Preclinical Models of Brain Metastases in Breast Cancer
Abstract
:1. Background
2. Models of Breast Cancer Brain Metastases
3. Detection Methods of BCBM
4. Discussion and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
231BR | MDA-MB-231BR |
BBB | blood–brain barrier |
BCBM | breast cancer brain metastasis |
BCF | breast cancer specific frequencies |
BLI | bioluminescence imaging |
BC | breast cancer |
CT | computed tomography |
ER | estrogen receptor |
FDG | fluorodeoxyglucose |
FLI | fluorescence imaging |
Gd | gadolinium |
HER2 | human epidermal growth factor receptor 2 |
IBCC | human immortalized breast cancer cell |
MRI | magnetic resonance imaging |
PDO | patient-derived organoids |
PDOX | patient-derived organoid xenografts |
PDX | patient-derived xenografts |
PET | positron emission tomography |
PR | progesterone receptor |
SPIO | superparamagnetic iron oxide particles |
TNBC | triple negative breast cancer |
VEGF-A | vascular endothelial growth factor A |
WBRT | whole brain radiotherapy |
eGFP | enhanced green fluorescent protein |
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Cell Type | Origin | Subtype | Animal Model | Injection Method | Detection Method | Drugs Studied | Original Reference | |
---|---|---|---|---|---|---|---|---|
Xenogeneic | MDA-MB-361 | Brain metastasis | ER+/PR+/HER2+ | Nude mice | Intracarotid | Histology | Docetaxel, doxorubicin and cyclophosphamide [20] | [21] |
MDA-MB-468 | Pleural effusion | TNBC | Nude mice | Intracarotid | Histology | Docetaxel [22] | [21] | |
MA11 | Bone marrow aspirate | TNBC | BALB/C nu/nu nude mice | Intracardiac | Autopsy, Histology, and MRI | Ionizing radiation and trichostatin A (HDAC inhibitor) [23] | [24] | |
MDA-MB-231BR | Pleural effusion | TNBC | Nude mice | Intracardiac | Histology | Vorinostat [25] DAPT [26] GSK461364A [27] HA-paclitaxel nanoconjugate [28] Saracatinib with lapatinib [29] Whole brain radiotherapy [30,31] BCF [32] ANG1005/GRN1005 [33] iRGD nanoparticles [34] Azacitidine [35] WP1066 [36] Radiation with ultrasound-ruptured oxygen microbubbles [37] mTOR inhibitors (rapamycin, Temsirolimus-CCI-779) [38] | [39] | |
MDA-MB-231BR1, -BR2, -BR3 | Pleural effusion | TNBC | Athymic NCr-nu/nu mice | Intracarotid | Histology | PTK787/Z 222584 [40] Temozolomide [41] | [40] | |
MDA-MB- 231-BrM2 | Pleural effusion | TNBC | Athymic nude mice | Intracardiac | BLI, MRI, Histology | GDC-0068 [42] | [43] | |
MDA-MB-231BR-HER2+ | Pleural effusion, then brain metastases in mice | ER-/PR-/HER2+ | BALB/c nude mice | Intracardiac | Immunofluorescence | Lapatinib [44] Pazopanib [45] LRRC31 nanoparticles with radiation [46] Whole brain radiotherapy [47] | [48] | |
CN34-BrM2 | Pleural effusion | TNBC | Beige nude mice | Intracardiac | BLI, MRI, Histology | mTOR inhibitors (rapamycin, Temsirolimus-CCI-779) [38] | [43] | |
JIMT-1-BR3 | Pleural effusion | HER2+ | NRC nu/nu mice | Intracardiac | Histology | Temozolomide [41] | [41] | |
SUM190-BR3 | Primary tumor | HER2+ | Athymic NIH nu/nu mice | Intracardiac | Immunofluorescence | N/A | [49] | |
BT474.br/Br.2/Br.3 | Primary tumor | ER+/PR+/HER2+ | Swiss nude mice | Intracarotid | Confocal microscopy, Immunofluorescence | Vardenafil and trastuzumab [50] Lapatinib and trastuzumab [51] TAK-285 [52] Saracatinib with lapatinib [29] | [29] | |
SKBrM3+ | Plural effusion | ER-/PR-/HER2+ | Athymic nude mice | Mammary fat pad | BLI, Histology | Cabozantinib and Neratinib [53] | [53] | |
Syngeneic | Br7-C5 | N-ethyl-N nitrosourea-induced mammary adenocarci- noma | Unspecified | Berlin–Druckrey IV rat | Intracardiac | Histology | N/A | [54] |
4T1BM | Murine mammary carcinoma | TNBC | Syngeneic BALB/c mice | Mammary fat pad | Histology | N/A | [55] | |
