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

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.

Imaging angiogenesis in an intracerebrally induced model of brain macrometastasis using αvβ3-targeted iron oxide microparticles

“…Further, histological analysis showed marked endothelial VCAM-1 expression at the margins of the tumours, and single MPIO bound to VCAM-1 positive blood vessels. These data are in accord with previous studies in the micrometastatic stages of the 4T1-GFP model 47,49 and other macrometastasis models 52 showing that antibody-conjugated MPIO are capable of sensitive and specific imaging of VCAM-1 positive blood vessels. However, neither of the two animals imaged with IgG-MPIO showed any MRI-detectable hypointensities or macrophage uptake by immunohistochemistry, in line with our previous studies.…”

“…To this end, a CINC-1 induced model of BBB breakdown was used. As non-specific accumulation of MPIO had not previously been observed in models of brain macrometastasis when targeted with antibodies rather than peptides 52 , both peptide- and antibody-targeted MPIO were again evaluated. BBB breakdown was confirmed in all animals using gadolinium-enhanced imaging (Supplementary Figure 9A).…”

“…Mice were injected with either targeted VCAM-MPIO or control IgG-MPIO (Figure 4B-C). VCAM-1 has previously been shown to be upregulated on the vascular endothelium in close association with brain metastases 47,49,52,53 . In the mice receiving VCAM-MPIO, MPIO induced hypointense voxels were observed in the tumour-bearing, but not the contralateral, striatum (Figure 4D).…”

A transformer-based deep-learning approach for classifying brain metastases into primary organ sites using clinical whole-brain MRI images

“… 6 A study has found that inflammation for brain metastases from breast cancer can be detected from magnetic resonance imaging (MRI). 7 Additionally, breast, lung, and melanoma primaries are more likely to yield multiple brain metastases, while tumors of the gastrointestinal tract are more likely to seed the posterior fossa. 8 Such patterns are readily visible on MRI examinations and have been previously noted in population studies.…”

Principles of Lung Cancer Metastasis to Brain

“…[25] Preclinical studies using rodent models have demonstrated early detection of BrMs by employing molecular MRI with contrast agents that highlight tumor vascular factors ALCAM21 and VCAM-1. [38][39][40] Routine pre-operative and post-operative imaging should also be considered: a study by Yokoi, et al, showed that CT and MRI detected brain metastases in 6.8% and 7.1% of 155 and 177 patients, respectively, during the perioperative period for patients with non-squamous cell lung cancer. [41] Preclinical rodent studies have also indicated that brain metastases can be diagnosed even at micrometastatic stages by screening for urine metabolites; however, these were not specific for lung cancer.…”