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Abstract
Triple negative breast cancer (TNBC), ~ 10–20% of diagnosed breast cancers, metastasizes to brain, lungs, liver. Iodine nanoparticle (INP) radioenhancers specifically localize to human TNBC MDA-MB-231 tumors growing in mouse brains after iv injection, significantly extending survival of mice after radiation therapy (RT). A prominent rim of INP contrast (MicroCT) previously seen in subcutaneous tumors but not intracerebral gliomas, provide calculated X-ray dose-enhancements up to > eightfold. Here, MDA-MB-231-cells, INPs, CD31 were examined by fluorescence confocal microscopy. Most INP staining co-localized with CD31 in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells are seen to line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+ blood-vessels. The significant radiation dose enhancement to the prolific collagen I containing, INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new drug/NP, particularly INP, tumor-homing target.
Highlights
Triple Negative Breast Cancer (TNBC) accounts for 10–20% of diagnosed breast cancers
The most intense fluorescence is seen at the tumor edge where Iodine nanoparticle (INP) labeling appears to be predominantly around irregularly-shaped spaces (ISS) that are labeled by anti-CD31 (Fig. 2C)
Careful inspection shows that these grape-like clusters of tumor cells typically are surrounded by CD31 and INP staining that form the boundaries of the ISS
Summary
Triple Negative Breast Cancer (TNBC) accounts for 10–20% of diagnosed breast cancers. Microlocalization studies performed on mouse brains bearing advanced human U87 gliomas showed the INPs to be largely localized to the tumor endothelium[8] suggesting that the resulting increased radiation dose may cause greater damage to the tumor e ndothelium[18]. Consistent with this finding was the observation that INP-enhanced RT (INP-RT) synergized with DOXIL chemotherapy greatly increasing the efficacy of chemotherapy to treat an advanced glioma in m ice[8]. ISS/VM could represent an INP/nanoparticle/drug-homing therapeutic target and that INP-enhanced RT would likely benefit patients with breast cancer-brain metastases since a correlation between vascular mimicry and poor outcome has been made[24]
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