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A Guide to Preclinical Models of Brain Metastases

An overview of brain metastases
in vivo selection of metastatic brain cells
Genetically Engineered Mouse Models (GEMM)
Challenges
conclusions
References
Read further


The metastasis of certain cancers to the brain poses a major challenge to oncologists seeking to eradicate these tumors. The complexity of the blood-brain barrier (BBB) ​​and the aggressive cancers that can invade the central nervous system (CNS) often limit the effectiveness of current therapies.

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As a result, many researchers around the world have turned to different in vitro and in vivo models of brain metastases to better understand how these cancers migrate to the brain and which treatments have a promising future in the clinic.

An overview of brain metastases

When a local tumor spreads to different organs, it becomes a systemic disease that is often much more difficult to control through therapeutic interventions. Unfortunately, several cancers will often travel to the CNS, with brain metastases accounting for up to 80% of all brain tumors. While lung and breast cancer are the most common causes of brain metastases, other cancers, including melanoma and kidney cancer, are also commonly associated with metastatic spread to the CNS.

One of the largest targets for the treatment of brain metastases is the BBB, as most systemic chemotherapeutic agents cannot penetrate this barrier and reach the tumor. The use of radiation for brain tumors is also associated with certain limitations, as this therapeutic approach may irreversibly limit brain plasticity and progress to radiation necrosis, a potentially fatal complication, and cranial radiotherapy.

Due to the lack of available and effective treatments, cancer patients diagnosed with brain metastases often have a dismal prognosis associated with increased morbidity, mortality and cost of treatment, making palliative care the only treatment option for many. patients with this stage of cancer.

in vivo selection of metastatic brain cells

One of the main approaches to studying brain metastases is the development of specific cell line clones that can reach the brain. These cell lines are developed by an in vivo selection strategy in which the parental cancer cell line is injected into a mouse via the intracarotid or intracardiac route.

Any cancer cells that successfully reach the brains of the injected mice are then recovered and cultured. Usually this is in vivo selection process is repeated several times to increase the efficacy of the selected cancer cells upon reaching the brain. The final cloned cell line is typically termed a brain metastatic (BrM) derivative of the parent cell line.

Image Credit: Nemeziya/Shutterstock.com

Image Credit: Nemeziya/Shutterstock.com

Once successfully cultured, the BrM cell line can be reintroduced into mouse models via the above systemic injections of intracardiac or intracarotis pathways, as well as via local intracranial injections or orthotopic approaches. In particular, the systemic inoculation of BrM cells is most similar to the true brain metastasis process, in that it requires the cells to survive in the circulation after injection, penetrate the BBB and colonize in the brain.

Genetically Engineered Mouse Models (GEMM)

GEMMs are made by removing tumor suppressor genes or activating oncogenes that are poorly metastatic. To date, two GEMMs of melanoma have been reported to cause brain metastases due to the activation of the ret oncogene and activation of AKT1 respectively.

In addition to GEMMs for studying brain metastases from melanomaanother GEMM created by the inactivation of Trp53 and Rb1 has also been developed to study the metastasis of small cell lung cancer to the brain. Aside from the brain, other organ targets of this GEMM include the bones, adrenal glands, ovaries, and liver.

Challenges

The experimental models of brain metastases are associated with several advantages. For example, these methods allow researchers to control the number of cells delivered to the brain, often resulting in a relatively uniform size of metastases in injected mice.

Despite these advantages, these preclinical models of brain metastases are also associated with several limitations. For example, while the intracardiac injection of tumor cells bypasses the lungs, tumor cells can also reach other organs and the brain as they travel through the arterial circulation. So if the injected cells reach other tissues, such as the liver or bone marrow, this organ may become the primary concern rather than the brain.

While the intracranial injection of tumor cells provides a direct route for tumor cell implantation, it is a much more complex process requiring specialized equipment. In addition, this pathway also bypasses the earlier stages of the metastatic cascade that may be the target of certain treatment strategies to reduce the occurrence or size of brain metastases.

What are brain metastases? Chapter 1 — Brain Metastases: A Documentary

conclusions

Despite the availability of certain preclinical models, brain metastasis research remains challenging. Nevertheless, significant progress has been made in developing specific models to study metastatic cancers such as triple-negative breast cancer and melanoma. In addition, optimizing these models has also supported research projects on different treatment approaches that may reduce the clinical impact of these aggressive cancers in patients.

References

Further Reading

 

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