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

BMC Cancer

Research Article

Patricia Nunes Luiza Costa¹  Lie Sam Chan¹  Mehrdad Nikfarjam¹  Christopher Christophi¹  Vijayaragavan Muralidharan¹  Theodora Fifis¹  Linh Nguyen¹  Caterina Malcontenti-Wilson¹ 

[1] Department of Surgery, University of Melbourne, Austin Health, 3084, Heidelberg, Victoria, Australia;

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

DOI  :  10.1186/1471-2407-12-522

 received in 2011-12-16, accepted in 2012-11-07,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundTreatment 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.MethodsUsing 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.ResultsSignificant 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.ConclusionsThe 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.

【 授权许可】

Unknown   
© Nguyen et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.