The central importance of CXCL8 signaling to inflammatory-based tumour initiation and invasive prostate carcinoma.

Lead Research Organisation: Queen's University Belfast
Department Name: Centre for Cancer Res and Cell Biology


Approximately 10,000 men each year die from aggressive prostate cancer (CaP) in the UK, due to a poor response to common therapeutic approaches and the spread of disease to other critical organs and tissues. Functional loss of the tumour suppressor gene PTEN has been strongly associated with aggressive (CaP). PTEN is the most frequently mutated gene in CaP, while expression of this gene is also down-regulated in many patients. Loss of PTEN correlates with increased resistance to radiotherapy, hormonal therapy and chemotherapy, and increased spread of the disease to the skeleton. Therefore, understanding the biology of PTEN-depleted CaP will provide new insights into the treatment of these aggressive cancers.

Our proposed research is founded on our observation of a very selective increase in the expression and signaling of a pro-inflammatory protein called CXCL8 following PTEN loss in CaP cells. Our published research has confirmed the increased expression of CXCL8 in human CaP and demonstrated the relevance of CXCL8 expression to diminished response of CaP cells to multiple therapeutic interventions. In work now submitted for publication, we have demonstrated that the marked increase in CXCL8 signaling experienced by PTEN-depleted cancer cells plays a vital role in maintaining the viability of the CaP cells as they adapt to the stress arising from the genetic instability caused by loss of functional PTEN. In addition to the effects on the cancer cells, we propose that the increased production of CXCL8 by PTEN-depleted cells has marked effects on neighbouring cells within the tumour. For example, the classical function of CXCL8 is to promote the recruitment of inflammatory immune cells including neutrophils and macrophages to sites of infection. However, in tumours, this immune infiltrate often serves not to eradicate the cancer but is subverted by the cancer cells to establish an environment that is conducive to progression and spread. Moreover, CXCL8 has a well-established role in promoting blood vessel formation, which serves to increase nutrient and oxygen supply to sustain tumour growth. Thus given its impact on cancer cell survival, inflammatory cell infiltrate and angiogenesis, we propose that repressing CXCL8 signaling may be an ideal and novel strategy to specifically target PTEN-depleted tumours.

We will employ a series of well-established in vitro and in vivo models of PTEN-deficient CaP to model the impact of repressing CXCL8 signaling upon early tumour development and late-stage progression to invasive CaP. Our strategy will employ both molecular and pharmacological approaches to reduce CXCL8 signaling. More specifically, we will target the cell-surface receptor/s that mediate the biological activity of CXCL8 and which are expressed on CaP cells, immune cells, and the endothelial cells lining developing blood vessels. Our first objective will determine whether the knockdown of this CXCL8 signaling can prevent the early development of tumours in the PTEN-deficient background. Secondly, we will seek to demonstrate that knockdown of CXCL8 signaling can repress the infilitration of immune cells into the microenvironment of PTEN-deficient prostate cancers, and that in addition, this prevents or retards the development of locally invasive cancer in the prostate gland. Our thid objective will seek to understand how cancer cell-derived CXCL8 signaling educates the response of neighbouring inflammatory cells to facilitate cancer cell invasion, and thus initiate the early stages of tumour escape throughout the body.

Our overall objective is to generate the pre-clinical data that will validate the use of CXC-chemokine receptor antagonists as relevant interventions in both early and late-stage PTEN-depleted CaP to impove patient outcomes in this high-risk group of patients.

Technical Summary

We will exploit well-established transgenic lines modeling Pten loss in the prostate. Models have been chosen due to their suitability in (i) studying the development of pre-malignant tumours, (ii) modelling inflammatory cells recruitment into Pten-depleted tumours and (iii) studying progression to invasive carcinoma. The importance of CXCL8 to tumour initiation and inflammation-promoted disease progression will be studied through a molecular approach. Cross-breeding of Pten-depleted mice with CXCR2-null mice will model the effects of dampening the microenvironment response to cancer cell-derived CXCL8 signaling. Moreover, using adoptive bone marrow transfer from CXCR2-null mice, we can study in isolation the importance of CXCL8-promoted inflammatory cell infiltrate to disease progression and invasive carcinoma. A pharmacological approach exploiting selective CXCR2 antagonists or a non-selective CXCR1/CXCR2 compound in these models will also be performed. Phenotypic effects will be evaluated by post-mortem histopathology of excised prostate tissue, complemented by gene expression analysis of epithelial and stromal tissue isolated by laser-capture micro-dissection to understand the basis of CXCL8-promoted tumour-stromal communication, and the pathways associated with disease progression in Pten-depleted tumours. In vitro experiments will further characterize CXCL8-promoted tumour-stromal communication using co-culture systems; clones modeling the effects of dose-dependent decreases in Pten expression, conditional re-expression of Pten and reductions of CXCL8 in Pten-depleted cells have already been developed for this purpose. Experiments will study the impact of CXCL8 in amplifying inflammatory responses, upregulating other chemokine pathways to stimulate directional chemotactic cell migration and promoting the protease activity required to underpin the matrix remodelling associated with invasive prostate cancer.

