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Open Access Research article

Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments

Linh Nguyen, Theodora Fifis*, Caterina Malcontenti-Wilson, Lie Sam Chan, Patricia Nunes Luiza Costa, Mehrdad Nikfarjam, Vijayaragavan Muralidharan and Christopher Christophi

Author Affiliations

Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia

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BMC Cancer 2012, 12:522  doi:10.1186/1471-2407-12-522

Published: 15 November 2012

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords:
Vascular disruptive agent; OXi4503; Tumor periphery; Hypoxia; Growth factor; Infiltrating cells; EMT