Original Academic Latitude Academic Latitude 2024-06-26 08:04 Shanghai
In our perception, cancer cells are tenacious beings that can evade the net laid by the immune system, leaving immune cells with no choice but to slowly develop into tumors in a corner of the body. But tenacity is only one of the characteristics of cancer cells, they are also a very cunning type of cells. To help them grow and metastasize, cancer cells have come up with a variety of strategies, such as building nanotubes to draw mitochondria from surrounding cells for energy.
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Image source: 123RF
When metastasizing, cancer cells choose to degenerate into a more primitive, stem cell-like state, ensuring that they still have a strong ability to grow when colonized in a new place. In addition to this, they can also be deformed to facilitate their own extrusion and passage through various tissue gaps.
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And just recently, in the journal Science, scientists have discovered a new way of metastasizing cancer, which will help them migrate from the breast to the brain, which is far away! Unlike the previous way of thinking that cancer cells need to break through the blood-brain barrier to colonize the meninges, breast cancer cells can climb all the way up the outer surface of the vertebral blood vessels to the leptomeningeal, thereby bypassing the blood-brain barrier to achieve brain metastasis, which also confirms a new and special way of metastasis of cancer cells.
The researchers found that this method is not unique to cancer cells, but may be a "mimicry behavior". In their natural state, hematopoietic lineage cells in our body are able to migrate all the way to the leptomeninges along the vertebral bodies or the emissary veins of the bone marrow of the brain. The catheter vein enters the leptomeningeal from the vertebral body and becomes a direct part of the cerebral vascular system, so the cells do not need to break through the blood-brain barrier to connect with the central nervous system, which also gives cancer cells a chance to learn.
▲Breast cancer cells can enter the brain with the help of blood vessels in the vertebral body (Image source: Reference [1])
In the new study, researchers have unearthed key details about this peculiar cancer metastasis. The reason why they are eyeing breast cancer is because there are two special points in breast cancer patients, firstly, there is a higher proportion of patients with brain metastases, and secondly, some of the breast cancer patients will be diagnosed with leptomeningeal disease, and most of them have developed vertebral bone metastases.
In the author's eyes, these conditions sound too coincidental, and all the elements involved in the metastasis of the vertebral body are actually gathered together! They tried to construct a special batch of breast cancer model mice, these cancer cells will target leptomeningeal migration, and in continuous observation, the authors found that breast cancer cells gradually express a special protein, integrin alpha 6, and have a large number of cohesin on the surface of the guide vein that can bind to integrin alpha6, which allows cancer cells to move tightly on blood vessels and enter the leptomeninges without hindrance.
▲ Cancer cells were observed to move on the surface of the guide vein (Image source: Reference [1])
Entering the leptomeninges does not mean that the metastasis is complete, the cancer cells still have a problem to solve, and the leptomeninges have too low nutrient levels here. Since there are no conditions, cancer cells have to actively create conditions. The authors performed RNA sequencing on cancer cells that had metastasized, and the data showed that cancer cells selectively upregulate neuronal adhesion molecules (NCAMs), which are originally expressed by neurons and link to glial cell line-derived neurotrophic factor (GDNF) produced by macrophages in response to tissue damage.
However, cancer cells do not express NCAM with good intentions, it is intended to divert the GDNF of macrophages for their own use. The authors found that breast cancer cells in the leptomeninges prefer to stay next to GDNF-expressing macrophages, and blocking the NCAM-GDNF link prevents tumors from continuing to grow.
▲Schematic diagram of the steps in which breast cancer cells metastasize to the brain (Image source: Reference [2])
So far, the mystery of brain metastasis of breast cancer has been successfully solved, and cancer cells express integrin α6 to migrate along the guide vein, and NCAM is expressed to obtain nutrients from macrophages. The discovery of this mechanism also brings us more targets for cancer treatment, and the authors speculate that this metastasis along the surface of blood vessels will not be confined to the vertebral bodies, and that some venous networks may facilitate the early metastasis of cancer cells, especially from organs to bones, which may have occurred before the events identified by the new study.
Resources:
[1] Breast cancer exploits neural signaling pathways for bone-to-meninges metastasis. Science (2024). DOI: 10.1126/science.adh5548
[2] An unexpected corridor to brain metastasis. Science (2024). DOI: 10.1126/science.adq4019