title: Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.
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.
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.forename: Theodora
authors.initials: T
authors.lastname: Fifis
authors.forename: Caterina
authors.initials: C
authors.lastname: Malcontenti-Wilson
authors.forename: Lie Sam
authors.initials: LS
authors.lastname: Chan
authors.forename: Patricia Nunes Luiza
authors.initials: PN
authors.lastname: Costa
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Nikfarjam
authors.forename: Vijayaragavan
authors.initials: V
authors.lastname: Muralidharan
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011756:Diphosphates / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005346:Fibroblast Growth Factors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D013267:Stilbenes / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014746:Vimentin / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; D011756:Diphosphates; C497443:Hif1a protein, mouse; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051741:Kruppel-Like Transcription Factors; C465018:Oxi 4503; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D014746:Vimentin; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin; C467480:vascular endothelial growth factor A, mouse; D005346:Fibroblast Growth Factors