Role of C5a as a Hallmark of Cancer

3221 words (13 pages) Essay in Biology

23/09/19 Biology Reference this

Disclaimer: This work has been submitted by a student. This is not an example of the work produced by our Essay Writing Service. You can view samples of our professional work here.

Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of UK Essays.

The Emerging Role of C5a as a Hallmark of Cancer and How it is Being Used as a Potential Therapy

Introduction

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).

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

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).

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.

Summary

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.

References

  • Afshar-Kharghan, V. (2017) The role of the complement system in cancer. Journal of Clinical Investigation. 127(3), pp.780-789.
  • Ajona, D., Ortiz-Espinosa, S. and Pio, R. (2019) Complement anaphylatoxins C3a and C5a: Emerging roles in cancer progression and treatment. Seminars in Cell & Developmental Biology. 85, pp.153-163.
  • Ajona, D., Pajares, M., Corrales, L., Perez-Gracia, J., Agorreta, J., Lozano, M., Torre, W., Massion, P., de-Torres, J., Jantus-Lewintre, E., Camps, C., Zulueta, J., Montuenga, L. and Pio, R. (2013) Investigation of Complement Activation Product C4d as a Diagnostic and Prognostic Biomarker for Lung Cancer. JNCI: Journal of the National Cancer Institute, 105(18), pp.1385-1393.
  • Corrales, L., Ajona, D., Rafail, S., Lasarte, J., Riezu-Boj, J., Lambris, J., Rouzaut, A., Pajares, M., Montuenga, L. and Pio, R. (2012) Anaphylatoxin C5a Creates a Favorable Microenvironment for Lung Cancer Progression. The Journal of Immunology, 189(9), pp.4674-4683.
  • Dembic, Z. (2015) The cytokines of the immune system. 1st ed. Amsterdam: Elsevier/Academic Press, pp.17-56.
  • Diebolder, C., Beurskens, F., de Jong, R., Koning, R., Strumane, K., Lindorfer, M., Voorhorst, M., Ugurlar, D., Rosati, S., Heck, A., van de Winkel, J., Wilson, I., Koster, A., Taylor, R., Ollmann Saphire, E., Burton, D., Schuurman, J., Gros, P. and Parren, P. (2014) Complement Is Activated by IgG Hexamers Assembled at the Cell Surface. Science. 343(6176), pp.1260-1263.
  • Dragomir, C., Scott, J., Perino, G., Adler, R., Fealy, S. and Goldring, M. (2012) Acute inflammation with induction of anaphylatoxin C5a and terminal complement complex C5b-9 associated with multiple intra-articular injections of hylan G-F 20: a case report. Osteoarthritis and Cartilage. 20(7), pp.791-795.
  • Fonseca, M., McGuire, S., Counts, S. and Tenner, A. (2013) Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology. Journal of Neuroinflammation. 10(1).
  • Gasque, p., Singharo, S., Neal J., Götze, O. and Morgan, B. (1997) Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. The American Journal of Pathology. 150(1), pp.31-41.
  • Gerard, N., Lu, B., Liu, P., Craig, S., Fujiwara, Y., Okinaga, S. and Gerard, C. (2005) An Anti-inflammatory Function for the Complement Anaphylatoxin C5a-binding Protein, C5L2. Journal of Biological Chemistry. 280(48), pp.39677-39680.
  • Guo, Y., Xu, F., Lu, T., Duan, Z. and Zhang, Z. (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treatment Reviews. 38(7), pp.904-910.
  • Hanahan, D. and Weinberg, R. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144(5), pp.646-674.
  • Hofree, M., Carter, H., Kreisberg, J., Bandyopadhyay, S., Mischel, P., Friend, S. and Ideker, T. (2016) Challenges in identifying cancer genes by analysis of exome sequencing data. Nature Communications. 7(1).
  • Iwai, Y., Hamanishi, J., Chamoto, K. and Honjo, T. (2017) Cancer immunotherapies targeting the PD-1 signaling pathway. Journal of biological science. 24(1), pp.26.
  • Khöl, J. (2006) Self, non-self, and danger: a complementary view. Advances in experimental medicine and biology. 586, pp.71-94.
  • Klos, A., Wende, E., Wareham, K. and Monk, P. (2013) International Union of Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors. Pharmacological Reviews, 65(1), pp.500-543.
