The Hallmarks of Cancer
The “Hallmarks of Cancer” help us understand the kinds of changes that must occur in normal cells for cancer to develop. This is an overview.
Bullet Points:
• Cancer development is a complex process and the “hallmarks of cancer” help us understand specific changes in normal cells that must occur for cancer to develop.
• Diet and lifestyle choices can help our bodies prevail against cancer for each hallmark are provided.
The Hallmarks of Cancer
Cancer development is a complex process, and the so-called “hallmarks of cancer” were developed as a useful framework to understand and categorize the kinds of changes that must occur in normal cells for cancer to develop. So, the hallmarks of cancer are not specific symptoms that all patients experience. Rather, the hallmarks describe the biological processes that are exploited or hijacked by cancer to form and grow.
Here are the 11 currently accepted hallmarks of cancer:
Hallmark 1: Genomic Instability
Your genome is the full set of DNA instructions contained in every cell of your body. While every cell has the same DNA, cells take on different forms (like blood cells, muscle cells, and so on) when specific genes in our genome are expressed, or “switched on.”
When DNA is changed or damaged through mutations, cells can develop incorrectly and multiply uncontrollably. The more they multiply, the more likely they are to accumulate more damaging mutations. This is what is meant by genomic instability (Nowell 1976).
The average human body consists of 37 trillion cells and there are 2 trillion cell divisions in your body every day. Every time a cell divides, a copy of its DNA is made and passed to its daughter cell. Even though the mistake rate is amazingly low when making a copy of the genome, the sheer size of the genome (about 3 billion base pairs) means at least 100,000 mistakes every time a cell divides, but luckily our bodies have many different mechanisms to prevent these mistakes from resulting in cancer formation! Organs with more frequent division such as breast, prostate, and skin are common organs of cancer development as there are more chances for a mutation to occur.
Genomic instability can be a result of inherited or epigenetic (non-inherited, behavior-based) changes in the DNA. There are specific genes that maintain genomic stability, and they either promote cell growth (oncogenes) or suppress unwanted growth (tumor suppressor genes). These genes, whether turned off or on, can result in transformation of normal cells into cancer cells. The maintenance of genomic stability is essential for cells to prevent errors from DNA replication. For example, a well-known and studied example of genomic instability resulting in cancer formation are mutations in the BRCA genes. BRCA1 and BRCA2 are key players in DNA repair pathway and act as tumor suppressors by maintaining genome stability. BRCA mutations are associated with increased risk for breast, ovarian and other cancers.
Curcumin and resveratrol, have been shown to protect against genomic instability of cells.
Hallmark 2: Sustained Proliferative Signaling
One of the most important things our cells do is recognize when to grow and multiply. When you get a cut, your body springs into action, clotting the wound, protecting it from infection, and allowing your skin cells to regenerate and heal the cut. Cell growth and multiplication are carefully controlled by the body through chemicals called growth factors. The cells can detect the concentration of growth factors and use that information to know whether to keep growing. This is essential for maintaining the architecture of the body.
In cancer cells, the chemical signals that lead to proliferation (multiplication) are sustained indefinitely. An analogy would be like driving a car with the gas pedal stuck on and no brakes! For example, HER2 is an epidermal growth factor receptor whose overexpression in breast cancer is associated with increased disease recurrence and a worse prognosis (Esteva et al., 2010). HER2 positive breast cancers have many copies of these growth factors compared to normal breast cells, enabling rapid growth. So, they do not stop even if the body runs out of room for new cells. These extra cells are what form cancerous tumors.
Research demonstrates that over time, environmental factors, lifestyle choices, and age can cause cells to be less sensitive to the chemical signals that regulate growth. This is why cancer is more common in older people, as well as those who smoke, abuse drugs, or have a sedentary lifestyle.
Curcumin, green tea, resveratrol, milk thistle, Astragalus membranaceus and Panax notoginseng, and piperine have been shown to promote appropriate cellular response to growth signals.
Hallmark 3: Evasion of Anti-growth Signaling
On the other end of the spectrum, the next hallmark of cancer cells is their ability to avoid chemical signals that suppress growth. When normal cells encounter chemical anti-growth signals, they either stop growing or die as needed. This does not happen in cancer cells.
In cancer cells, these signals are either bypassed or suppressed, so the cells continue to grow out of control in places where they should not be. This, combined with sustained cell growth from Hallmark 2, is why cancer can grow and cause damage so quickly.
Curcumin, green tea, resveratrol, milk thistle and reishi mushroom have been shown to support normal cellular response to anti-growth signals.
