What is cancer?

When hearing the word “cancer”, it is almost impossible not to feel cold chills down your back. Although the disease is widely known, what cancer actually is and how it works is not so clear to everyone. Therefore, we will try to explain here the basics of cancer and how it is formed.

So, what is cancer?

As we have defined previously (here) our bodies are made of cells. The cells divide as the body grows, to repair tissues and structures, or to replace damaged cells. Such cell multiplication is usually strictly regulated and one cell is only able to divide a determined number of times. There are plenty of control mechanisms to ensure cell division occurs properly: i.e. that a cell divides only when it should and it does not replicate too much. However, sometimes these control mechanisms can fail.

When a cell is able to “escape” the tight regulation, it is not in sync with the rest of the cells of the body and it can start dividing in an uncontrolled manner. The body has mechanisms in place to fix this (one of them the immune system), but sometimes a derailed cell can form a cancerous tumor, commonly defined as a mass of cells that divides uncontrollably. Note here that we mentioned a cancerous tumor. Why do we make this distinction? Well, although tumor and cancer are terms that are often used interchangeably, they are not the same thing. A tumor is defined as an abnormal mass of cells [1] and is not necessarily cancerogenous. Therefore, we can make a distinction between benign tumors, that are not able to spread through the body and are not life-threatening, and malignant tumors, or cancerogenous tumors, that are also known as cancers and have the ability to “conquer” other tissues or organs. For simplicity, when mentioning tumors from now on in the text we will mean cancerogenous tumors, unless the contrary is stated.

What makes a tumor a bad tumor?

Having made this distinction, to be able to replicate an infinite number of times and without control is the main characteristic of cancerogenous tumors or cancers. However, extensive research in oncology (the field of science that studies cancer) during past decades has shown that tumors are way more than a mass of cells replicating like crazy. They have many other capabilities that help them survive in the body (and that make them dangerous and difficult to treat). These capabilities have been summarized in what is known as the six hallmarks of cancer [2,3]:

Chronic proliferation. As above-mentioned cancer cells are experts at escaping the control mechanisms that prevent them from dividing uncontrollably. Such deregulation is due to mutations, which are changes in the genetic material (DNA) of the cells, or in other words, changes in the instruction book governing the cells.

Evading growth suppression. As previously mentioned, proteins are the “workers” of the cell. There are proteins, such as TP53 or RB, whose task is to control cell cycle progression (the set of organized steps that lead to cell development and division). If these proteins are altered, as usually happens in tumors, cells that otherwise should stop growing will continue to divide.

Resistance to cell death. As we do, cells can also get “old” and lose some of their qualities, so at some point they should be replaced to keep our organism healthy. Cell death must be strictly controlled through processes known as “programmed cell dead” that cancer cells can also evade.

Immortality. Normal human cells can divide a limited number of times, which is known as the Hayflick limit [4]. A way to track the number of divisions would be to have a little mark in the cell every time it divides. This is actually happening: the DNA, here referred to as the instruction book of the cell, is actually structured in 23 pairs of books called chromosomes that should be copied in every cell division. The extremities of chromosomes are called telomeres and are hard to replicate, so every time a cell divides, they get shortened; when their length reaches a threshold, the cell cannot divide anymore. Tumoral cells usually have a protein called telomerase that can avoid this telomere shortening and helps the cell to divide beyond the Hayflick limit.

Inducing angiogenesis. Tumoral environments favour the development of blood vessels that will provide the cancer cells with nutrients and oxygen and will evacuate their waste products – this is known as angiogenesis. So, basically, tumoral cells will be in an all-inclusive hotel in the Caribbean, where the workers facilitating all types of commodities are particular proteins (like VEGF-A) and cells (such as pericytes).

