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

在英国，每年大约有10,000名男性死于侵袭性前列腺癌（CaP），原因是对常见治疗方法的反应不佳，以及疾病扩散到其他关键器官和组织。肿瘤抑制基因PTEN的功能丧失与侵袭性（CaP）密切相关。PTEN是CaP中最常见的突变基因，同时在许多患者中该基因的表达也下调。PTEN的丧失与对放射治疗、激素治疗和化疗的抵抗力增加以及疾病向骨骼的扩散增加有关。因此，了解pten耗尽的CaP的生物学将为这些侵袭性癌症的治疗提供新的见解。我们提出的研究是基于我们对CaP细胞中PTEN缺失后促炎蛋白CXCL8的表达和信号传导的选择性增加的观察。我们发表的研究证实了CXCL8在人类CaP中的表达增加，并证明了CXCL8表达与CaP细胞对多种治疗干预的反应减弱有关。在现在提交发表的研究中，我们已经证明了PTEN缺失的癌细胞所经历的CXCL8信号的显著增加在维持CaP细胞的生存能力方面起着至关重要的作用，因为它们适应由功能PTEN缺失引起的遗传不稳定所引起的压力。除了对癌细胞的影响外，我们提出pten缺失细胞增加CXCL8的产生对肿瘤内邻近细胞有显著影响。例如，CXCL8的经典功能是促进炎症免疫细胞（包括中性粒细胞和巨噬细胞）募集到感染部位。然而，在肿瘤中，这种免疫浸润往往不能根除癌症，而是被癌细胞破坏，建立一个有利于进展和扩散的环境。此外，CXCL8在促进血管形成方面具有明确的作用，其有助于增加营养和氧气供应以维持肿瘤生长。因此，鉴于其对癌细胞存活、炎症细胞浸润和血管生成的影响，我们提出抑制CXCL8信号可能是特异性靶向pten -缺失肿瘤的理想和新颖策略。我们将采用一系列完善的pten缺陷CaP体外和体内模型来模拟抑制CXCL8信号对早期肿瘤发展和晚期侵袭性CaP进展的影响。我们的策略将采用分子和药理学方法来减少CXCL8信号。更具体地说，我们将针对介导CXCL8生物活性的细胞表面受体/s，这些受体/s在CaP细胞、免疫细胞和发育中的血管内皮细胞上表达。我们的第一个目标是确定在pten缺乏的背景下，CXCL8信号的敲除是否可以阻止肿瘤的早期发展。其次，我们将试图证明敲低CXCL8信号可以抑制免疫细胞向pten缺陷前列腺癌微环境的浸润，此外，这可以防止或延缓前列腺局部浸润性癌症的发展。我们的第三个目标将寻求了解癌细胞衍生的CXCL8信号如何教育邻近炎症细胞的反应，以促进癌细胞的入侵，从而启动整个身体肿瘤逃逸的早期阶段。我们的总体目标是生成临床前数据，以验证使用cxc趋化因子受体拮抗剂作为早期和晚期pten衰竭CaP的相关干预措施，以改善这一高危患者群体的患者预后。

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.