The Emerging Role of C5a as a Hallmark of Cancer and How it is Being Used as a Potential Therapy
In the complex world of complement immunity there are three primary routes that the body uses to form a membrane attack complex, each pathway differs in the way it is activated, these three pathways are named the classical, alternative, and lectin pathways (Afshar-Kharghan, 2017). The first two of these pathways, the classical activated via the interaction of antibodies produced by namely the IgG class that activates the first protein complex C1 in this pathway (Diebolder et al., 2014), whereas the lectin pathway activated and mediated by pattern recognition proteins such as mannan-binding lectin (MBL) and MBL associated serine proteases (MASPS) directly acts on the second and forth complexes of the pathways C2 and 4 (Dembic, 2015) instead of indirect activation as seen in the classical pathway. Despite the differing activation processes both the lectin pathways follow the same cascade after the initial step resulting in the production of C3 convertase followed by C5 convertase and finally the membrane attack complex that aids in the lysis of foreign and non-self cells via pore formation as part of the immune response (Rosbjerg et al., 2016). The alternative pathway and the final of three has a vastly different cascade than the other two in that it is activated by lipids, proteins, and carbohydrates found on foreign or “non-self” cell surfaces, in this case C3 is constantly hydrolysed forming C3b that binds to its target such as bacteria where factors D and B attach forming C3bBb which can be stabilised by properdin, the C3bBb then binds to a molecule of C3b and acts in a similar fashion to C5 convertase and the final stages are similar to that of the other two pathways (Sarma and Ward, 2011).
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One of the most common diseases in the 21st century, and has been estimated to have been the cause of death in 1 in 6 people worldwide with an estimated 9.6 million people dying from this group of diseases in 2018 alone, is cancer (WHO, 2019). Cancer refers to a cell mass or tumour that exhibits specific hallmarks such as, being unresponsive to anti-proliferative signals, being able to proliferate self-sufficiently, the potential to replicate unlimitedly and if the cancer is malignant the ability to invade other tissues and metastasis (Rakoff-Nahoum, 2006). However there are ways to identify cancers namely by investigating changes to a patients genome comparing unaffected tissue to the cell mass, and compare factors such as single nucleotide variation (SNV’s), copy number variations (CNV’s), there are other factors like oncogenes and proto-oncogenes that if mutated dramatically increase a patients chance of forming a tumour (Hofree et al., 2016) with an example of this being the gene TP53 that if unmutated produces the protein P53 that regulates cell proliferation and stops the formation of a tumour. However when mutated can stop this process and lead to tumour growth and uncontrolled cell proliferation (Olivier et al., 2010).
At first there may not be an obvious link between cancer and the complement system however in recent years scientists have uncovered a relationship between the two that may help in our developing understanding of the area.
C5a is a by-product of the complement system when C5 is enzymatically cleaved and activated, unlike C5b that is used in the formation of the membrane attack complex, C5a is involved in areas outside of the complement system such as adaptive immunity (Khol, 2006). Despite C5a’s primary function as a proinflammatory anaphylatoxin (Dragomir et al., 2012) there are numerous cell types that C5a has an impact on and can produce an array of effects dependent on the cell it is acting on, an example of this is can be found on one of the primary cells C5a is associated with, neutrophils; where it has been found that C5a is not only responsible for cytokine and superoxide release but also reduces neutrophil apoptosis (Monk et al., 2007). Another important interaction C5a has is with its receptors classically C5aR1 where its inflammatory and chemotactic nature can be employed on target cells such as mast cells, neutrophils, and hepatocytes etc. (Gasque et al., 1997). However in more recent years it has been found that C5a binds to other secondary receptors such as C5L2 (Fonseca et al., 2013). However an interesting result can be seen when C5a acts on the C5L2 receptor as it the complete opposite effect happens as it acts in an anti-inflammatory manner in several pathologies by interacting with C5aR1 and β-arrestin which down regulates the C5aR signalling causing this anti-inflammatory response (Gerard et al., 2005).
C5a and its Role in Cancer
In recent years the anaphylatoxic nature of C5a has been linked as a contributing factor in cancer progression, as when C5a is produced during a tumour linked complement activation it has been shown to reshape the tumours micro-environment and helps tumour growth and even as far as the metastatic spread of the tumour (Ajona et al., 2019). The C5aR1 receptor has also been shown to increase inflammation within astrocytoma cells in the brain of animal models via the upregulation of the gene responsible for the production of the interleukin IL-6 (Sayah et al., 1999) that induces inflammation via the JAK-STAT3 pathway and helps the tumour evade apoptosis as well as help provide some resistance to drugs used to treat cancers (Guo et al., 2012). The expression of C5aR has been found in over 10 different cancers across the body including breast, bladder, kidney, and oesophagus (Nitta et al., 2013). High expression levels of C5aR have been linked in a 2016 study (Xi et al.) to a poor prognosis in some of these tumour types named above but in this case focused around renal cancer.