  • Kumari, N., Dwarakanath, B., Das, A. and Bhatt, A. (2016) Role of interleukin-6 in cancer progression and therapeutic resistance. Tumor Biology, 37(9), pp.11553-11572.
  • Kurihara, R., Yamaoka, K., Sawamukai, N., Shimajiri, S., Oshita, K., Yukawa, S., Tokunaga, M., Iwata, S., Saito, K., Chiba, K. and Tanaka, Y. (2010) C5a promotes migration, proliferation, and vessel formation in endothelial cells. Inflammation Research, 59(8), pp.659-666.
  • Marc, M., Kristan, S., Rozman, A., Kern, I., Flezar, M., Kosnik, M. and Korosec, P. (2010) Complement Factor C5a in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Scandinavian Journal of Immunology, 71(5), pp.386-391.
  • Markiewski, M., DeAngelis, R., Benencia, F., Ricklin-Lichtsteiner, S., Koutoulaki, A., Gerard, C., Coukos, G. and Lambris, J. (2008) Modulation of the antitumor immune response by complement. Nature Immunology, 9(11), pp.1225-1235.
  • Monk, P., Scola, A., Madala, P. and Fairlie, D. (2007) Function, structure and therapeutic potential of complement C5a receptors. British Journal of Pharmacology. 152(4), pp.429-448.
  • Mukherjee, P. and Pasinetti, G. (2001) Complement anaphylatoxin C5a neuroprotects through mitogen-activated protein kinase-dependent inhibition of caspase 3. Journal of Neurochemistry, 77(1), pp.43-49.
  • Nabizadeh, J., Manthey, H., Steyn, F., Chen, W., Widiapradja, A., Md Akhir, F., Boyle, G., Taylor, S., Woodruff, T. and Rolfe, B. (2016) The Complement C3a Receptor Contributes to Melanoma Tumorigenesis by Inhibiting Neutrophil and CD4+T Cell Responses. The Journal of Immunology, 196(11), pp.4783-4792.
  • Nitta, H., Wada, Y., Kawano, Y., Murakami, Y., Irie, A., Taniguchi, K., Kikuchi, K., Yamada, G., Suzuki, K., Honda, J., Wilson-Morifuji, M., Araki, N., Eto, M., Baba, H. and Imamura, T. (2013) Enhancement of Human Cancer Cell Motility and Invasiveness by Anaphylatoxin C5a via Aberrantly Expressed C5a Receptor (CD88). Clinical Cancer Research, 19(8), pp.2004-2013.
  • Olivier, M., Hollstein, M. and Hainaut, P. (2009) TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harbor Perspectives in Biology. 2(1).
  • Pio, R., Ajona, D. and Lambris, JD. (2013) Complement inhibition in cancer therapy. Seminars in Immunology. 25(1), pp.54-64.
  • Rakoff-Nahoum, S. (2006) Why Cancer and Inflammation? Yale Journal of Biology and Medicine. 79(3-4), pp.123-130.
  • Rosbjerg, A., Genster, N., Pilely, K., Skjoedt, M., Stahl, G. and Garred, P. (2016) Complementary roles of the classical and lectin complement pathways in the defense against Aspergillus fumigatus. Immunobiology. 221(10), p.1199.
  • Sarma, J. and Ward, P. (2010) The complement system. Cell and Tissue Research, 343(1). pp.227-235.
  • Sayah, S., Ischenko, A., Zhakhov, A., Bonnard, A. and Fontaine, M. (2002) Expression of Cytokines by Human Astrocytomas Following Stimulation by C3a and C5a Anaphylatoxins. Journal of Neurochemistry. 72(6), pp.2426-2436.
  • Vadrevu, S., Chintala, N., Sharma, S., Sharma, P., Cleveland, C., Riediger, L., Manne, S., Fairlie, D., Gorczyca, W., Almanza, O., Karbowniczek, M. and Markiewski, M. (2014) Complement C5a Receptor Facilitates Cancer Metastasis by Altering T-Cell Responses in the Metastatic Niche. Cancer Research, 74(13), pp.3454-3465.
  • WHO. (2019) Cancer. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/cancer [Accessed 6 Jan. 2019].
  • Xi, W., Liu, L., Wang, J., Xia, Y., Bai, Q., Xiong, Y., Qu, Y., Long, Q., Xu, J. and Guo, J. (2016) Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma. Oncotarget, 7(49).

 

Cite This Work

To export a reference to this article please select a referencing stye below:

Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.
Reference Copied to Clipboard.

Related Services

View all

DMCA / Removal Request

If you are the original writer of this essay and no longer wish to have the essay published on the UK Essays website then please: