VCAM-1-targeted MRI Improves Detection of the Tumor-brain Interface

Vinton W T Cheng, Nicholas de Pennington, Rasheed Zakaria, James R Larkin, Sébastien Serres, Manjima Sarkar, Matthew A Kirkman, Claire Bristow, Paula Croal, Puneet Plaha, Leticia Campo, Michael A Chappell, Simon Lord, Michael D Jenkinson, Mark R Middleton, Nicola R Sibson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

PURPOSE: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI.

EXPERIMENTAL DESIGN: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1-targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression.

RESULTS: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA-enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI.

CONCLUSIONS: This work illustrates the potential of VCAM-1-targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.

Original languageEnglish
Pages (from-to)2385-2396
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume28
Issue number11
DOIs
Publication statusPublished - 1 Jun 2022

Bibliographical note

©2022 The Authors; Published by the American Association for Cancer Research.

Keywords

  • Animals
  • Brain/diagnostic imaging
  • Brain Neoplasms/metabolism
  • Disease Models, Animal
  • Glioblastoma/diagnostic imaging
  • Humans
  • Inflammation/metabolism
  • Magnetic Resonance Imaging/methods
  • Rats
  • Vascular Cell Adhesion Molecule-1/metabolism

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