Invasion. Normal cells are attached to one another with adhesion molecules such as E-cadherin. However, cancer cells go through different steps by which they acquire the capacity to detach from one another and travel to different parts of the body where they can proliferate and induce new tumors. This process is known as metastasis and it is what determines the malignant switch of the cells forming the tumor (now referred to as cancer due to this malignancy)

Even though this seems to be an extensive description of cancer, there is still much that we do not know and as we learn, other hallmarks continue to be added to this list [3]. The latest two hallmarks being: reprogramming of energy utilization in order to fuel the growth and division of tumoral cells (which means that the cell “reprograms” itself to be able to consume more and put more energy into growing) and evading the immune system that otherwise would protect us by destroying these malignant cells.

These hallmarks are characteristics that cancer cells acquire and that distinguish them from healthy cells. In the beginning, cells from one or more different populations start forming the tumor by replicating and forming more (cancerogenous) cells [5]. As tumoral cells can divide without limit, one “rebel” cell would be enough to form a tumor (monoclonal origin). However, there is evidence that cancers can be originated from multiple cells that accumulate mutations (polyclonal origin) [5]. Independently of their monoclonal or polyclonal origin, genetic instability [6] will ease the accumulation of mutation in the already tumoral cells and will promote the appearance of new subpopulations [3]. As a result, tumors will have various subpopulations and different cell types involved. The different cells in a tumor and how they interact with each other constitute what we know as a tumor microenvironment [3,6], which has been shown to have an important role in how a tumor will respond to therapy.

description of the tumor environment and the different cell types that compose it. from Hanahan and Weinberg (2011)

Why do we get tumors?

But how does it all occur? There are different mechanisms that can trigger the growth of a cancerogenous tumor. First of all, mutations in the DNA or what is the same, changes in the “instruction book” of tumoral cells. Mutations can contribute to the dysregulation of different processes and also to the variability between tumors. This means that tumors that are caused by different mutations are also very different, which makes the treatment of cancer complicated. Second, the immune system, which always fights to protect us from pathogens and even cancer, not always works perfectly and under certain situations, it can even trigger the development of a tumor [7]. However, the role of the immune system in cancer development is not fully understood yet. A third cause of cancer would be certain viruses (for example VPH) or bacteria. Finally, certain cancers that are associated with specific genes can be inherited (for example some types of breast cancer).

transformation of a healthy cell into a cancerous cell due to different stimuli.

Why is cancer so hard to treat?

One important remark that we should make about cancer is that cancer is not only one disease. Each cancer is unique, and therefore treatment is very difficult. We have already explained the reasons for this variability, but they can be summarized here: first, the molecular biology of a tumor is very complex, and we still do not know everything about it. This means that two tumors in the same organ (e.g. lung cancer) may actually work in slightly or even very different ways. In addition to this, a tumor will be different depending on what caused it (i.e. different mutations will cause different tumors). To add even more complexity to the equation, the genetic background of a person also influences how they will respond to therapy, etc. A way to fight this would be personalized medicine [8].

So, we need different treatments for different tumors and even then, the outcome of different patients with the “same” kind of cancer can be very different, and the sensitivity to different therapies is not always the same.

The text in blue indicates the different hallmarks that cancer cells acquire. the text in the different boxes exemplifies different types of drugs that can be used to attack them. FROM HANAHAN AND WEINBERG (2011) [3]

Another problem with cancer treatment is that most of the therapies focus on trying to kill the tumoral cells. However, cancerogenic or not, cells are still cells, so it is hard to have drugs that only kill the “bad” cells and not the healthy ones. This does not mean a cancer patient should not undergo the therapy that the doctors prescribe them but is a reminder that is important to keep looking for better or more selective treatments.

At this point you are probably thinking that cancer is a super complicated thing and that it is super difficult to find a good cure for it. However, there are reasons to be optimistic. Even though our body sometimes fails to control cancer, there is extensive scientific research on the topic, and several treatments and strategies are currently under development. Of course, there is still a long way to go, and we might find particular solutions for specific types of cancers (e.g. the cure of chronic myeloid leukemia[9]) rather than a general panacea, but overall science is walking in the right direction.

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