VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Vinton W.T. Cheng; Manuel Sarmiento Soto; Alexandre A. Khrapitchev; Francisco Perez-Balderas; Rasheed Zakaria; Michael D. Jenkinson; Mark R. Middleton; Nicola R. Sibson

doi:10.1158/1078-0432.CCR-18-1889

VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Vinton W.T. Cheng, Manuel Sarmiento Soto, Alexandre A. Khrapitchev, Francisco Perez-Balderas, Rasheed Zakaria, Michael D. Jenkinson, Mark R. Middleton, Nicola R. Sibson^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

Purpose:

A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.

Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5–6/group) were injected intravenously with VCAM-1–targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T₂*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.

Results:

All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T₂*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood–brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1–positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.

Conclusions:

VCAM-1–targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.

Original language	English
Pages (from-to)	533-543
Number of pages	11
Journal	Clinical Cancer Research
Volume	25
Issue number	2
DOIs	https://doi.org/10.1158/1078-0432.CCR-18-1889
Publication status	Published - 15 Jan 2019

Bibliographical note

Funding Information:
This work was supported by a Cancer Research UK programme grant (C5255/A15935) to N.R. Sibson, M.S. Soto, A.A. Khrapitchev, and F. Perez-Balderas; and a Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology–funded clinical research fellowship to V.W.T. Cheng. We gratefully acknowledge Prof Patricia S. Steeg (National Cancer Institute, Bethesda, MD), Prof Frits A. Thorsen (University of Bergen, Bergen, Norway), and Prof Geoffrey Pilkington (University of Portsmouth, Portsmouth, United Kingdom) for their kind gift of the human cell lines, MDA231Br-GFP, H1_DL2, and SEBTA-001, respectively, used in this study. We also gratefully acknowledge support from Mr Khaja Syed at the Walton Research Tissue Bank (Liverpool, United Kingdom).

Publisher Copyright:
© 2018 American Association for Cancer Research.

ASJC Scopus subject areas

General Medicine

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@article{e5cc76184e7b4b868e40966164e2c7fb,

title = "VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors",

abstract = "Purpose:A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5–6/group) were injected intravenously with VCAM-1–targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of na{\"i}ve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.Results:All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T2*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood–brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1–positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.Conclusions:VCAM-1–targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.",

author = "Cheng, {Vinton W.T.} and Soto, {Manuel Sarmiento} and Khrapitchev, {Alexandre A.} and Francisco Perez-Balderas and Rasheed Zakaria and Jenkinson, {Michael D.} and Middleton, {Mark R.} and Sibson, {Nicola R.}",

note = "Funding Information: This work was supported by a Cancer Research UK programme grant (C5255/A15935) to N.R. Sibson, M.S. Soto, A.A. Khrapitchev, and F. Perez-Balderas; and a Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology–funded clinical research fellowship to V.W.T. Cheng. We gratefully acknowledge Prof Patricia S. Steeg (National Cancer Institute, Bethesda, MD), Prof Frits A. Thorsen (University of Bergen, Bergen, Norway), and Prof Geoffrey Pilkington (University of Portsmouth, Portsmouth, United Kingdom) for their kind gift of the human cell lines, MDA231Br-GFP, H1_DL2, and SEBTA-001, respectively, used in this study. We also gratefully acknowledge support from Mr Khaja Syed at the Walton Research Tissue Bank (Liverpool, United Kingdom). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",

year = "2019",

month = jan,

day = "15",

doi = "10.1158/1078-0432.CCR-18-1889",

language = "English",

volume = "25",

pages = "533--543",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research",

number = "2",

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TY - JOUR

T1 - VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

AU - Cheng, Vinton W.T.

AU - Soto, Manuel Sarmiento

AU - Khrapitchev, Alexandre A.

AU - Perez-Balderas, Francisco

AU - Zakaria, Rasheed

AU - Jenkinson, Michael D.

AU - Middleton, Mark R.

AU - Sibson, Nicola R.

N1 - Funding Information: This work was supported by a Cancer Research UK programme grant (C5255/A15935) to N.R. Sibson, M.S. Soto, A.A. Khrapitchev, and F. Perez-Balderas; and a Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology–funded clinical research fellowship to V.W.T. Cheng. We gratefully acknowledge Prof Patricia S. Steeg (National Cancer Institute, Bethesda, MD), Prof Frits A. Thorsen (University of Bergen, Bergen, Norway), and Prof Geoffrey Pilkington (University of Portsmouth, Portsmouth, United Kingdom) for their kind gift of the human cell lines, MDA231Br-GFP, H1_DL2, and SEBTA-001, respectively, used in this study. We also gratefully acknowledge support from Mr Khaja Syed at the Walton Research Tissue Bank (Liverpool, United Kingdom). Publisher Copyright: © 2018 American Association for Cancer Research.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Purpose:A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5–6/group) were injected intravenously with VCAM-1–targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.Results:All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T2*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood–brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1–positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.Conclusions:VCAM-1–targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.

AB - Purpose:A major issue for the effective treatment of brain metastasis is the late stage of diagnosis with existing clinical tools. The aim of this study was to evaluate the potential of vascular cell adhesion molecule 1 (VCAM-1)-targeted MRI for early detection of brain micrometastases in mouse models across multiple primary tumor types.Experimental Design: Xenograft models of brain micrometastasis for human breast carcinoma (MDA231Br-GFP), lung adenocarcinoma (SEBTA-001), and melanoma (H1_DL2) were established via intracardiac injection in mice. Animals (n = 5–6/group) were injected intravenously with VCAM-1–targeted microparticles of iron oxide (VCAM-MPIO) and, subsequently, underwent T2*-weighted MRI. Control groups of naïve mice injected with VCAM-MPIO and tumor-bearing mice injected with nontargeting IgG-MPIO were included.Results:All models showed disseminated micrometastases in the brain, together with endothelial VCAM-1 upregulation across the time course. T2*-weighted MRI of all tumor-bearing mice injected with VCAM-MPIO showed significantly more signal hypointensities (P < 0.001; two-sided) than control cohorts, despite a lack of blood–brain barrier (BBB) impairment. Specific MPIO binding to VCAM-1–positive tumor-associated vessels was confirmed histologically. VCAM-1 expression was demonstrated in human brain metastasis samples, across all three primary tumor types.Conclusions:VCAM-1–targeted MRI enables the detection of brain micrometastases from the three primary tumor types known to cause the majority of clinical cases. These findings represent an important step forward in the development of a broadly applicable and clinically relevant imaging technique for early diagnosis of brain metastasis, with significant implications for improved patient survival.

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VCAM-1–targeted MRI Enables Detection of Brain Micrometastases from Different Primary Tumors

Abstract

Bibliographical note

ASJC Scopus subject areas

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