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I am long overdue to continue the Hallmarks of Cancer series! We are on Hallmarks of Cancer #8, which is “Tumor Promoting Inflammation”.
Inflammation, like every other biologic process in our body, is a complex cascade of events and it happens after injury, during illness, or as a result of exposures to offending agents. The inflammatory cascade consists of signaling molecules, proteins, and immune cells (mainly white blood cells). It’s so very complex that its hard to wrap my head around, so like most things, I try to think of it in real world terms. In this case, I think of inflammation as different types of fires.
The Burn Barrel Fire: If you have a small cut with an infection, the area gets swollen, red, hot/warm and painful; these are all signs of associated acute inflammation. This limited inflammation is a protective mechanism to prevent the infection from becoming out of control and is contained. This is like a contained trash fire in a burn barrel and serves a specific purpose.
The 5 Alarm House Fire: Overwhelming whole body inflammation happens in states of extreme illness such as sepsis or injury such as major trauma or body burns. This is the raging inferno of inflammation and is often deadly. Wherever this fire goes, it causes so much damage that it can result in organ failure. This is very bad when this happens and despite our most advanced medical care, many people still die each year from this. Reports estimate that 250,000 Americans die from sepsis each year.
The Smoldering Fire: Chronic inflammation is a slow smoldering fire that slowly eats away at the foundation of the structure. This type of inflammation is caused by prolonged insult and the insults can be things in our environment (sun exposure), chronic infections (hepatitis B and C), autoimmune conditions, and toxins (smoke exposure). Chronic inflammation causes damage to the cells that are affected by the inflammation and increases the risk of developing cancer at that site and cancer itself also causes chronic inflammation.
So inflammation can be helpful or harmful depending on the situation. Once a tumor is formed it acts like a small wound that won’t heal and promotes chronic inflammation. The type of white blood immune cell that is recruited to sites of chronic inflammation (and tumors) is different than the cells that are recruited to sites of acute inflammation. The bad actors that are recruited to cancer sites are cells called ‘tumor associated macrophages’ or TAMs. Macrophages are a part of the normal immune system that are meant to heal your body, so why are TAMs bad?
- As we discussed in Hallmarks #1, tumors grow unchecked. Many tumors harbor genetic mutations that can make them independent for the need growth factors. The tumor sets off the inflammatory cascade by activation of a protein called NF-kappa-B and recruits TAMs to infiltrate the tumor. In fact, some studies show that up to 50% can be comprised of these TAMs. The TAMs secrete growth factors such as Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and other small molecules known as cytokines, primarily IL-6 and TNF that support the uncontrolled growth of the cancer.
- We also discussed that tumors need to establish their own blood supply in Hallmark #5. Those nasty TAMs also secrete growth factors to help establish new aberrant blood vessels such as Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF).
- In Hallmarks #6, we discussed how tumors must leave the original location, enter the blood stream and hop off and set up a new home in a distant site. This process requires degrading the extracellular matrix by utilizing special proteins called matrix metalloproteases. You guessed it, the TAMs also can secrete these enzymes to aid in this metastatic process.
- Lastly, we know that our immune system is important in cancer surveillance. This means that the immune system can identify a cancer cell and kill in a way similar to the way it kills bacteria or virus. Obviously, this surveillance system is not perfect and tumors have found ways to circumvent this system in order to exist. TAMs produce immunosuppressive molecules that allow the tumor to evade the immune system and go about their business largely unchecked or unrecognized.
These tumor associated macrophages are one of the reasons that cell therapy is so difficult in solid tumors. When scientists engineer T-cells to attack the tumor, these are the cells that are largely responsible for neutralizing the engineered cells at the tumor site. There are many people working fervently to try to overcome this issue to make these therapies more effective for solid tumors.
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