Hallmarks of Cancer Part 3
We continue our adventure through what cancer really is, why it is so difficult to treat, and to help give you, the audience, why there is not a one size fits all cure!
6. Activating Invasion and Metastasis
One of the key features that cancer cells have is the ability to leave their starting location and migrate to other areas in the body. This is accomplished through a series of events that have still to be fully figured out. In the past 16 years, this area has been a subject that scientists have thrown a large amount of effort. Imagine a tumor as a bug hive that grows and grows without anything stopping it. Eventually, some bugs will gain the ability to go off on their own and start their own colony hive elsewhere. These stray bugs are cells that have shed their old hive mentality, and rewired themselves into standalone bugs. The process is very complex, and there are still many gaps in the knowledge of how cancer cells leave its home locations, get into the blood stream, leave the blood stream, and make a colony.
•The EMT Program Broadly Regulates Invasion and Metastasis
As we mentioned previously, the way cells do this is to rewire themselves to be able to not need contact with their foundation and their neighbor cells. They do this by losing their neighbor connector proteins that are called E-cadherins to N-cadherins, and they also change internal wiring so the cells can float around in the body to their new location. This transition from the grounded neighbor cell is called a Epithelial to Mesenchymal Transition, or EMT. Proteins called Transcription Factors work like a crew to change the cells wiring by causing genes that are normally turned off to be switched on. Some examples of these Transcription Factors include Snail, Twist, Slug, and Zeb 1/2. Think of these are the carpenters, electricians, etc. that rewire the cell into changing into a cell that can transport itself to other areas of the body.
• Heterotypic Contributions of Stromal Cells to Invasion and Metastasis
The best way to get a construction project finished is to hire sub-contractors. There are cells called neoplastic stroma that surround the cancer cells we have been discussing. These are the sub-contractors that help get the cancer cells to become metastatic. They send in signals to these cells to help rewire them to be able to leave the current area they are in to the area that they will eventually seed and begin to grow again. Some of these cells that assist are the very same immune cells that should be demolishing the tumor. This crosstalk of rewiring is one big area that really makes treating and curing cancer a moonshot!
• Plasticity in the Invasive Growth Program
So, that EMT thing we were talking about, well there is the opposite process call Mesenchymal to Epithelial Transition, or MET. This occurs after the metastatic cells gets to its new home(s). This is thought to happen because the sub-contractor cells (desmoplastic stroma) are no longer helping to keep the rewired state of the cell. The lack of signals causes the adventurous cells that colonize the new area to change back to the way they were before the left the home tumor site (primary tumor).
• The Daunting Complexity of Metastatic Colonization
How do the cells decide where they want to settle down for their new settlement? Do they send scouting cells to investigate the new areas? Do they send out signals to see if the area is ripe for the taking? Do the cells go to the areas themselves and seed the area for distant tumors? Or, do they send little packages of proteins (exosomes) to new areas to make that area suitable for colonization? These are some of the questions that researchers are currently trying to understand, and adds to the evidence that there won’t be a cure-all for cancer. Once they figure this out, they may be able to develop drugs that block this colonization from occurring. This type of treatment of cancer would be similar to HIV treatments that do not cure the disease, but rather extend life expectancy by blocking the spread of the disease.
• Programming of Hallmark Capabilities by Intracellular Circuitry
Now, I have been describing the wiring of cells to you for the entirety of this series, but now I want to elaborate just a little bit more. All cells have proteins that communicate with one another. Think of each protein like a computer on the internet. They all send communication and messages to one another on how to act, how to respond to messages, and can pass messages along to others. These proteins are “nodes” where they get a lot of information from many sources all at once, and have to act as processing stations to decide to send a go message along, or a stop message along (this is a very simple yes or no function, and can be thought of as binary 0 or 1 in computer terms. This doesn’t exactly convey all that these nodes can do, but we’ll leave it there to keep it simple.) These nodes are connected to other nodes like a web, and their receiving and processing of a message can result in them passing this message onto to several other hubs that in turn can do the same thing. One signal from outside of the cell can go through several nodes and amplify the signal to cause what is called an enzymatic cascade with far reaching consequences. This is one of the many reasons why the cure for cancer is difficult, because these nodes crisscross and overlap one another. If you shut down one node, other nodes can be activated to get the signal to where it needs to go. This would be the same as your phone dying when you need to make an important phone call, and you ask someone to borrow their phone to make the phone call, or using a computer to tell everyone on Facebook your phone is broken. You can still get information to the person/people you need to, but you go through a different way to achieve it.
7. Genome Instability and Mutation
This concept has been covered before in my posts, but we’ll now examine it under the context of having many cancer cells competing against one another. All tumors are made up of many different cancer cells which is another reason why it is so difficult to find a cure for cancer. By “different” cancer cells, I mean that individual cells of the tumor could have different wiring, or different mutated nodes, from one another. One set of wiring may be killed off by one drug, but the other “differently” wired cells could live even when treated with that type of drug. This occurs because the “different” cells have mutations in different nodes, or the same nodes have mutations that are not the same. The proteins, or nodes, could behave another way depending on the type of mutation they have. Not only would this allow them to not respond to a treatment, these mutations could allow this group of “different” cells to outgrow and beat out the other cells in the tumor.
I know this is very complicated, but let’s break it down very simply. Let’s say a tumor has 100 cells, and 80 of the have mutation A and the other 20 have mutation B. The 80 A cells, don’t grow as fast as the mutation B cells, so eventually the tumor would have mostly mutation B cells. This is one way that tumor cells can continually change and evolve to compete with themselves to make a stronger, faster, and “better” tumor (This tumor would be more deadly).
Now let’s say this same tumor with 100 cells is treated with anti-A drug, and it kills off the A cells. That still leaves 20 mutation B cells. These little guys can grow back quicker, and would eventually give you a tumor that is resistant to anti-drug A treatment. This is “relapse” in clinical terms when the tumor regrows after being beaten down. This exemplifies the complexity of trying to win the battle over cancer, and why there is no panacea of cancer.