503 treatment resulted in collapse of vessels in the tumor center; however vasculature in the periphery remained patent. Similarly, tumor apoptosis and proliferation were differentially modulated between centre and periphery after treatment.The molecular and morphological differences between tumor periphery and center may account for the observed differential resistance to OXi4503 treatment and could provide targets for drug development to totally eliminate metastases.
Gov't Doc #: 23153292
DOI: 10.1186/1471-2407-12-522
Type: Journal Article
Subjects: Animals
Antineoplastic Agents.pharmacology
Apoptosis.drug effects.genetics
Cell Hypoxia.physiology
Cell Line, Tumor
Cell Proliferation.drug effects
Colorectal Neoplasms.drug therapy.genetics.pathology
Drug Resistance, Neoplasm
Fibroblast Growth Factors.genetics
Homeodomain Proteins.genetics
Hypoxia-Inducible Factor 1, alpha Subunit.genetics
Kruppel-Like Transcription Factors.genetics
Liver Neoplasms.drug therapy.genetics.pathology.secondary
Mice, Inbred CBA
Transforming Growth Factor beta.genetics
Tumor Microenvironment.drug effects.genetics
Vascular Endothelial Growth Factor A.genetics
beta Catenin.genetics
Appears in Collections:Journal articles

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