The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, smouldering inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.

We are researching a particular class of receptors involved in inflammation called GPCRs, or G protein coupled receptors. GPCRs account for up 30% of the targets of drugs currently on the market and are of interest to Big pharma, academia and biotech. They are commonly referred to as 7TM proteins as they are composed of seven helices that span the membrane. They are implicated in many disease types, due to their widespread expression in a number of different cell types, particularly immune cells. We are interested in GPCRs and the pathology of native and synthetic ligands for these receptors that play a central role in host defence [1].  Excessive receptor activation and disregulation has been linked to a number of different disease types, including rheumatoid arthritis [2], sepsis [3] and Alzheimer’s [4]. Whilst much effort (20 years+) has been put into the development of potent antagonists against this receptor, there are no marketed antagonists to date.

The phenomena of ligand directed signaling [5-7], whereby different ligands acting on one receptor may elicit qualitatively different response patterns, or one ligand may signal strongly through one pathway, yet weakly through another, is another significant component of this research. We have investigated this phenomenon using a panel of compounds targeted at the receptor using a range of secondary messenger assays and label-free detection platforms. Using these technologies we have analysed over-expressing transfected cells, native cells and null cells to derive a comprehensive map of ligand-directed signaling in different cell types and cell states. In this way we hope to be able to select for candidate drugs using the appropriate cellular model; for example there are reports in the literature which show that an agonist can behave as an antagonist when receptor expression levels are high [8,9].

Ultimately, our aim is to dissect individual signalling pathways, in the hope that we can understand what happens at the cellular and molecular level after a compound binds to a GPCR implicated in inflammation and cancer. We are using a number of different approaches, such as shRNA, fluorescent labelling, silencing using toxins, and others, to thoroughly dissect and attribute a signal to a specified signalling event. This will help us to identify compounds which specifically target, not only one receptor, but show bias for one signalling pathway towards a highly selective drug profile.

The complement system is a very important part of the innate immune system that helps us to combat invading pathogens. Activation of the complement cascade is a tightly regulated and well-maintained process, however when dysregulated it has been implicated in a number of inflammatory and autoimmune disorders. The research in our lab focuses predominantly on the C5a and C3a complement proteins, both key inflammatory mediators. C3a binds to C3aR and C5a binds to either C5a1 and C5a2.

Our group has attempted to understand the complex relationship between the two different receptors of C5a, demonstrating that C5a2 is not just a ‘dud’ receptor, as previously believed. Our findings have given us a foundation to pursue novel therapeutics that specifically act via C5a2 and not C5a1. Furthermore, in light of recent evidence that suggests C3a agonism is key in ameliorating neutrophil driven pathologies, we have programs to develop novel C3a ligands as therapeutics

Key publications

  • Klos, A., Wende, E., Wareham, K.J., and Monk, P. N. International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors. Pharmacol Rev (2013), 65, 500-543
  • Schofield, Z.V, Woodruff, T.M., Halai, R., Wu, M.C.L., Cooper, M. A. Neutrophils-a key component of ischemic reperfusion injury.(2013), Shock, 40, 463-70
  • Croker, D. E., Halai R., Fairlie, D. P., Cooper M.A. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5aR and C5L2. (2013) Immunol Cell Biol, 91, 625-633
  • Wu, M.C.L, Brennan, F.H, Lynch, J.P., Mantovani, S., Phipps, S., Wetsel, R.A., Ruitenberg, M.J., Taylor, S.M., Woodruff, T.M. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization (2013) PNAS, 110, 9439-9444
  • Reid, R.C., Yau, M., Singh, R., Hamidon, J.K., Reed, A.N., Chu, P., Suen, J.Y., Stoermer, M.J., Blakeney, J.S., Lim, J., Faber, J.M., & Fairlie, D.P. Downsizing a human inflammatory protein to a small molecule with equal potency and functionality (2013), Nat. Commun. 4, 1-9


[1] Monk, P. N.; Scola, A. M.; Madala, P.; Fairlie, D. P., Br. J. Pharmacol. 2007, 152, 429.

[2] Jose, P. J.; Moss, I. K.; Maini, R. N.; Williams, T. J., Ann. Rheum. Dis. 1990, 49, 747.

[3] Czermak, B. J.; Sarma, V.; Pierson, C. L.; Warner, R. L.; Huber-Lang, M.; Bless, N. M.; Schmal, H.; Friedl, H. P.; Ward, P. A., Nat. Med. 1999, 5, 788

[4] Velazquez, P.; Cribbs, D. H.; Poulos, T. L.; and Tenner, A. J., Nat. Med. 1997, 3, 77.

[5] Gilchrist, A., Trends Pharmacol. Sci. 2007, 28, 431.

[6] Urban, J. D.; Clarke, W. P.; von Zastrow, M.; Nichols, D. E.; Kobilka, B.; Weinstein, H.; Javitch, J. A.; Roth, B. L.; Christopoulos, A.; Sexton, P. M.; Miller, K. J.; Spedding, M.; Mailman, R. B., J. Pharmacol. Exp. Ther. 2007, 320, 1.

[7] Michel, M. C.; Alewijnse, A. E., Mol. Pharmacol. 2007, 72, 1097.

[8] Hutchinson, D. S.; Chernogubova, E.; Sato, M.; Summers, R. J.; Bengtsson, T., Naunyn-Schmiedeberg's Arch. Pharmacol. 2006, 373, 158.

[9] Sato, M.; Horinouchi, T.; Hutchinson, D. S.; Evans, B. A.; Summers, R. J., Mol. Pharmacol. 2007, 72, 1359.

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