The biological hallmarks of cancer: What makes a cancer cell, cancerous?

Introduction

In Singapore, about 37 people are diagnosed with cancer every single day. The most common cancer among men is colorectal cancer, whereas breast cancer is the most prevalent cancer afflicting women. In 2012, the latest year in which information is available to the World Health Organisation (WHO), 8.2 million people died from cancer worldwide. 14.1 million new cancer cases were diagnosed. These grim statistics are unlikely to improve in the decades to come.

A Brief history of cancer

Cancer is not a new phenomenon in human society. It was first described by the Egyptians written in several papyri around 1600 BC. At around 460 BC, Hippocrates gave a name to this disease, karkinos (carcinos), the Greek word for crab or crayfish. He associated crabs to the malignant tumors he observed on the surfaces of human bodies, “the veins stretched on all sides as the animal the crab has its feet, whence it derives its name.” In 25 BC, Celsus translated karkinos into cancer, the latin word for crab or crayfish. Thus the term to describe this terrible disease was born.

So what is cancer?

Simply put, cancer is a group of diseases that involves abnormal cell growth with the potential to invade or spread to other parts of the body. The abnormal cell growth leads to a formation of tumors, which is basically a group of cells that are dividing indefinitely forming a clump of cells. Not all tumors are cancerous. Benign tumors do not spread to other parts of the body. Tumor formation can happen anywhere in the body. All it takes is just one cell in your body to go rogue and form a macroscopic tumor.

The eight hallmarks of cancer

Modern medicine and cutting edge research beginning in the 20th century have allowed doctors and scientists to peer deeper into the biological aspects of cancer than ever before.

What makes a cancer cell behave like a cancer cell? What are some of the biological hallmarks that cancer cells all have in common, no matter its origin, to be defined as such?

Douglas Hanahan, from the Swiss Institute for Experimental Cancer Research (ISREC), in Lausanne, Switzerland and Robert A. Weinberg, from the Whitehead Institute for Biomedical Research in MIT wrote a landmark paper in 2000, distilling decades of cancer research from hundreds of prominent research papers on the subject. The collective knowledge of what we know so far about cancer ultimately boiled down to just six biological capabilities that cancer cells acquired during tumor formation. These are known as the hallmarks of cancer. In 2011, the paper was updated and expanded to include two additional hallmarks of cancer, to a total of eight. The update is a sign of significant progress made in cancer research. So what are the eight hallmarks of cancer?

hallmarks-of-cancer

  • Sustaining Proliferative Signaling

The most fundamental trait of cancer cells is their ability to sustain chronic proliferation. In other words, to divide indefinitely. Normal cells receive signals from their external environment, telling them when to start and stop dividing. Growth factors, which are secreted by neighboring cells, are finely tuned so that cells nearby receive just the right amount of signals to control this process. The organs in our body are made out of millions of cells working in tandem, communicating with each other to maintain homeostasis. Take driving a car as an analogy. As you drive down the street you step on the gas paddle. But as soon as you reach a pedestrian crossing and the light turns red, you immediately hit the brakes. The traffic lights, much like the growth factors, tells the cell when to start and stop dividing.

Cancer cells deregulate these signals, becoming masters of their own destiny. They turn into reckless drivers, constantly flooring the gas paddle, ignoring all traffic light signals, and even speed limits. In fact, they hack the traffic light signals to always turn green. Cancer cells secrete their own growth factors not for the benefit of other cells, but for themselves, internalizing those very same signals they put out into the environment to promote cell division. They may even fool normal cells nearby, sending signals to trick them to release more growth factors for their own greedy benefit. And thus the cycle continues. There will be so much growth factors secreted that the cancer cells continues to divide at a ferocious pace.

  • Evading Growth Suppressors

As cancer cells take advantage of the growth factors to fuel their growth and proliferation, cancer cells must also acquire the ability to ignore, or circumvent powerful signals that prohibit cell proliferation. There is a group of genes called the tumor-suppressing genes that does this job. The two most important ones are called the RB genes and TP53 genes. Both codes for the RB protein and TP53 proteins. Their main job is to take in information, both from the external environment and from within the cell and decide if the cells are ready to divide. If the cells are undergoing stress; lacking nutrients, oxygen, or detect severe genetic damage, those two proteins will tell the cell to halt cell division and take a breather, to give it time to repair any damage before proceeding. If substantial damage is found in the cell, the cell can simply undergo programmed cell death by apoptosis or suicide to prevent harmful genetic mutation from passing on.

