Many types of cancer are capable of spreading or metastasizing to the brain including lung, breast, melanoma and colorectal cancer. There is no cure for metastatic cancer of any type, but treating brain metastasis poses unique challenges.In two recent review articles, President-Elect of the Metastasis Research Society, Dr. Dihua Yu, and colleagues discuss what is currently known about the complex biology of brain metastasis and which therapies or strategies are most promising.
The brain is unique. It supports and preserves neuron functions with a network of specialised cells including astrocytes and microglia, and is protected by the ‘blood-brain barrier,’ which separates the brain from the circulating bloodstream. So how do cancer cells survive in the foreign environment of the brain and grow into metastatic brain tumors? Simply put, these cells are endowed with aggressive traits that enable them to cross the blood-brain barrier, escape recognition by anti-cancer immune cells in the brain, use the existing brain vasculature for nourishment, and they can even ‘educate’ other normal cells in the brain to support their growth and survival. Unfortunately, the aggressive traits of metastatic brain tumors can also make them resistant to standard systemic cancer therapy. In addition, more than 80% of patients with metastatic brain cancer already have multiple metastatic tumors at the time of diagnosis, making them ineligible for surgery.
Dr. Yu and colleagues note that the support of cancer growth in the brain by surrounding resident brain cells is a major contributor to therapy resistance. Therefore, counteracting the ability of metastatic cancer cells to communicate with resident cells of the surrounding microenvironment should increase the clinical benefit of standard therapies.It may also be possible to target the unique metabolic needs of brain metastatic cancer cells therapeutically. Metastatic cancer cells must alter their metabolism to survive and grow in the brain. For example, cancer cells can adapt to use neurotransmitters of the brain as metabolites. Cancer cells may also become addicted to certain metabolites that could potentially be limited. But, the concept of targeting metastatic cancer cell metabolism isn’t ready for primetime in the clinic because many aspects of these molecular pathways still need to be clarified.
Much insight in the field of brain metastasis is expected to come from studies with preclinical models that recapitulate the entire metastatic process, and the intimate interactions between tumor cells and cells within the tumor microenvironment (cells in the area surrounding the brain tumor). Moreover, advancements in neuroimaging techniques are providing new tools for live imaging. This technology is increasing our understanding of metastasis in experimental models and improving diagnostics in patients.The extensive characterization of genes (genomic characterization) and molecules that are transcribed from genes to create proteins (transcriptomic characterization) in metastatic tumors isolated from patients is also providing clues to how tumor cells that metastasized to the brain differ from normal cells and from each other. Tumor cells may be heterogeneous (different) and endowed with different molecular features and abilities even if they are within the same tumor.
With this information, new hypotheses on the molecular mechanisms that orchestrate the establishment and progression of brain metastases are developing and creating new opportunities to find therapies that target a specific molecular feature of brain metastatic cancer cells.
In addition to targeted molecular therapies, immunotherapies are emerging as a potentially efficacious strategy for the treatment of brain metastases. These therapies don’t target brain metastatic cancer cells themselves, but instead enhance the function of immune cells to suppress tumor growth. Clinical investigations are now demonstrating that the ability of immune checkpoint inhibitors to effectively inhibit metastatic brain tumors is similar to their ability to treat metastatic tumors outside of the brain. However, they could produce severe side effects. This concept is explored in another article here.
Despite encouraging progress in this field, the clinical management of patients with brain metastases is still challenging and financial support for studies on metastatic cancers is limited. Further effort is required and active cooperation among biologists, neuroscientists and oncologists is the key to targeting metastatic cells early and from different fronts.
Source Articles:C. Zhang and D. Yu. Advances in decoding breast cancer brain metastasis. Cancer Metastasis Reviews. 2016. 35:677-684.F.J. Lowry and D. Yu. Brain metastasis: unique challenges and open opportunities. Biochimica et Biophysica Acta. 2017. 1867:49-57.
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The Metastasis Research Society (MRS) is a 31 year-old, non-profit, international professional society for researchers, clinicians, members of industry, and entrepreneurs who are dedicated to solving the problem of cancer metastasis. The mission of the MRS is to support progressive research on any processes fundamental to metastasis. This includes supporting the exchange of information between all stakeholders in metastasis research and treatment via conferences, networking events, webinars, and the two official journals of the society (Clinical and Experimental Metastasis and Cancer and Metastasis Reviews). We also strive to educate the public about metastatic cancer, and raise awareness about the funding discrepancy for metastatic research worldwide.
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