Hallmarks of Cancer: A layman perspective

The year 2000 review by Hanahan and Weinberg was the first concise and influential review into the known hallmarks of cancer at the time. There were 6 known hallmarks in 2000 and the discussed topics were: 

   (1) Self sufficiency in growth signalling, 

   (2) insensitivity to anti-growth signals, 

   (3) evading apoptosis, 

   (4) limitless replicative potential, 

   (5) sustained angiogenesis and 

   (6) tissue invasion/metastasis.

         Approximately 10 years later, an update on the original article titled Hallmarks II added two more  emerging hallmarks: Reprogramming metabolism and evading immune response. For a simpler understanding, the study can be compared to learning how to make a fire. You identify what you need to start a fire. Obviously in this example, the common aspect is wood or dried plant and plant products or fuel; we may use a lighter, a matchbox, a convex glass, fuel. Now the end result like tissue regeneration, is a fire. However, the problem arises when you realise the fire is going out of control. So to control the fire you would look for the following possibilities: 

1. Can you Remove the fuel from the fire? 
2. Can you remove the ability for the fire to expand? 
3. Will the fire continue to spread if you removed the fuel? 
4. Can I add another fire to kill the main fire sooner? 
5. Can you stop the fire from affecting the adjacent grass?
6. Is there something else causing or adding on to the fire?

The equivalent questions if asked for cancer would be:

1. What caused the cancer?
2. Where is it getting its energy from?
3. How is it not killing itself?
4. How is it able to grow without control?
5. What is supplying energy to the cancer to grow?
6. Is this cancer growing elsewhere?

I would like to now ask you to compare the two sets and see the similarity. You would find that modern medicine and diagnostics has enabled us to identify a list of genes in the mammalian body that is, during the phases of replication and regeneration, tightly controlling and regulated bodily functions to operate within a range that keeps us functioning optimally. In the cases of tumourigenesis (tumour growth), the cells lose their ability to regulate cell cycle differentiation. 

    At this point, much like a fire, the fuel can be compared to angiogenesis or formation of new blood vessels to keep the tumour supplies with oxygen and glucose that it would need to sustain growth and development (We will dwell deeper on the impact of energy and metabolic defects and their role in cancer at a later stage). So can we remove the fuel from the fire?

    Next we have to try to control the tumour growth (anti-growth signalling) from expanding further, obviously the body has genes whose function is specific to controlling the cancer from spreading further. These anti growth signals are often the ones that ae mutated and altered or just deleted/inactivated from the tissue leading to the lack of regulation. In the absence or lack of anti growth signals, the tumour begins to grow, like a streak of kerosene that leads from a campfire in the clearing to the forests. So can you stop the fire from expanding further, is the extinguisher not working?

    Subsequently, a natural reaction is to try and add water to the fire. They are opposite so surely a fire should die out if sprayed with water. However, in the case of a cancer, most cancers have an ability to trigger apoptosis, also known as programmed cell death (PCD). Under ordinary cell cycle control, when a cell loses its ability to regulate cellular replication, apoptosis prevents the cell from growing further and causes the cell to rupture by killing itself. But again, much like the previous paragraph where we spoke about the inactivation or deletion of anti-growth signalling, the genes responsible for apoptotic control are deregulated and lead to loss of apoptotic control (NF-kappaB pathway deregulation). In this case, fire does not kill fire but the fire is now growing larger and larger.

    The fire is now spreading, its caught onto the kerosene leading to the forest and the extinguishers don't work on a fire this size, neither does the water. The formation of new blood vessels along with the possibility that the tumour is growing close to a artery or a vein increases the possibility of the cells possessing uncontrolled differentiation potential from spreading to other parts of the body and attaching to new sites along the body (metastasis). Like embers from a fire that climb higher from the heat and drop on leaves a few metres away, slowly burning away at healthy leaves (a simile to healthy tissues) until these embers turn to larger fires. So how do you stop these fires from spreading to the adjacent areas?

    And finally, the biggest problem of all, How do you stop an enemy with a resource potential larger that the host itself? The fire that wont die until there is nothing more left to burn? A limitless potential to replicate as the only regulators are inactivated and the ones that exist have been able to stop only their cells from turning to tumours.

This is just a recap to understand what we initially understand as the problems when fighting a tumour. There have been updates on our understanding on the hallmarks that have been released in 2011 and in 2017 that go further in depth. But if you have understood the comparison with a fire, You would hopefully understand better when we dwell deeper into the role of vascularization, senescence, autophagy, TME modulation, Immune modulation, altered stress response, genetic predisposition and metabolic reprogramming.

Thank you for reading and please feel free to get in touch with your thoughts and opinions and ill aspire to get back to you within a week.