4T1Br4 | Murine mammary carcinoma | TNBC | Syngeneic BALB/c mice | Mammary fat pad | Histology | Trebananib [56] | [57] | |
4T1-Luc | Murine mammary carcinoma | TNBC | Syngeneic BALB/c mice | Intracranial, intracardiac, spontaneous | BLI | Fluphenazine hydrochloride [58] | [59] | |
TBCP-1 | Spontaneous BALB/C mammary tumor | ER-/PR-/HER2+ | Syngeneic BALB/C mice | Intracardiac | Histology | Neratinib [60] | [60] | |
Patient-Derived | F2-7 | Patient brain metastases | TNBC | NSG mice | Intracardiac | BLI | N/A | [61] |
Brain-orthotopic PDXs | Patient brain metastases | TNBC and ER+ varied | NSG mice | Intracranial (pipette method) | Histology | N/A | [62] | |
BM-E22-1 | Patient brain metastases | TNBC | NSG mice | Intracardiac | MRI | N/A | [61] | |
DF-BM#Ni7, DF-BM#656 | Patient brain metastases | ER+ HER2+ (DF-BM#Ni7), TNBC (DF-BM#656) | NOD/SCID mice | Intracarotid (ligation method) | BLI | N/A | [63] | |
WHIM 2/WHIM5 | Primary tumor/patient brain metastases | TNBC | NOD/SCID mice | Mammary fat pad | Histology | Carboplatin, cyclophosphamide, bortezomib, dacarbazine [64] | [65] | |
PDX1435/PDX2147 | Patient brain metastases (PDX1435), primary tumor (PDX 2147) | TNBC | NOD/SCID mice | Intracranial | MRI | BCF [32] | [32] | |
Orthotopic HER2+ PDXs | Patient brain metastases | HER2+, ER/PR status varied | NOD/SCID mice | Intracranial | BLI, MRI | Combination of PI3K inhibitor (BKM120) and mTORC1 inhibitor (RAD001) [66] | [66] | |
Subcutaneous PDXs | Patient brain metastases | Unspecified | SCID BALB/c mice | Subcutaneous (trocar method) | PET/CT | N/A | [67] |
Imaging Modality | Principles | Reporters /Detection Used | SR/S/HS/Sp | Information | Advantages | Disadvantages and Limitations for Imaging |
---|---|---|---|---|---|---|
BLI | Optical detection of light emitted from BLI reporters. | Genetically expressed proteins such as luciferase | SR—~1 mm S—Medium (1000 s of cells) HS—one cell Sp—High | Probe uptake, cell presence, and cell viability. | Minimally invasive, inexpensive, allows for signal quantification, whole mouse imaging and has high throughput. BLI signal is only produced by viable cancer cells permitting distinction between viable and dead cells. | Requires stable transfection of the reporter into cancer cells and injection of substrate into a mouse a. Limited depth penetration and therefore, not clinically translatable. Challenging to determine depth of a tumor within the body based on the signal. False negative effects can occur in areas where the substrate cannot easily accumulate, such as the brain, or in tumors with compromised vasculature. Probe uptake in the brain and limited imaging depth in biological tissues. |
FLI | Optical detection of light emitted from fluorescent reporters. | GFP, eGFP, EYFP, mCherry, TagRFP, Dendra2, tdTomato. | SR—~1 mm S—Medium Sp—High | Probe uptake, cell presence and cell viability. | Minimally invasive, inexpensive, allows for whole mouse imaging and has high throughput. Does not require injection of substrate. The signal is quantifiable. | Requires stable transfection/transduction of the reporter into cancer cells and excitation by an external light source. Background autofluoresence decreases sensitivity. Challenging to determine depth of a tumor within the body based on the signal. Probe uptake in the brain and limited imaging depth in biological tissues. |
