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

点击翻译按钮获取中文摘要

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.