What are the Hallmarks of Cancer and what mutations are crucial for tumour formation?
"On average, it is estimated that 10,000 to 1,000,000 mutations occur in a single human cell every day." However, the cell's DNA repair system successfully deals with those errors in DNA. However, sometimes, the DNA repair system fails to repair some errors and DNA. These can lead to mutations, but not all mutations lead to Cancer. The mutations can be split into two groups. "Driver mutations" are the mutations in the areas of DNA responsible for key functions of the cell, like cell division, DNA repair or growth. They confer a growth advantage to the cell. "Passenger mutations" do not confer the growth advantage to the cell and thus do not tend to cause Cancer. [1]. The idea that mutations lead to Cancer is generally what stands behind the Hallmarks of Cancer.
Hallmarks of Cancer are a set of functional capabilities that normal cells need to acquire to become Cancerous. As more Cancer research is being conducted, new hallmarks appear. However, the main eight ones are proliferative signalling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism, and avoiding immune destruction. [2] Each will be briefly discussed below. The more hallmarks a cell acquires, the higher the chances it will become a Cancer cell.
Proliferative signalling-Normal cells rely on carefully managed growth signals that ensure the number of cells in the body stays approximately constant (in children, the number of cells increases as they grow, but is still carefully controlled) for normal body functions. This means that cells cannot divide just whenever they can. To form tumours, the Cancer cells need to divide a lot and thus be independent of those growth signals. They can do that by either creating their own growth-signalling molecules, having faulty receptors (that do need growth-signalling molecules to stay "on" and thus tell the cell that it can divide) or simply bypassing these mechanisms and activating the growth pathways directly. [3]
Evading growth suppressors- Being independent of a cell's growth signals is not everything. The cells that divide uncontrollably also need to ignore the boys growth-inhibiting signals, which are supposed to act as "brakes" on the cells and prevent them from diving too much. This can be done by disabling the proteins that are responsible for regulating cell division or changing the signalling pathways to their advantage. [3]
Resisting cell death cells kill themselves if they are no longer needed or if they have too many mutations. Apoptosis (programmed, controlled and regulated cell death) is one of the natural defence mechanisms protecting the body from Cancer. The Cancer cells need to resist apoptosis to gain more mutations and divide uncontrollably. This can be done by disabling the proteins that can trigger cell death and increasing the number of proteins that block cell death. [3]
Enabling replicative immortality- Normal cells usually have a certain number of divisions they can undergo, usually around 50. [4] This process is controlled by telomeres (tips of chromosomes), which shorten every time a cell divides, and when they are too short, a cell stops diving. Cancer cells need to divide quickly and do not stop to form tumours. They can do it by making telomerase enzymes that prevent telomere shortening. [3]
Inducing/accessing vasculature- All cells need nutrients that are carried by blood to survive. Amino acids, sugars and fats. Cancer cells need more of them, as they replicate a lot more than any other cells. Normal cells grow new blood vessels only when they really need to (heal a wound). As the Cancer cells grow, the tumour increases in size and so needs more blood vessels to supply more nutrients to it to divide even more. Thus, Cancer cells need to constantly form new blood vessels in the cells through a process called angiogenesis. They can do it by producing more proteins that stimulate angiogenesis and reduce the number of angiogenesis-inhibiting molecules. [3]
Activating invasion and metastasis-Metastasis is the process by which Cancer cells spread to other parts of the body, away from the organ where they originated. This generally happens by Cancer cells chipping away into the bloodstream, via which they travel to the new organs and form new tumours. It is responsible for 90% of Cancer fatalities [5]. The Cancer cells usually obtain the ability to metastasise by producing less adhesive proteins (allowing them to chip into the bloodstream) and more enzymes to digest surrounding tissue (to make a new tumour in a new organ). [3]
Reprogramming cellular metabolism-The Cancer cells divide a lot more than normal cells, meaning they need a lot more energy. To get it, they change the chemical reaction in their cells. They prioritise the speed of energy production rather than its efficiency [1] and produce special molecules that help them resist treatments and make more lipids to make more cell membranes (for new cells). [6]
Avoiding immune detection mentioned in the "Why Cancer appears?" post, the immune system also plays a crucial role in preventing Cancer. The immune cells patrol your tissues and can detect if a cell has too many mutations to kill it. This immune surveillance is a huge problem for Cancer cells, as the immune system can not just halt the growth of the tumour but also eradicate it. Cancer cells learn to avoid the immune surveillance by producing the immune-system inhibiting molecules and immune checkpoint proteins (see "What is immunotherapy and how it can help your immune system fight Cancer back) that disable the nearby immune cells leaving Cancer cells untouched [3]
At the moment, there are new, emerging hallmarks that include altering gene expression without mutations in DNA (to help in invasion and metastasis), adapting to different environments by switching cellular states (survival, growth, etc.), using microbes and damaged cells to help tumour growth [2]. However, the eight above are the main ones at this point. However, as said before, the more research there is, the more characteristics are attributed to the hallmarks.
References:
Pecorino L. Molecular biology of cancer : mechanisms, targets, and therapeutics. Oxford: Oxford University Press; 2012.
Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discovery [Internet]. 2022 Jan 12;12(1):31–46. Available from: https://aacrjournals.org/cancerdiscovery/article/12/1/31/675608/Hallmarks-of-Cancer-New-DimensionsHallmarks-of
Hanahan D, Weinberg Robert A. Hallmarks of cancer: the next Generation. Cell. 2011 Mar;144(5):646–74.
Watts G. Leonard Hayflick and the limits of ageing. The Lancet. 2011 Jun;377(9783):2075.
Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Critical Reviews in Oncogenesis. 2013;18(1-2):43–73.
Phan LM, Yeung SCJ, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer biology & medicine [Internet]. 2014 [cited 2019 Jun 16];11(1):1–19. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969803/