Another view is that the presence of C5a within a tumour could be used as a cancer hallmark as it causes a number of the hallmarks postulated in a paper by Hanahan and Weinberg (2011) including the fact the presence of C5a along with another of the complement by-products C3a can lead to the development of the classical hallmarks of cancer. The first of these hallmarks is the evasion of cell death, that is caused by C5a activating the mitogen-activated protein kinase or MAPK and in turn the caspase-cascades MAPK mediates may lead to protection against glutamate and caspase 3 induced apoptosis (Mukherjee and Pasinetti, 2008). Another of these hallmarks is the induction of angiogenesis as it was found that when C5a is introduced to a human microvascular endothelial cell line it proliferated, migrated and formed a ring shaped formation and when a specific antagonist of C5a these actions stopped, suggested that in both inflammatory diseases and cancers C5a may be responsible for vessel formation (Kurihara et al., 2010). Some of the other hall marks that C5a has been linked with are the promotion of tumour inflammation (Ajona et al., 2013), and the activation of metastasis and invasion as seen when C5aR1 muffles the effect of T cell responses via a shift in the balance of Th1 and Th2 in favour of Th2 which have been demonstrated to be tumoricidal therefore helping the metastatic activation of a tumour (Vadrevu et al., 2014). A final hallmark that C5a can be attributed with is the evasion of the Immune system as it has been found that both C5a and its receptor play a role in the recruiting the aid of other immunosuppressive cells for the inactivation of effector T cells (Iwai et al., 2017).
The role of C5a in developing cancer therapies
In the past decade the developments in our knowledge related to the complement and cancer have leapt forward, now the focus has begun to shift towards how we can use these complement proteins to aid in the development of cancer therapies. As C5a is found in broad range of cancers one potential use for this by-product is that molecules such as this could be used as biomarkers and a way of monitoring the progression and course the disease is taking and consequently anaphylatoxins in general may be used in the future to measure the progress of cancers (Klos et al., 2013). In one specific cancer type C5a levels were specifically higher than in the studies control group (Corrales et al., 2012), it has been suggested that through the research of anaphylatoxins in lung cancer that C5a may act via independent pathways than the traditional pathways associated with complement as researchers found that when local C5a levels were increased around tumour tissue in patients with chronic obstructive pulmonary disease levels of C3a did not increase accordingly (Mark et al.,2010).
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When looking at complement activation one of the main issues surrounding many chronic conditions including caner is the chronic inflammation that can arise as other factor such as angiogenesis , As a pre-emptive measure it has been suggested that the inhibition of complement related functions may aid in the treatment of cancers (Pio et al., 2013). Pharmacological testing has been carried out on various cancer models where the focus has been around the interaction of C5a and C5aR1, where it was hypothesised that the blockage of C5aR1 using the drug Eculizumab that is normally used to treat conditions such atypical haemolytic uremic syndrome may cause a reduction in tumour growth where a 2008 study (Markiewski et al.) found that when the drug is used on a syngeneic model of cervical cancer a reduction in tumour size was experienced that was similar to the effect seen by anti-cancer drugs. In other testing the blockade of C5aR1 was once again the focus but instead using the chemical PMX53 in a melanoma model and found that once again the tumour in question had reduced in size (Nabizadeh et al., 2016). However other studies reported that in animal models of breast tumours the same chemical had no impact on tumour growth (Kumari et al., 2016),however the same study found that the chemical had a dramatic effect the tumours metastatic burden.
As our understanding of cancer has evolved many of the mechanisms still are still not understood about this disease today, however with the developed understanding of the complement system it has become more obvious at how intricately intertwined the bodies biological mechanisms and systems are. Traditionally the complement system was seen as part of the bodies defence against foreign and non-self cells as an extension of the immune system. But now mounting evidence has found the many of the complement by-products such as C5a could well be part of the many underlying mechanisms behind a cancers progression. The literature has now suggested that C5a is behind many of the classical hallmarks of a cancers progression via various interactions with its receptors. However with this understanding it is now possible to focus research into using these complement by-products as both biomarkers to monitor progression of the diseases course, but also as a way to possibly stop the progression of tumours by targeting these receptors and stopping many of the cascading reactions that have been associated with C5a and its receptor C5aR1 that cause these hallmarks.
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