About the Cellular Basis of Cancer
How it works
At a cellular basis, cancer cells are not that different from normal cells.
In fact, from a biological view point cancer cells originate from normal cells. The features of a cancer cell; such as migrating away from its origin point, mutating and replicating itself, evading cell death and providing itself with a supply of oxygen and nutrients, can all be found in normal healthy cells (Oppenheimer 2006; Tu 2010). However, it is what these cells then do to the surrounding tissue of the body that differentiates cancer cells from normal cells. Cancer cells use these features at an uncontrollable rate and do not stop, causing damage to organ tissue by developing tumours that effect the normal functioning of the body (Garrett 2001). Little is known about why exactly cells develop into cancer cells but some information is known on how cancer cells develop and what they do at a cellular level to cause cancer.
During the cell cycle of a normal cell, damage of the DNA and mutation of the genome can cause the cell to develop into a cancer cell. Cancer cells are mutated cells that are found in and caused by abnormal and damaged DNA (Stratton et al. 2009). Therefore, the cancer cell genome can be found on the DNA sequence and is thus hereditary, however, it also means the cancer cell can evolve and change as the DNA sequence does (Stratton et al. 2009). Studies into the cancer genome have found that certain cancer cell chromosomes are associated with certain types of cancer; such as chronic myeloid leukaemia which is said to be caused by chromosomes 9 and 22 (Stratton et al. 2009). DNA in normal cells is often damaged by genetic mutations, although this damage is usually repaired (Stratton et al. 2009). However, this damage and mutations can also lead to the development of cancer cells (Stratton et al. 2009).
Cancer can develop if DNA becomes damaged at a cellular level, however, DNA is capable of repairing itself by inciting cell death or stopping the progression of the cell cycle (Kastan & Bartek 2004). The cell division cycle is the process where the cell grow, replicates its DNA and then divides (Garrett 2001). A normal cell makes sure that the genome is duplicated only once per cell cycle which it ensures by having cell cycle checkpoints (Bandura & Calvi 2002). Cell cycle checkpoints regulate the movement into each phase of the cell cycle and will not allow progress through the cycle until the previous stage is complete (Garrett 2001). An increase in genes that encourage cell division is a factor in the rapid growth of the cancer cell (Bandura & Calvi 2002). Due to the cessation of the cell cycle, and subsequent DNA repair, this allows the chance of genomic instability to occur (Kastan & Bartek 2004).
Genomic instability is where the genome mutates during cell division and this mutation can lead to the cell developing into a cancer cell (Mareel & Leroy 2003). Mutations in the response to DNA damage process can also lead to the development of malignant cancer cells (Kastan & Bartek 2004). However, despite this cancer cells are rare. The mutation rate is estimated at 1 in 2 × 10 per gene cell division and 10 target cells in the average human (Evan & Vousden 2001). Not all mutations in the cancer genome promote the development of cancer. A driver mutation gives the cancer cells an advantage in growing and helps the cancer cells survive in the environment of the organ (Stratton et al. 2009). A passenger mutation, on the other hand, is the opposite and does not contribute to the development of cancer even though it is still present on the cancer genome (Stratton et al. 2009). Another type of mutation, a resistance mutation, can provide protection from cancer therapies (Stratton et al. 2009). Studies have found that only 1.6% of protein coding genes show mutations of cancer cells that lead to cancer development (Stratton et al. 2009). Of all the mutated cancer genes 90% are dominate; this means only one allele needs to be mutated to lead to the development of cancer; the other 10% are recessive with both alleles needing to be mutated (Stratton et al. 2009). Abnormal signal pathways and the structure of the cell can also play a part in the development of cancer.
In normal cells the cytoskeleton and the extracellular matrix of the cell are important for normal function. The cytoskeleton of the cell is mainly made up of proteins and the extracellular matrix binds cells together to create tissue (Suresh 2007). These structures are altered by cancer; changes in protein structures give cancer cells their ability to move through tissue and thus spread to other parts of the body (Suresh 2007). Cancer cells also have their own signal pathways which allow them to survive and grow (Suresh 2007). Recent studies have stated that the cell that cancer arise from is just as important in the development of cancer as the genetic mutations and abnormal signal pathways within the cell (Tu 2010). In this case, this point of origin would be stem cells and cells like them (Tu 2010). Epithelial cells, or carcinomas, are usually where cancer starts; with the epithelial cells originating from glandular cells, or adenocarcinomas (Fischer et al. 2010). Normal epithelial cells are characterised as regularly space, whereas papillary growth of the epithelial cells or lack of binding between cells can be indications that cancer is developing (Fischer et al. 2010). A random variation of cells is a characteristic of genomic instability which is also a factor in cancer development (Fischer et al. 2010). Stem cells, on the other hand, are the main favourite origin point of cancer in research due to the fact that they share many similar features to cancer cells (Tu 2010). These similarities include; drug resistance, evading apoptosis which is cell death, hypoxia or oxygen deficiency, sustained angiogenesis which is a constant supply of oxygen and nutrients via blood vessels, the ability to continue to replicate itself and active telomerase (Tu 2010). Therefore, it is easy to see how cancer can emerge from cells that originated as stem cells of cell that are like stem cells (Tu 2010).