Planned Impact

Prostate cancer (CaP) is a heterogenous disease yet current treatments are provided without true consideration of the underlying biology of the patients tumour. Despite its prevalence and importance to aggressive CaP, there has been limited activity to identify tailored therapeutic strategies that are effective in treating patients with cancers that harbour lost PTEN function. PARP inhibitors are currently being evaluated in this context, however, recent trials show that even these promising agents have limited utility to exploit genetic instability in all tumours. In evaluating the relationship of PTEN-deficiency to inflammation, we propose that pro-inflammatory CXCL8 signaling is a major drive for the propogation of PTEN-null prostate cancers. We will extend our demonstration of the critical role this chemokine plays in maintaining the survival of PTEN-deficient CaP cells, moving from in vitro to in vivo models. Moreover, using sporadic models of PTEN-driven CaP, we will model the wider effects that this pro-inflammatory agent plays within the microenvironment to establish its full relevance to cancer progression. The principal outcome of our research will be to exploit these in vivo models to demonstrate what happens to PTEN-deficient CaP in the absence of CXCL8 signaling. Molecular and pharmacological strategies that repress CXCL8 signaling will demonstrate the impact on early-stage tumour development in PTEN-null backgrounds, characterize the effect upon the influx of inflammatory cells to the microenvironment of PTEN-deficient prostate tumours, and establish whether inhibiting CXCL8 signaling can either halt further progression or induce regression once invasive PTEN-deficient CaP has become established. Therefore, we propose that there are two key downstream groups that will benefit from the successful outcomes of this research:
(1) patients with aggressive, PTEN-mutant or null CaP for whom we have currently ineffective treaments and limited options and
(2) the pharmeutical companies who will deliver such agents to the clinic.
Large pharmaceutical companies including Schering, GSK, and AstraZeneca have already developed CXCR2 inhibitors which are being prioritized for clinical development in treating inflammation-associated respiratory disease (eg. COPD). Clinical development of these agents in cancer has lagged behind, principally due to the absence of appropriate validation in sporadic tumour models and where/when antagonists may be effective. A demonstration of desirable CXCR2 antagonist efficacy in halting progression in models of early or late-stage PTEN-depleted CaP would provide strong encouragement to move these agents into clinical development in cancer. Since CXCR2 antagonists have entered phase II trials in COPD, it suggests that they have limited and acceptable toxicities, and thus the impact to clinical practice may be readily achievable, once the stratified approach has been demonstrated. The applicants have a long-standing communication with the scientific leads of chemokine receptor-associated programmes within several of the large pharmaceutical companies. The interaction with companies is further enhanced through the involvement of CCRCB and the N. Ireland Cancer Clinical Trials Centre with the UK Experimental Cancer Medicine network. Where our research outcomes support, the applicants and the QUB Knowledge Enterprise Unit together with the MRC would lobby industry to ensure that IP is not only protected but is executed, encouraging the development of trials to evaluate CXCR2 antagonists in PTEN-depleted CaP. In addition, it would be the desire of the Belfast ECMC and NICCTC to take the national lead on such trials, co-ordinating multi-Centre trial activity and leading the associated biomarker and PTEN-diagnostic testing that would be implicit to such a trial protocol.


10 25 50

publication icon
Campbell LM (2013) Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer. in Pharmaceuticals (Basel, Switzerland)

Amount £5,000,000 (GBP)
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2014 
End 06/2019
Description CXCR2 antagonists in trials in Castrate-Resistant Prostate Cancer 
Organisation Canadian Institutes of Health Research
Department Institute of Cancer Research
Country Canada 
Sector Public 
PI Contribution This collaboration with Prof Johann deBono at ICR and Prof Andrea Alimonti in Bellinzona, Switzerland is focused on addressing the significance of administering the CXCR2 inhibitor AZD5069 to patients with metastatic castrate-resistant prostate cancer who are developing or have already acquired resistance to enzalutamide. The trial and the translational research is associated with the research that we have conducted under prior MRC funding.
Collaborator Contribution Prof Johann deBono and his team at ICR are leading the ACE trial. Prof Alimonti and his team are collaborating on pre-clinical research related to the tumour microenvironment of PTEN-deficient prostate cancers
Impact No formal publications or outputs arising yet.
Start Year 2017
Description Movember PCUK Centre of Excellence 
Organisation University of Manchester
Department Manchester Cancer Research Centre
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution This collaborative project complements our existing proposal examining the relationship of PTEN status and chemokine CXCL8 in driving disease. Through this funding we will determine whether PTEN status correlates with elevated CXCL8 expression in patient samples.
Collaborator Contribution Partners will be providing access to extensive tissue collections.
Impact Not yet available
Start Year 2013
Description MRC-sponsored Debate 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact 40 pupils from three schools attended and participated in a debate about scientific related issues and whether these were morally/ethically correct or wrong.

Impacts were that Schools became knowledgeable about Medical Research conducted in Northern Ireland at Queen's University Belfast.
Year(s) Of Engagement Activity 2013
Description Radio Interview, 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Radio Interview to discuss how research has impacted on improved survival data for prostate cancer patients.

Public awareness of how research can improve outcomes for patients
Year(s) Of Engagement Activity 2013
Description Research Engagement Activity 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 60 members of staff visited the centre to learn of MRC and CRUK-funded work conducted in the Centre

Centre has enhanced its very significant profile across the University and the local sector
Year(s) Of Engagement Activity 2013
Description Research Innovation Book 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The booklet was circulated widely throughout Belfast and Northern Ireland. A presentation was also made at the launch event which precipitated a range of discussions across a broad sector of the public.

University received significant recognition for its cancer research programmes and specifically, prostate cancer research onging in Belfast
Year(s) Of Engagement Activity 2013