Mouse Models of Brain Metastasis for Unravelling Tumour Progression

Soto, Manuel Sarmiento; Sibson, Nicola R.

doi:10.1007/978-3-319-26666-4_13

Cited by 4 publications

(5 citation statements)

References 14 publications

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“…Female RNU nude rats (5–6 weeks old; 200 ± 20 g; Charles River Laboratories) were anesthetized with 2%–3% isoflurane in oxygen and injected in the left striatum, with 5 × 10 3 MDA231Br-GFP or U87MG cells in 0.5 μL PBS, as described previously ( 13 ). For the medulloblastoma model, 10 4 DAOY cells in 1 μL PBS were injected intracerebrally in the cerebellar vermis, as described previously ( 14 ).…”

Section: Methodsmentioning

confidence: 99%

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

Cheng

Pennington

Zakaria

et al. 2022

Clinical Cancer Research

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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.

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Section: Methodsmentioning

confidence: 99%

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

Cheng

Pennington

Zakaria

et al. 2022

Clinical Cancer Research

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“…Finally, starting from the evidence that LNPs‐miR‐182‐3p cross the blood–brain barrier, we decided to test their efficacy on a model of breast cancer brain metastases by intracranial implantation of luminescent TNBC cells (MDA‐MB‐436) (Soto & Sibson, 2016 ). One week after cell implantation, mice were treated with LNPs‐miR‐Control or LNPs‐miR‐182‐3p by tail vein injection as previously described (Fig 5A and B ).…”

Section: Resultsmentioning

confidence: 99%

MiR ‐182‐3p targets TRF2 and impairs tumor growth of triple‐negative breast cancer

et al. 2022

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The telomeric repeat‐binding factor 2 (TRF2) is a telomere‐capping protein that plays a key role in the maintenance of telomere structure and function. It is highly expressed in different cancer types, and it contributes to cancer progression. To date, anti‐cancer strategies to target TRF2 remain a challenge. Here, we developed a miRNA‐based approach to reduce TRF2 expression. By performing a high‐throughput luciferase screening of 54 candidate miRNAs, we identified miR‐182‐3p as a specific and efficient post‐transcriptional regulator of TRF2. Ectopic expression of miR‐182‐3p drastically reduced TRF2 protein levels in a panel of telomerase‐ or alternative lengthening of telomeres (ALT)‐positive cancer cell lines. Moreover, miR‐182‐3p induced DNA damage at telomeric and pericentromeric sites, eventually leading to strong apoptosis activation. We also observed that treatment with lipid nanoparticles (LNPs) containing miR‐182‐3p impaired tumor growth in triple‐negative breast cancer (TNBC) models, including patient‐derived tumor xenografts (PDTXs), without affecting mouse survival or tissue function. Finally, LNPs‐miR‐182‐3p were able to cross the blood–brain barrier and reduce intracranial tumors representing a possible therapeutic option for metastatic brain lesions.

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“…Without drilling a burr hole in the skull, mice received an inoculation of 4T1Br cells (5 000 cells in 15 μL of PBS) into the right frontal lobe of the brain using a 29 G needle as previously reported. 41 Instead of an intracardiac injection, 42 the injection to the brain was selected to increase the success rate of tumor growth in the brain and reduce the number of mice needed. After 2 days of recovery, the mice received an i.p.…”

Section: Methodsmentioning

confidence: 99%

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

et al. 2021

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Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

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Mouse Models of Brain Metastasis for Unravelling Tumour Progression

Cited by 4 publications

References 14 publications

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

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

MiR ‐182‐3p targets TRF2 and impairs tumor growth of triple‐negative breast cancer

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4

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