Elucidating how Dysbiosis, Senescence and Inflammatory Storms Impact Prostate Carcinogenesis and Treatment Resistance to Transform Care.

前列腺癌是男性最常见的癌症，也是男性癌症中最常见的杀手之一。在全球范围内，该病的发病率正在上升，在过去认为受该病影响较小的大陆，包括亚洲和非洲，死亡人数不断增加。在英国，每8名男性中就有1人会患前列腺癌（每年5万人），每45分钟就有1人死于前列腺癌。有趣的是，尽管前列腺癌仍然是整个欧洲癌症死亡的主要原因，但其发病率和死亡率在北欧明显更高；这种情况，以及亚洲和非洲发病率的上升，很可能是由于饮食和其他生活方式的改变。加勒比马提尼克岛和瓜达卢佩岛是世界上前列腺癌发病率最高的岛屿，这与接触在香蕉种植园中用作杀虫剂的致癌化学物十氯酮有关；氯十酮增加前列腺暴露于雄性雄激素的机会，支持了这些激素参与致癌的其他积累证据。通过饮食、胃肠道功能和胃肠道细菌的变化来进一步了解饮食变化如何影响前列腺癌风险，还需要进一步研究。人们设想，更好地了解前列腺癌的病因将减少这种最常见的男性癌症的痛苦。我们的工作有助于改变对侵袭性前列腺癌的理解，在基因组测序研究中描述导致这些疾病的DNA损伤，以及识别不同类型的前列腺癌，包括与DNA修复相关的基因遗传突变（如BRCA2和ATM）或更常见的基因变异（称为单核苷酸多态性或snp）相关的癌症，这些基因突变增加了雄性激素受体的信号传导。我们还利用这些信息开发了多种前列腺癌的新疗法，包括阿比特龙、卡巴他赛、恩杂鲁胺、奥拉帕尼，并改变了遗传突变的正常DNA和肿瘤突变/改变的前列腺癌DNA的基因检测指南。尽管如此，男性患前列腺癌的寿命比以往任何时候都长，但每天仍有男性死于致命的前列腺癌，更好地了解导致这些疾病的原因对于改善护理和减少这些疾病的痛苦是必要的。我们假设，与饮食相关的雄激素水平的变化会引起前列腺炎症，这种炎症会迅速自我延续，并导致前列腺细胞DNA受损，最终导致恶性肿瘤。我们将在各种前列腺癌模型中研究这些过程，利用获得的信息来提高放射治疗和激素治疗等标准治疗的抗肿瘤活性，同时也剖析促进这些癌症发展和生长的复杂细胞相互作用。我们设想这项研究将改变我们对前列腺癌发展和生长方式的理解，并导致影响前列腺癌预防和治疗的变革性策略。

Prostate cancer is the commonest cancer in men, and one of the commonest killers from cancer in men. It is increasing in incidence globally with increasing numbers of deaths in continents previously thought to be less impacted by this disease including Asia and Africa. In the UK, 1 in 8 men will have prostate cancer in their lifetime (50,000/year) and a man will die from prostate cancer every 45-minutes. Interestingly, although prostate cancer remains a major cause of cancer mortality across Europe, its incidence and mortality are significantly higher in Northern Europe; this, and the increasing incidence in Asia and Africa, is likely due to dietary and other lifestyle changes. The Caribbean islands of Martinique and Guadalupe have the highest incidence of prostate cancer in the world, with this being associated with exposure to the carcinogenic chemical chlordecone used as an insecticide in banana plantations; chloredecone increases prostatic exposure to male androgen hormones supporting other accumulating evidence that these hormones are involved in carcinogenesis. Further understanding of how dietary changes impact prostate cancer risk, through changes in diet, gastrointestinal tract function and bacteria in our gastrointestinal tract need further study. It is envisioned that a better understanding of what causes prostate cancer will decrease suffering from this most common of male cancers. Our work has helped transform understanding of aggressive prostate cancers, describing the DNA damage that causes these diseases in genomic sequencing studies, as well as identifying the different types of prostate cancers including cancers associated with inherited mutations of genes involved in DNA repair such as BRCA2 and ATM or more common gene variations (called single nucleotide polymorphisms or SNPs) that increase the signalling of the male hormone receptor. We have also used this information to develop multiple new treatments for prostate cancer including abiraterone, cabazitaxel, enzalutamide, olaparib as well as change guidelines on genetic testing of both normal DNA for inherited mutations as well as prostate cancer DNA for tumour mutations/alterations. Despite this, and men living longer than ever with these diseases, men are still dying every day from lethal prostate cancer and a better understanding of what causes these diseases is necessary to improve care and decrease suffering from these.We have postulated that changes in androgen levels associated with diet induce inflammation in the prostate, that can rapidly become self-perpetuating and lead to damaged DNA in prostatic cells that will eventually lead to malignancies. We will study these processes in various models of prostate cancer, utilising the acquired information to improve the anti tumour activity of standard treatments such as radiotherapy and hormonal therapy while also dissecting the complex cellular interactions that fuel the development and growth of these cancers.We envision that this research will transform our understanding of the way prostate cancer develops and grows, and lead to transformative strategies impacting prostate cancer prevention and treatment.