In the case of driving a car, in a normal situation, say for example you were driving and then someone spilled a cup of coffee all over the seat. In an ideal situation, you would try to stop the car somewhere, clean the mess before moving on. The spilling of coffee is much like the stresses cells undergo within, which signals the tumor-suppressing proteins that it is not ready to proceed with cell division. However in cancer cells, the car has no brakes, and thus cannot stop the car despite spilling the coffee all over. These cancer cells have the tumor suppressing genes altered or mutated, and the altered protein in turn, are unable to function to process these signals. Without these signals, the gatekeepers of cell-cycle progression is lost, and therefore, cancer cells are freely able to continue to divide.

  • Resisting Cell Death

Programmed cell death by apoptosis is the process when cells are given signals to commit suicide. There are a few reasons why this is an important biological process. It’s main function is to kill off cells that are undergoing extensive genetic damage. This is to prevent genetic damage to be passed on. Death inducing signals are released to tell the signal that it is time to die. There are several checks and balances happening from within the cell before it finally deciding whether to kill itself. It is also important in embryogenesis. Take for example, the development of  fingers on our hands. During embryonic development, the digits forming the fingers are webbed, much like an amphibian. But as the embryo develops further, the cells in between the digits undergo programmed cell death. They take in cues and signals from the external environment and directs them to kill itself off. This is why we don’t have web fingers or feet when we are born.

f1-large

Programmed cell death by apoptosis serves as a natural barrier to cancer development. However, cancer cells can be sneaky. They are able to severely reduce death-inducing signals happening within the cell, removing their ability to trigger apoptosis. Whatever genetic damage a cancer cell has accumulated, will be passed on as it divides, and thus future cell lineages accumulate even more devastating genetic mutations. In other words, these mutated cells, aside from being able to divide endlessly, simply won’t die.

  • Enabling Replicative Immortality

We all grow old and eventually die. Death is a natural process. But to cancer cells it’s an abomination. They will do anything to evade death. The organs in our human body have a limited lifespan. This is because the cells that make up our organs can only divide a certain number of times before they stop dividing and eventually die. There is a limited number of successive cell growth-and-division cycles that the cells can take. The number of neurons in our brain decreases as we age. Muscle mass decreases as we grow old because there are less cells replacing the old ones that died.

Telomeres are regions of repetitive nucleotide sequences at each end of a chromosome. They protect the chromosomes from damage.  As cells divide, the telomeres get shorter. Eventually they get so short, that they are unable to protect the chromosomes from damage. When DNA mutations and damage is detected, the cells receive signals to stop dividing, and will eventually die if enough external stresses are imposed upon them.

shorteningdna

In cancer cells, they are able to maintain the lengths of the telomeres by switching a gene on that expresses a protein called telomerase. Telomerase maintains the length of the telomeres, preventing it from eroding after successive cell divisions. Normal cells do not have telomerase, with the exception of stem cells, that have indefinite replicative potential. Thus cancer cells are,  by its basic definition, immortal.

  • Inducing Angiogenesis

Angiogenesis is the process of building blood vessels within an organ or tissue. The endothelial cells proliferate and then assemble into tubes which would serve as blood vessels to transport oxygen rich blood and dispose waste from the surrounding tissue. During embryonic development, these cells are particularly active, giving rise to new blood vessels in regions where cells are actively dividing. In the adult, these cells lay dormant. We simply stop growing. There is no need to activate these cells further to make new blood vessels, unless it’s for wound healing or as part of the female reproductive cycling.

fig1

In cancer cells, as they rapidly divide and spread outwards, they form tumors, mass of cells without any definitive shape. As the tumors get bigger, cells from within the tumors are starved of oxygen and important nutrients. In order to ensure their survival, cancer cells often exploit the ‘angiogenic switch’, making sure that it is always activated and switch on, causing normally dormant blood vessels to continually sprout new vessels that help sustain tumor growth. These forms for growth result in excessive branching of vessels that are usually convoluted and messy. Thus, cancer cells from deep within a tumor now have access to oxygen and nutrients to ensure their survival.