Hallmark 4: Resistance to Apoptosis
Though it may seem counterintuitive, sometimes cells need to die in order to keep the body healthy. Apoptosis is the scientific term for programmed cell death. This occurs when a cell becomes too old and damaged to be repaired, so it’s more efficient for the body to get rid of the cell and recycle its materials.
Unlike death from damage or injury, apoptosis is a normal part of our biology. We lose about 10 billion cells each day to apoptosis. This makes room for younger, healthier cells and prevents abnormal cells from growing.
Cancer cells ignore the chemical instructions to undergo apoptosis, so they stick around much longer than they should. They do this so consistently that many anti-cancer therapies are designed to induce apoptosis.
Green tea, quercetin, Reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng, and piperine have been shown to support appropriate cellular response to programmed cell death.
Hallmark 5: Replicative Immortality
In cases where cells are damaged but do not need to be killed, the body can also stimulate them to undergo senescence, which is when the cell replication cycle is permanently halted. These cells will eventually die by other means without passing down their mutations through replication.
Cancer cells develop mechanisms that allow it to avoid senescence triggers, which leads to unregulated cell growth and significant damage to the body. This state is termed replicative immortality.
One benefit of targeting replicative immortality in cancer treatments is that it can sometimes take lower doses of medication to induce senescence than it would to kill cells outright. This can result in treatments with less severe side effects.
Curcumin, Green tea, quercetin, Reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng have been shown to facilitate a normal cellular response to senescence.
Hallmark 6: Dysregulated Metabolism
The word metabolism refers to the sum of all chemical reactions that occur inside of an organism or a cell to sustain life. Healthy cells need to have a well-regulated metabolism to make sure they are getting enough energy and producing the compounds they need.
Metabolic processes are a carefully balanced system - disrupting this delicate balance can cause negative effects on the health of the cell and the body.
Glucose is an essential nutrient and is our body’s main source of energy. Energy production is most efficient when oxygen is present (aerobic metabolism) but can still occur, for a limited time, without oxygen (anaerobic metabolism). Though inefficient, cancer cells are able to utilize multiple alternative energy pathways to survive, allowing the cancer cells to adapt to difficult environments such as hypoxia (low oxygen) and support their accelerated growth. In fact, cancer metabolism is so complex, Pavlova and Thompson have determined that there are 6 categories of cancer metabolic alterations that cancer cells use to accelerate growth and progression!
Cancer cell energy production is much lower than a normal cells, but cancer cells can consume more than 20 times more glucose compared to normal cells in order to compensate for their less efficient energy production. This phenomenon was originally noted by Dr. Otto Warburg, known as a Warburg effect. In fact, it is this principle of excess glucose use that is exploited for PET scans ([18F]fluoro-deoxyglucose positron emission tomography) used to detect cancer. Patients are given “tagged glucose” through the IV that can be detected on the scan where it is being used by cancer calls. Since cancer cells metabolize glucose faster and differently than normal cells, the cancer cells “light up” on the scan.
Research shows that poorly regulated metabolism can lead to oncogenesis, or the growth of cancerous cells. Cancer cells need to hijack and modify normal metabolic pathways in cells to continue to grow uncontrollably.
Resveratrol and milk thistle have shown to support a healthy cellular metabolism.
Hallmark 7: Tumor-promoting Inflammation
Acute inflammation is a normal and healthy part of response to injury or infection and is part of our immune response. Most people are familiar with symptoms of acute inflammation of pain, warmth/fever, swelling and redness. The acute inflammatory response is a cascade of growth factors and chemical signals that recruit healing cells and factors. In addition, increased blood flow allows healing factors to be transported to the site of concern to allow healing to begin.
Chronic inflammation occurs when, for example, an infection or injury goes untreated, is the result of an autoimmune process, or chronic exposure to a toxic substance. Chronic inflammation has a role in many illnesses and is strongly linked to cancer. Inflammation is a key requirement for cancer to grow and survive.
White blood cells are part of our inflammatory response and they have been observed in tumors as far back as the 19th century, so the link between cancer and inflammation is well-established. The chronic inflammatory environment becomes a tumor-promoting inflammation environment when a cycle of normal inflammatory cells being hijacked to support cancer growth ensues. Hijacked cells contain growth factors and other pro-inflammatory chemicals that promote vessel formation and allows the cancer cells to hide from the immune system. This creates a vicious cycle of tumor growth and inflammation and is one of the reasons many cancer often emerge at sites of chronic inflammation.
Curcumin, Green tea, quercetin, reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng have been shown to promote a healthy inflammatory response.