The features of the cancer cells play a large roll in the uncontrollable growth and spread of cancer. These features are; ignoring signals to stop multiplying, and to stop changing or mutating, the ability to continuously replicate, stop cell death and gain its own blood supply (Ponder 2001). These features allow cancer cells the ability to invade other tissue, with irregular cell growth and the suppression of cell death being the building blocks to abnormal tissue growth in the body, i.e. tumours (Even & Vousden 2001). Once a tumour created by cancer cells reaches angiogenesis and has its own blood supply the cells are considered malignant, cancer cells can enter the blood and lymphatic vessels, a process called intravasation, and they now have access to nutrients and can interact with the blood (Suresh 2007). Cancer cells will the move through the circulatory system and enter the blood vessels of other organs where the can corrupt the tissue, a process called extravasation, cancer cells then form new tumours of metastases (Suresh 2007). This production of secondary tumours is known as the metastatic process.
The metastatic process occurs because the primary tumour acquires a blood supply, which in turn provides a pathway for cancer cells to spread (Chambers et al. 2002). Cancer cells move from the origin point and enter a secondary location via the circulatory system; at these secondary sites cancer cells either go dormant, die or produce new tumours, or metastases (Chambers et al. 2002). Cancer cells are not the only factor in the growth of tumours, host cells also play a part in the process; which is known as desmoplasia (Mareel & Leroy 2003). This is because the secondary site, usually an organ, has to be an environment the cancer cells can survive in (Oppenheimer 2006). While many organs are subject to secondary tumours some, like the heart, rarely are, therefore, there must be an environmental factor to the growth of metastases (Oppenheimer 2006). This could be because certain molecules found in cancer cells, could also be present in the secondary site; this similarity could provide the cancer cells an optimum place to grow and thrive (Chambers et al. 2002). Another factor in the spread of cancer cells may be due to the fact that cancer cells do not bind to each other well (Oppenheimer 2006). Unlike normal cells that meet and bind to one another, cancer cells will break away from each other and form new tumour growths (Oppenheimer 2006). This weaker binding strength may be due to a lower amount of calcium in cancer cells compared to normal cells, and/or because the enzyme, proteases is more prevalent in cancer cells which could be breaking down the proteins that help cells bind together (Oppenheimer 2006). This metastatic process could be a leading factor to how cancer spreads so uncontrollably but to really gain an understanding of the cellular basis of cancer it is best to look even closer, all the way to the mitochondria.
Mitochondria is the source of ATP production and reactive oxygen species; it contains mitochondrial DNA, or mtDNA, which produces proteins (Singh & Kulawiec 2009). Studies have found that mutations that lead to cancer are often found in the mtDNA (Singh & Kulawiec 2009). This concept was first hypothesized in 1930 by Warburg, who thought that mutations of the mitochondria, and thus in the cancer cells, where linked to cancer development (Singh & Kulawiec 2009). The mitochondrial genome, which can only be passed on by the mother, is responsible for 2 rRNAs, 22 tRNAs and 13 proteins and yet mtDNA makes up less that 1% of all cellular DNA, however, without it a cell can not function properly (Singh & Kulawiec 2009). Despite this mtDNA is also more prone to mutations (Singh & Kulawiec 2009). Specifically, the displacement loop, or D-loop, an area of the mtDNA that is responsible for the replication and transcription of the molecule, has been seen to be the site of many mutations that lead to cancer (Singh & Kulawiec 2009). Therefore, mutations in this area would affect how many genes are copied and how they are expressed (Singh & Kulawiec 2009). Mitochondrial DNA, or rather a lack of normal mtDNA due to mutations, may also play a part in how cancer cells evade apoptosis (Dakubo 2010). Apoptosis, or cell death, is a normal function of all living organisms (Dakubo 2010). It is a function that helps ensure tissue in the body is normal and removes damaged cells without doing anything to adjacent cells (Dakubo 2010). Cancer cells, in order to survive, alter how apoptosis functions (Dakubo 2010). Thus, tumours can avoid cell death which allows the cancer cells to survive and continue growing (Dakubo 2010). Therefore, at a cellular basis, cancer development may come down to a mutation on less than 1% of the cellular DNA.
While studies have shown what and how the cells of the body develop into cancer, little information is know as to why they do this. For now, though, at a cellular level, cancer originates from mutations on normal cells and uses its uncontrollable replication and movement to spread to and invade the rest of the body. Despite its differences, similarities can still be seen between cancer cells and other cells in the body and this could be a factor in how cancer is so uncontrollable. What is known about the cellular basis of cancer is not all there is to know however, and so there is more to learn out there.