An investigation of the pro-tumorigenic activity of the chemokine receptor CXCR2 using models of de novo tumorigenesis.

In humans and animals, persistent inflammation of tissues can increase the likelihood of developing cancer. In addition, cancers induce inflammation to create an environment that helps support their development and progression. We are interested in understanding these links between cancer and inflammation at the level of individual molecules. Our research has focused on the migration of white blood cells into tissues from the blood, a key component of all inflammation. These cells normally provide protection from infection and help repair damaged tissue, but they also bring with them a host of molecules that inadvertently help support cancers. If we could understand how white blood cell migration occurs, we may be able to develop medicines that interfere with it. This is a relatively under-explored area of cancer biology, but could yield new medicines for treating cancer patients. Excitingly, we have found that a molecule called CXCR2, which is critical for the migration of white blood cells into tissues during inflammation, plays an indispensable role in assisting the development of cancers in the skin and colon of mice. The proposed work plans to build on these observations and aims to fully understand how and why CXCR2 has such profound pro-cancer activity. Significantly, medicines that block the function of CXCR2 are already under development and, using mouse models of cancer, we plan to test whether they have real therapeutic potential. We believe these studies will not only advance our understanding of the interactions between inflammation and cancer, but also have the potential to lead to the development of novel approaches to cancer treatment in humans.

Inflammation and tumorigenesis are intimately linked. Chronic inflammation increases the risk of developing many cancers, and tumours use inflammatory signals to establish supportive microenvironments. Pro-inflammatory molecules that contribute to these processes represent a relatively under-explored source of possible therapeutic targets. Chemokines and their receptors are of fundamental importance in orchestrating inflammatory responses, and we have recently discovered that the chemokine receptor CXCR2 plays a profound pro-tumorigenic role in mouse models of de novo tumorigenesis in both the skin and the intestine. These observations, in combination with a wealth of data generated by us and others, have lead us to hypothesise that CXCR2 makes a major contribution to both inflammation-driven and spontaneous tumorigenesis in multiple tissues, and that this is because of its ability to recruit leukocytes, particularly neutrophils, into these tissues and the tumours developing within them. We will use genetically-modified mice and models of cutaneous and intestinal tumorigenesis to rigorously test this hypothesis. In addition, we will perform proof-of-concept studies in mice exploring CXCR2 inhibition as an anti-cancer therapy. Collectively, we believe these studies will advance our understanding of the links between inflammation, chemokines and cancer. Moreover, with high expression of CXCR2 ligands common in many human cancers, and CXCR2 antagonists already in clinical trials, this work could lead to the rapid development of novel cancer therapies worthy of consideration for treating human disease.