▎ WuXi AppTec content team editor
Melanoma is an extremely deadly type of skin cancer, but this cancer also has a strange property: it likes to metastasize to the brain, and about 40% of melanomas will have brain metastases, which is a very high proportion of all common cancer types. But how do cancer cells in the skin run into the brain?
The problem may lie in the β-amyloid protein, which is often mentioned in Alzheimer's disease, β-amyloid, according to a paper in Cancer Discovery, can help melanoma invade brain tissue, eventually allowing cancer cells to settle and develop in the brain. The most intuitive result is that melanoma obtained from the brain contains 3 times more β-amyloid than in other metastatic regions.
At the beginning, the research team tried to place the melanoma in the brain in vitro for culture, and harvested the proteins of the cancer cells in a short time, and the analysis results showed that the most eye-catching of these culture samples was β-amyloid protein, which could be determined that these proteins did not come from brain cells.
But why do melanoma cells need β-amyloid? The researchers first speculated that this protein can help it survive and develop, they first directly interfered with the expression of the gene encoding amyloid precursor protein (APP) in melanoma, which can become β-amyloid protein with the help of some enzymes. As a result, these modified cancer cells lost the ability to migrate to the brain after being injected into mice.
Melanoma from the brain will still have a stronger brain transfer ability after transplantation into mice (Image source: Reference[2])
Judging from the imaging results, once the β-amyloid is lost, the mouse brain basically does not see the shadow of melanoma. In addition to the inability to metastasize, the establishment of an army of cancer cells seems to be damaged. After the inability to make β-amyloid, melanomas become more difficult to divide and expand, and they can no longer easily form clumps of cancer cells because the immune system is more sensitive to these cancer cells and clears them before the hidden dangers take root.
Once melanoma begins to make β-amyloid protein and enters the brain, many cells in the brain are affected, first of all, these proteins will significantly change the gene expression of astrocytes, which would have secreted some neurotransmitters that regulate the microenvironment around neurons. But after being exposed to melanoma, they behave abnormally and begin to secrete proteins that can suppress the immune response, allowing cancer cells to escape the hunt.
▲After inhibiting the synthesis of β-amyloid, the efficiency of melanoma brain metastasis is greatly reduced (Image source: Reference[2])
Microglia in the brain that assume immune function will also be impaired by the β-amyloid secreted by melanoma, and microglia will not choose to engulf or clear melanoma. Therefore, cancer cells directly or indirectly malfunction the immune defenses in the brain, and eventually settle and metastasize successfully.
A β secretory enzyme inhibitor LY2886721 was used in tumor mice, which inhibited the synthesis of β-amyloid protein, and the size of melanoma in the brain of these mice was reduced by 50% compared to the control. "This study reveals the unexpected role of tumor secretion β-amyloid in cancer metastasis, and we have a potential means to prevent it from happening," said Professor Eva Hernando, lead author of the study.
There have been many studies of drugs that reduce β-amyloid levels, and although these drugs are not effective in treating Alzheimer's disease, they are likely to be used to prevent melanoma metastasis. The research team plans to evaluate the effect of these drugs in inhibiting tumor brain metastasis in animals in the future.
Resources:
[1] Skin cancer cells use Alzheimer's protein to sabotage brain's immune defenses. Retrieved Mar 11th, 2022 from https://medicalxpress.com/news/2022-03-skin-cancer-cells-alzheimer-protein.html
[2] Kevin Kleffman et al, Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis, Cancer Discovery (2022). DOI: 10.1158/2159-8290.CD-21-1006
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