Hallmark 8: Angiogenesis
Angiogenesis is the process in which the body forms blood vessels. It is a critical component in development, and most angiogenesis occurs during fetal development. An important growth factor that promotes new blood vessel formation is vascular endothelial growth factor (VEGF), which attaches to the cell receptor vascular endothelial growth factor receptor (VEGFR) to start the cascade of angiogenesis.
While more blood vessels may sound like a good thing, angiogenesis only occurs in adults in very controlled ways: in response to injury or menstruation. Runaway angiogenesis can cause blood to be diverted from the places it needs to go and rerouted to places it doesn’t belong.
Angiogenesis is one of the hallmarks of cancer because tumors require blood in order to grow to substantial size. Given that cancer cells grow quickly and indefinitely, they can outgrow their initial blood supply and become “stranded”, isolated from nutrients needed for survival. So, cancer cells can stimulate angiogenesis and grow their own blood supply in order to provide oxygen and nutrients for continued growth and unlimited division. The more they do this, the larger they can grow and the more easily they can spread. In fact, some very effective chemotherapy drugs target the process of angiogenesis through inhibitors that inhibit the activity of VEGF and VEGFR.
Curcumin, Green tea, quercetin, Reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng, and piperine have been shown to maintain normal angiogenesis.
Hallmark 9: Tissue invasion and Metastasis.
Human bodies are made of a complex network of tissues formed by cells that work together and adhere to each other. Healthy cells are well-organized into tissues and organs that perform the functions of the body and repair themselves when needed.
Cancerous cells lose their ability to remain tightly organized, which is evident in the large, undifferentiated tumors that form from cancer. Another symptom of this disorganization is the ability of cancer cells to invade other tissues and move to different areas of the body through the blood stream or the lymphatic system. Once cancer cells develop the ability to break free from their neighboring cells, they can then penetrate blood or lymphatic vessels, circulate through the lymphovascular system, and then grow elsewhere in the body. This movement is called metastasis (Folkman 1971).
Cancer that has metastasized is much more serious than cancer that remains localized to one area. Many patients die as the result of metastatic cancer.
Quercetin, Reishi mushroom, milk thistle, and piperine have been shown to support appropriate cellular localization and mobility.
Hallmark 10: Tumor Microenvironment
All cells, healthy or cancerous, use physical and chemical signals to “talk” to one another or to influence cellular behavior, either directly or indirectly. These chemical communication signals help in organization and metabolism. The cellular microenvironment is the immediate area surrounding the cell and contains other cells, and physical and chemical signals. Think of a cell bathed in a chemical soup.
While healthy cells establish a microenvironment that is good for the function of tissues and organs, the microenvironment around a tumor is unhealthy and promotes the growth and movement of the tumor. We now know that the tumor microenvironment is one of the most important aspects for cancer behavior and causes local immunosuppression that allows for tumor formation and progression. In addition, new blood vessels are formed and our own white blood cells are recruited to provide a supply of nutrients and growth factors.
A tumor-promoting microenvironment is one of chronic inflammation and can develop with age, environmental factors, or lifestyle choices and lead to tumor growth. Cancerous growth itself also lead to the development of a tumor microenvironment. It goes both ways.
Tumor microenvironments are one of the recent treatment targets for cancer. If the chemical signals sustaining the tumor can be blocked or eliminated, tumors may be more easily treated and prevented.
Curcumin, Green tea, resveratrol, Reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng, and piperine have been shown to support a healthy cellular microenvironment.
Hallmark 11: Immune System Evasion
Our immune system is miraculous in its ability to find and destroy infections like bacteria and viruses. The immune system is also capable of finding and killing some cancer cells before they develop into larger, malignant tumors.
However, certain cancerous cells are able to block the function of genes that code for important molecules of the immune system. Immune checkpoints refer to the built-in control mechanisms of the immune system that maintain self-tolerance and help to avoid collateral damage during a physiological immune response. When this happens, cancer cells become “invisible” to the immune system and are thus free to divide and form tumors, evading immune surveillance and attack.
This is part of the reason why cancer can sometimes go undetected for long periods of time. Largely unrecognized by the immune system, cancer cells grow to a larger size until finally they have caused enough localized tissue damage to cause symptoms.
Reishi mushroom, milk thistle, Astragalus membranaceus and Panax notoginseng have been shown to promote normal response to the immune system.
Conclusion
As you have read, cancer development is a complex process. Thankfully, the diet and lifestyle choices that you make can have a profound influence on each of these hallmarks, leaving much control in your hands. We will address that topic in other articles on the blog.