Common Prostate Cancer Treatment May Compromise Blood-Brain Barrier
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Common Prostate Cancer Treatment May Compromise Blood-Brain Barrier, Exacerbating Alzheimer’s-Related Dementia
According to the latest data from the International Agency for Research on Cancer (IARC) under the World Health Organization (WHO), prostate cancer is the second most newly diagnosed cancer among men globally, second only to lung cancer.
Androgen Deprivation Therapy (ADT) is a common treatment for prostate cancer that works by lowering androgen levels to inhibit the growth of cancer cells. This therapy significantly improves survival rates and quality of life for patients. Due to its clear survival benefits in various clinical scenarios, half of the prostate cancer patients worldwide undergo ADT after diagnosis.
However, ADT is not without risks. Studies show that long-term ADT increases the risk of osteoporosis, obesity, and diabetes. More concerning is the finding from a 10-year follow-up study of over 300,000 prostate cancer patients, which revealed that those receiving ADT have a 1.5 to 2.5 times higher risk of developing Alzheimer’s disease (AD) and other dementias compared to the general population, posing a dilemma for the treatment of elderly prostate cancer patients.
Recent research conducted by researchers from the University of Alabama at Birmingham and Qin Wang from the Medical College of Georgia at Augusta University has uncovered the mechanism by which ADT influences the risk of dementia in prostate cancer patients. Their study was published in the journal *Science Advances*.
They discovered that ADT promotes the infiltration of peripheral immune cells into the brain by disrupting the blood-brain barrier (BBB), exacerbating neuroinflammation and gliosis without affecting amyloid-beta (Aβ) deposition, leading to cognitive dysfunction. By using drugs to reduce the infiltration of peripheral immune cells into the brain, cognitive function under ADT treatment can be improved.
In their study, the researchers used a mouse model of Aβ pathology. They implanted prostate cancer cells in 8-week-old mice, at which point the mice’s prostate development was complete and Aβ deposition had not yet occurred. After the tumors formed solid masses two weeks later, the mice underwent castration surgery and ADT treatment (with abiraterone acetate [ABA] and Degarelix), mimicking the clinical treatment regimen for prostate cancer patients.
By measuring tumor size and assessing peripheral immune responses, the researchers found that compared to placebo and sham surgery, ADT effectively inhibited tumor growth. ADT treatment also enhanced the anti-tumor immune response in mice, with increased numbers of natural killer (NK) cells, dendritic cells, and CD8+ T cells in the peripheral blood, and reduced numbers of CD4+ T cells and macrophages, along with decreased levels of inflammatory factors like TNF-α and IL-6.
Despite ADT’s efficacy in preventing tumor progression in prostate cancer mice, it also accelerated the onset of AD-related cognitive deficits and increased anxiety-like behavior as shown by various behavioral cognitive tests.
Investigating further into the mouse brains, the researchers found that while all mice exhibited significant Aβ deposition in the hippocampus and cortex, there were no significant differences in Aβ load levels between different treatment groups, indicating that neither the presence of tumors nor ADT induced cognitive damage through Aβ deposition pathology.
So, how does this happen?
Further studies revealed that the prostate cancer tumor itself can disrupt the BBB, increasing its permeability and leading to an increase in pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines in the brain, with particularly pronounced changes in the hippocampus.
When ADT is administered, these phenomena are exacerbated, leading to increased infiltration of peripheral immune cells into the brain, heightened brain inflammation, enhanced reactivity of astrocytes and microglia, and elevated levels of inflammatory factors IL-6 and IFN-γ, inducing cognitive deficits in mice bypassing Aβ deposition.
The level of Aβ deposition showed no significant differences, but neurogliosis and inflammation increased with ADT treatment.
To mitigate the damage ADT causes to the BBB, the researchers explored the use of Natalizumab, an antibody targeting integrins, approved by the FDA for treating multiple sclerosis. Natalizumab has been shown to reduce the infiltration of peripheral immune cells into the central nervous system.
Histological observations indicated that Natalizumab treatment significantly improved BBB integrity in prostate cancer mice undergoing ADT, reduced peripheral immune cell infiltration in the hippocampus and cortex, and decreased the release of pro-inflammatory factors from glial cells. However, Natalizumab treatment did not affect anti-inflammatory factor levels nor improve Aβ deposition.
Behavioral test results showed that Natalizumab treatment could rescue the cognitive deficits caused by ADT in prostate cancer mice. Compared to the control group, mice treated with Natalizumab exhibited enhanced associative learning abilities.
The study underscores that while ADT effectively controls prostate cancer, it also increases the risk of dementia, potentially negatively impacting the overall health and quality of life, especially in elderly patients.
However, the researchers’ findings suggest that inhibiting immune cell infiltration into the brain could be a promising treatment strategy to reduce the risk of cognitive impairment in prostate cancer patients undergoing ADT. Natalizumab, used for multiple sclerosis, might find a new application in this context.
Common Prostate Cancer Treatment May Compromise Blood-Brain Barrier, Exacerbating Alzheimer’s-Related Dementia
References:
[1]Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024. doi:10.3322/caac.21834
[2]https://www.science.org/doi/10.1126/sciadv.adn8709
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