  • Activating Invasion and Metastasis

As cancer cells acquire the hallmarks mentioned above to cement their survival, cancer cells become truly malignant when they finally acquire the ability to invade other organs by undergoing metastasis.

metastasis

Cancer cells develop the ability to alter their shape and lose its ability to adhere or stick to the extracellular matrix. Cancer cells lose a key cell-to-cell adhesion molecule called E-cadherin. In normal tissue, it is made up of millions of cells that are in contact with one another through adhesion molecules such as E-cadherin. With the loss of E-cadherin, cancer cells now have free reign to migrate to other organs, either by worming their way through blood or lymphatic vessels. They then exit these vessels, establishing a new colony in another part of the body. This is why cancer survivors may soon discover a new tumor developing in another part of the body that they missed during the initial diagnosis. Certain cancer cells can lay dormant for years, evading  early detection, and when the conditions are right, it can re-emerge with all the hallmarks of cancer intact. This can lead to an even more aggressive forms of cancer, often times with poor prognosis.

  • Reprogramming Energy Metabolism

A fast growing tumor containing millions of cancer cells requires a lot of energy to fuel their growth. However, cancer cells metabolizes glucose for energy differently as compared to normal cells. This is a fairly recent emerging hallmark of cancer that scientists are only beginning to understand.

In normal cells, energy from glucose is harvested efficiently by first undergoing glycolysis which produces pyruvate as a final by-product. Pyruvate is then utilized in the mitochondria -the cells’ powerhouse, together with oxygen. This process produces a lot of energy for every molecule of glucose.

Cancer cells undergo glycolysis as well, but very little pyruvate is produced and sent to the mitochondria. The net energy gain from just simply glycolysis produces around 18 times less energy as compared to fully metabolizing pyruvate in the mitochondria. Thus, to sustain their growth, they need a ridiculous amount of glucose to compensate for the inefficient harvesting of energy from a single molecule of glucose. If cancer cells requires a lot of energy, why are they metabolizing glucose inefficiently? This is one of the greatest paradoxes scientists have discovered about cancer.

image description

One plausible reason why cancer cells do this is because the glycolytic intermediates produced during the process of glycolysis is routed into other biosynthetic pathways, producing amino acids and nucleosides. The happen to be the building blocks of protein and DNA products. Glycolysis is a 10-step process, with each step producing an intermediate biochemical product. These intermediate products can be used for the biosynthesis of other macromolecules and organelles needed for assembling new cells. In other words, cancer cells not only use glucose purely for energy production, but the intermediate products of glucose are used to support cell division. They used those materials to build their houses before powering it.

  • Evading immune Destruction

The final emerging hallmark of cancer is its ability to hide their true identity from our immune system. Our cells and tissues are constantly monitored by an ever-alert immune system and it is responsible for recognizing and eliminating a large number of incipient cancer cells and nascent tumors. The cells in our body are constantly dividing in an ever continuing process of self-renewal. Occasionally the DNA replication system goes awry. Immune cells are able to detect these abnormal cells and eliminate them before they do any lasting damage.

Thus, it has been widely reported that patients who are chronically immuno-compromised (organ transplant patients, immune disorders, and certain chronic illnesses) have a greater risk of acquiring cancer during their lifetime.

How the cancer cells trick the immune system to thinking that it’s a normal cell is still largely a mystery. Studies have shown that cancer cells have the ability to destroy certain components of the immune system that would otherwise alert our immune cells to the presence of cancer cells nearby. In other words, cancer cells are able to eliminate the guards from the guard-posts before that have the chance to ring the bell and warn others.

Final Words

The eight hallmarks of cancer do not happen all at the same time. Normal cells evolve progressively to became cancerous, by acquiring a succession of these hallmark capabilities. A small number of mutations in certain regions of the DNA is hardly alarming, as cells acquire mutations all the time. Cells have several robust repair mechanisms to correct those mistakes and if the mistakes are overwhelming, they simply kill themselves. But sometimes, as these mutations accumulate and if these mutations happen at key genes that regulate cell division and cell cycle, then they have a greater tendency to become malignant. Without those checks and balances in place, they start to forge their own destiny, dividing at will. As they slowly acquire more of these hallmarks, they become more aggressive, leading to tumor formation. As they become bigger, they adapt to the surrounding environment, exploiting it to feed their growth. Once they gain the ability to undergo metastasis, that’s where they are truly malignant.

Sources

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013 

Cancer statistics in Singapore: http://www.singaporecancersociety.org.sg/learn-about-cancer/cancer-basics/common-types-of-cancer-in-singapore.html

Global cancer statistics from WHO: http://www.who.int/mediacentre/factsheets/fs297/en/

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s