Exposed Phosphatidylserine as a Biomarker for Clear Identification of Breast Cancer Brain Metastases in Mouse Models
by
, , ,
Lulu Wang
1, 
Alan H. Zhao
2,
Chad A. Arledge
1,
Fei Xing
3,
Michael D. Chan
4,
Rolf A. Brekken
5
,
Amyn A. Habib
6 and
Dawen Zhao
1,3,7,* 1
Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
2
School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
3
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
4
Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
5
Hamon Center for Therapeutic Oncology Research, Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
6
Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390, USA
7
Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(17), 3088; https://doi.org/10.3390/cancers16173088
Submission received: 13 August 2024
/
Revised: 1 September 2024
/
Accepted: 4 September 2024
/
Published: 5 September 2024
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
Simple Summary
The prognosis of brain metastasis is extremely poor, partly because of the concurrence of multiple brain lesions and their limited access to current systemic therapies. Applying a phosphatidylserine (PS)-targeting antibody, we identified abundant PS on the vasculature of brain metastases in mouse models. Given its location on the luminal surface of tumor blood vessels, exposed PS appears to be an ideal target for both diagnostic and therapeutic agents, which otherwise have difficulty penetrating the blood–tumor barrier (BTB) of brain metastases.
Abstract
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases.