CT (with and without contrast) | Combinations of multiple X-ray measurements taken from different angles to produce tomographic images. With a contrast agent, CT images can reveal the location and density of vessels (early), and contrast agent accumulation in the tissue (late). | Iodine-containing polymers [77], liposomes [78] or micelles [79] and gold nanoparticles [80]. | SR—~ 100 um S—Low Sp—Medium | Tomographic images, vessel density, and agent accumulation. | Low cost, fast acquisition and high spatial resolution of 3D volumes. | Radiation exposure, low contrast can make certain pathologies difficult to discern; contrast-enhanced micro-CT is more commonly applied. Low contrast does not allow for visualization of tumor detail, often needs contrast enhancement. |
PET | Detection of γ rays from positron emitting radioisotopes b. | FDG, 18F-FMISO. | SR—~1 mm S—High picomolar (100–1000 s of cells) Sp—High | Tracer uptake; biological and biochemical. Direct cell quantification, and signal specific to cells. | Can monitor tissue metabolism (glycolysis, DNA synthesis, amino acid transport and oxygenation state) in brain metastases, with excellent depth penetration. | Requires tracers, normal brain tissue has a high rate of glucose metabolism and therefore high FDG accumulation which decreases specificity. Signal decays over time (t1/2), and cells are exposed to radioactivity. Low radiotracer uptake in brain. |
MRI (proton) | Detection of water proton relaxation after RF absorption. | See below. | SR—500–2000 microns S—Low millimolar Sp—Medium | Anatomical information, morphology, and tissue composition. | No ionizing radiation exposure, provides excellent soft tissue contrast. | Potential tissue heating during long scans, risk of peripheral nerve stimulation, sensitive to motion. Poor sensitivity in detecting micrometastases. |
MRI (contrast) | MRI with use of contrast agents, administered to improve signal differences between normal and cancerous tissue. | Most common contrasts—gadolinium-based, manganese-based. | SR—500–2000 microns S—medium Sp—Medium | Improved visibility of tumors, inflammation, and blood supply. | No radiation exposure. Clinically, dynamic contrast enhanced (DCE) MRI can be used to image the tumor vasculature by acquiring sequential images during the passage of gadolinium through tissues and provides quantitative measures of perfusion, permeability and blood volume. | Requires administration of contrast. Heterogeneity of metastasis permeability in early and late stages of development. |
MRI (iron nanoparticles) | Detection of intracellular iron particles via distortion of the magnetic field. | SPIO nanoparticles labeling via co-incubation with cancer cells. | SR—200–1000 microns S—High picomolar HS—one cell Sp—Medium | Cell location and presence, including nonproliferative cells. | High sensitivity, non-proliferative, cancer cells do not dilute the SPIO and can be identified by MRI as persistent signal voids by virtue of their retaining iron. | SPIO are diluted in the progeny of proliferative cells and therefore labeled cells become undetectable by MRI after repeated cell divisions. Poor cell quantification. Other structures in brain appear with low signal (i.e., blood, air, bone). |
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Knier, N.N.; Pellizzari, S.; Zhou, J.; Foster, P.J.; Parsyan, A. Preclinical Models of Brain Metastases in Breast Cancer. Biomedicines 2022, 10, 667. https://doi.org/10.3390/biomedicines10030667
Knier NN, Pellizzari S, Zhou J, Foster PJ, Parsyan A. Preclinical Models of Brain Metastases in Breast Cancer. Biomedicines. 2022; 10(3):667. https://doi.org/10.3390/biomedicines10030667
Chicago/Turabian StyleKnier, Natasha N., Sierra Pellizzari, Jiangbing Zhou, Paula J. Foster, and Armen Parsyan. 2022. "Preclinical Models of Brain Metastases in Breast Cancer" Biomedicines 10, no. 3: 667. https://doi.org/10.3390/biomedicines10030667