July 13, 2024

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Breast Cancer Exploits Neural Signaling Pathways to Bypass Blood-Brain Barrier and Invade the Brain

Breast Cancer Exploits Neural Signaling Pathways to Bypass Blood-Brain Barrier and Invade the Brain

Breast Cancer Exploits Neural Signaling Pathways to Bypass Blood-Brain Barrier and Invade the Brain

Breast cancer is one of the most common malignant tumors in women. According to a report published in The Lancet in April 2024, the number of breast cancer cases worldwide reached 2.3 million in 2020, and it is estimated that new cases will exceed 3 million by 2040, with 1 million deaths annually due to breast cancer.

Notably, about 30% of early-stage breast cancer patients may progress to advanced-stage breast cancer each year. Advanced breast cancer is highly invasive, aggressive, and prone to rapid progression and metastasis, making it the leading cause of death among breast cancer patients.

On June 21, 2024, researchers from Duke University published a study in the top-tier journal Science titled “Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis.” This study discovered that breast cancer cells can bypass the blood-brain barrier and migrate along blood vessels connecting the spinal or cranial bone marrow to the meninges, invading the soft meninges. This process depends on breast cancer cells hijacking neural signaling pathways by expressing integrin α6, which binds to laminin in the vascular basement membrane.

Additionally, breast cancer cells that metastasize to the soft meninges can stimulate resident meningeal macrophages to secrete a protein that promotes neuron survival—glial cell-derived neurotrophic factor (GDNF). This supports the growth of metastatic tumors in the nutrient-poor environment of the meninges. These findings provide new clues about the interaction between tumors and the host in the meninges and point to potential new therapeutic targets for treating meningeal metastases.


Breast Cancer Exploits Neural Signaling Pathways to Bypass Blood-Brain Barrier and Invade the Brain



Poor Prognosis for Meningeal Metastasis

Meningeal metastasis from breast cancer has a poor prognosis. The meninges are membranes containing cerebrospinal fluid that cover the brain and spinal cord. Previously, the research team discovered that hematopoietic lineage cells could migrate along the laminin-rich peri-venous surface from the vertebral or cranial bone marrow to the meninges. The bone marrow is a common site for breast cancer metastasis, and most patients diagnosed with meningeal disease already have cancer cell metastasis.

This observation suggests that venous transport may be an effective mechanism for breast cancer cells to enter the meninges. However, compared to the nutrient-rich bone marrow, the nutrient-poor environment of the meninges poses a harsh survival challenge for breast cancer cells. The adaptive mechanisms that allow these cells to thrive under such cellular stress remain unclear. Additionally, while the meninges have relatively few immune cells, they contain a significant number of resident macrophages. The molecular mechanisms by which breast cancer cells resist macrophages and survive in the meninges are also not well understood.

Mechanisms and Therapeutic Targets

In this latest study, the research team used a combination of in vivo and ex vivo three-dimensional confocal microscopy, micro-computed tomography, and histological analysis to study mouse models of breast cancer bone and meningeal metastasis. They demonstrated that breast cancer cells could migrate from the bone marrow to the meninges through the intravascular venous route.

Moreover, the research team found that the expression of integrin α6, a laminin receptor on the surface of breast cancer cells, is crucial for this process. Using CRISPR gene editing technology, they created integrin α6 knockout breast cancer cells and implanted them into mice. The results showed that knocking out integrin α6 inhibited meningeal colonization, reduced the development of meningeal disease, and prolonged the survival time of tumor-bearing mice. Conversely, inducing integrin α6 expression in breast cancer cells promoted the development of meningeal disease.

Imaging studies revealed that most breast cancer cells co-located with macrophages after entering the meninges, and their presence stimulated macrophages to secrete GDNF. GDNF is minimally expressed in the healthy adult brain and meninges but is secreted by reactive central nervous system microglia and macrophages during brain injury, depositing in the extracellular matrix to prevent apoptotic neuronal stress responses.

Consistent with this, the research team found that breast cancer cells expressing the GDNF receptor—neural cell adhesion molecule (NCAM)—could transduce anti-apoptotic signals, enhancing their survival under nutrient-poor conditions. Furthermore, intrathecal GDNF blockade, macrophage-specific GDNF elimination, or NCAM knockout in breast cancer cells inhibited the growth of breast cancer cells in the meninges.

Clinical Implications

Finally, the research team analyzed clinical data from breast cancer patients. Immunohistochemical analysis of patient samples showed that integrin α6 expression is associated with meningeal metastasis and that the expression of breast cancer NCAM and stromal GDNF is highly enriched in these metastatic tumors.

In summary, this groundbreaking research published in Science provides substantial evidence that breast cancer cells hijack a hematopoietic lineage cell migration pathway to enter the meninges. Breast cancer cells mimic neurons under stress, utilizing meningeal macrophages to aid their survival. Importantly, this study reveals previously unknown roles of GDNF and integrin α6 signaling in promoting meningeal metastasis of breast cancer, laying the foundation for the prediction, prevention, and treatment of this deadly form of tumor brain metastasis.

Breast Cancer Exploits Neural Signaling Pathways to Bypass Blood-Brain Barrier and Invade the Brain

Reference: https://www.science.org/doi/10.1126/science.adh5548

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