Breast Cancer Brain Metastasis(BCBM)
Imagine a dandelion, it spreads everywhere. Sometimes you make a wish and blow, sometimes the wind blows. There might even be times where you make a wish and the wind blows it for you. And your wish may or may not come true. Or you might not get the chance to because right before you blow, your friend decides to stuff the dandelion in your mouth. Ewww.
Wherever the dandelion seeds land they grow or at least try to. But what if you have a vegetable garden in your backyard, you’re just trying to grow some nice carrots, squash, and peppers. Then some dandelion appears in your garden. What! You don’t want any stupid weeds in your garden. You want vegetables. Dandelions can be so annoying! Just like cancer, during a process called metastasis, it can break off the primary site and travel throughout the body. This time it’s not a harmless dandelion that can possibly grant wishes. Instead, it’s a disease where abnormal cells rapidly divide and damage tissues in the body.
In this article, I will explain the process a breast cancer cell will take on its journey to the brain. Let’s see the journey!
Let’s Get Moving
When cancer spreads to another part of the body no trails are connecting the multiple tumor sites. The metastasis process begins with cancer cells breaking off the tumor site. Cancer cells gain mobility through a transition known as epithelial-mesenchymal transition(EMT). During EMT the cytoskeleton, a structure that helps with the cell’s shape, internal organization, and mechanical functions gets reorganized. epithelial-like cells transform into mesenchymal-like cells which enable them to grow longer and gain directional motility. Epithelial-like cells are a barrier between the inside and outside of the body and they protect the body from viruses. Mesenchymal-like cells can transform into other types of cells and avoid the negative responses of the immune system.
Using these new features cancer cells move towards the blood vessel and continue until they come across a barrier which is usually the basement membrane. The basement membrane is a thin sheet of a group of non-cellular material that helps cells bind together and limit their functions(extracellular matrix). It’s located on the outside of the epithelial cells of the blood vessel. To get past it, cancer cells secrete a mixture of matrix metalloproteinases. These enzymes are basically “molecular scissors”, which in this case break down the proteins in the basement barrier and allow room for the cells to squeeze by. This leads to the entrance of the cancer cells into the blood vessel, known as intravasation.
A Trip to the brain
The cancer cells are now in the blood vessel, their transportation hub throughout the whole body. The path from the breast to the brain isn’t a very long trip but it’s still where most cancer cells die. Some causes of death can be not surviving in the bloodstream, damage from squeezing through tight spaces, damage from bumping into the blood vessel walls, or getting recognized and destroyed by cells of the immune systems. Cancer cells may die alone but when they’re traveling in groups one cell death will not cause death to the whole group or be the death of every cell in that group.
For the most part cancer cells can just follow the blood flow to the brain. They don’t need to go out of their way to hide from immune cells because they’re naturally protected. Not by the body but by the characteristics cancer cells are already equipped with during development. Some characteristics are only active in select cancers and some are active throughout cancers in general. Two of the few proteins and enzymes responsible for this are HK2 and FOXC1.
Hexokinase 2(HK2) is an enzyme that speeds up the slowest part and first obligatory step of the glucose metabolism cycle. Glucose metabolism provides energy specifically for the brain and red blood cells since they can’t use fat or protein. Every cell in the body uses glucose but cancer cells use about 200 times more. These massive amounts of glucose are mandatory to fuel the rapid growth of cancer cells.
Forkhead box C1(FOXC1) is a protein but the specific function is unknown just like my knowledge of the origin of its name. Although such a key element is unknown FOXC1 has still been observed to be overexpressed in breast cancer. FOXC1 enhances cancer-stem-cell-like properties, such as abnormal cell reproduction, cancer stem cell preservation, cancer migration, and the development of a new blood vessel(angiogenesis). Basically, FOXC1 is a tumor facilitator.
A Roadblock At the Brain
You’re now at a check-point, you’re at the brain but not inside the brain. The brain, holding the title of the most important organ has equipped with an elite protection and defense system, right? Its protection system is known as the blood-brain-barrier(BBB), and the defense system well that’s the neuroimmune system. But that’s not what I want to talk about. The BBB has a duty to keep the brain healthy and prevent malignant activity. A breach of the brain’s health has the potential to make severe impacts.
The BBB strictly regulates the movement of ions, molecules, and cells between the blood and the brain, acting as a strainer. Like all other blood vessels, epithelial cells line the inside, but in the brain, they’re packed tight not loosely connected. Some molecules can pass but toxins, bacteria, viruses or microorganisms that could inflict harm are strained out. Of course, some essential molecules can pass, water, select gasses, and lipid-soluble substances have easy access. Another essential molecule like glucose can pass but it just requires a little effort. The BBB doesn’t really have a gate that opens and closes from the BBB to the brain. These molecules can dissolve through the BBB and appear on the other side with the exception of glucose. Thanks to one of the BBB, there are many arrays of transportation. The larger molecules like glucose gain entrance from transporter proteins
Cancer obviously doesn’t fit into the essential molecules category, it should be more like the most unessential molecules category. As cancer isn’t welcome past the BBB, it has its own method. BUT WE DON’T COMPLETELY KNOW!! Sure there are hypotheses but that’s only a hypothesis, there isn’t rock-solid evidence confirming anything. But moving on to something we know about.
Tumor Development
This is the final destination of an exhausting journey. The cancer cells passed the BBB but they can still die at any point. Since they’ve now reached the target organ the only task left for these cells is to develop in a suitable environment. Cancer cells are used to following the blood flow so it plays a role in environment suitability. 80% flows to the cerebral hemisphere, 15% to the cerebrum, and 5% to the brainstem, we can see that the cerebral hemisphere is pretty easy to access. But that’s not the only factor to consider, there are the cancer cells themselves and the brain microenvironment. Breast cancer cells are highly adaptable to the brain. By expressing brain-specific gene products and mediators, the cancer cells gain the ability to hide and be perceived as brain cells. The brain microenvironment is a small-scale environment in a certain part of the brain. It consists of a variety of cells and undergo radical changes upon the arrival of cancer cells.
Cancer cells tend to travel and develop near blood vessels. That’s where they get their fuel for development. Even though cancer cells are basically immersed in blood cells during the whole journey, tumors can only develop when the cancer cells stop moving.
Once cancer cells have reached their desired environment they start mesenchymal epithelial transition(MET). Remember when I mentioned EMT earlier, this is just the opposite. Mesenchymal cells transition back into epithelial cells. With no need to possess STEM cell qualities anymore the cancer cells can transition back into epithelial cells that are part of the brain tissue. Like every other cancer, the cells now divide rapidly and the tumor grows bigger and goes through angiogenesis during development.
What About My Brain
Now there’s a tumor in the brain, even if the tumor is still developing changes in the brain may still occur. The tumor is a solid abnormal mass of extra cells. As the tumor grows in size it swells and creates pressure inside the skull. The pressure can change the function of the surrounding brain tissue and destroy normal tissue. By squeezing the brain tissue their becomes a shift in the placement of the functional network. These changes can lead to the symptoms of brain tumors such as:
- Unusual/progressive headaches
- Seizures
- Loss of balance
- Memory loss
- Speech, vision, and understanding disturbances
- Physical weakness or numbness
Will It Go Away
Cancer has never had the reputation to just go away, not naturally or after treatment. Cancer is just a very harsh and persistent disease. But isn’t brain cancer the worst whether it’s a metastatic or primary tumor? I mean it is the most important organ and basically controls the whole body after all. Even one negative characteristic in the brain has the ability to impair your speech. Here are the current treatments(some treatments can be combined):
- Whole-brain radiation therapy- Radiation applied to the whole brain
- Surgical resection- Surgical removal of all or part of a tissue or organ
- Stereotactic radiotherapy- A special device aimed at the patient to precisely deliver radiation to the tumor
- Systemic therapy- Drugs that spread throughout the body
- Prophylactic mastectomy- Surgery to remove one or both breasts
- Lumpectomy- Surgery removing a lump from the breast
- Bevacizumab- Chemotherapy and targeted therapy that inhibits the binding of vascular epithelial growth factor(VEGF) to its cell surface receptors
We have treatments but none have had success rates over 95%. Sometimes there are even combinations of treatments. This may be due to the fact we don’t have enough research. Remember when I was talking about cancer cells getting past the BBB, but I just moved on. That’s how some treatments are going. They’re being treated without being completely understood. There could be crucial information to enhance breast cancer brain metastasis treatment that we’re missing since we don’t have all the information. These current treatments could be inefficient.
Current treatments are mainly focusing on tumors. Cancer cells can exist in areas without causing trouble so targeting the tumor sites doesn’t reach them. What about focusing on something that’s involved with all cancers, but can be tailored for certain cancers and people. Bevacizumab focuses on VEGF, which is in all cancers could be a more effective route. There are other aspects involved in or interact with all cancers that can be targeted. There is the immune system, epithelial cells, angiogenesis, lymph nodes, and blood vessels. What do you think, do more research or expand our cancer treatment targets?
Thank you for reading my article! I’d love it if you’d react and comment!
