Vascular endothelium as the amplifying machinery of oncogene-induced senescence surveillance

当人体细胞对其DNA造成损伤时，就会发生癌症。这通常发生得很慢，但由于长期的炎症，如肝硬变或炎症性肠病，许多患者患癌症的风险增加。这种炎症会导致DNA损伤和致癌基因的激活。在癌症的早期阶段，在我们目前的癌症检测能力之前，人体具有抑制这些致癌基因并阻止癌症进展的防御机制。一种这样的机制被称为细胞衰老，身体的细胞感觉到这种损害，并通过不可逆转地阻止细胞进一步繁殖来做出反应。衰老的细胞也向周围的其他细胞发出信号，阻止它们繁殖并吸引循环免疫细胞，从而杀死衰老的细胞及其包含的致癌基因。因此，了解免疫系统是如何检测和杀死衰老细胞的很重要，这可能是治疗患者的一种方法，首先防止他们患上癌症。免疫细胞在我们的血液中循环，当它们检测到炎症等问题时，通过粘贴到血管壁进入我们身体的不同部位。在肝脏内，血管内排列着肝窦内皮细胞，这可以吸引免疫细胞进入肝脏杀死细菌和病毒。我们知道，当癌症发展时，免疫细胞会进入肝脏，但我们不知道当肝脏细胞衰老或癌变时，这是如何发生的。我们也不知道内皮细胞在这一过程中是否重要。如果我们能够了解导致免疫细胞进入肝脏杀死衰老细胞的过程，那么我们就可能针对这一途径，通过增强身体的自然防御从一开始就阻止癌症的发展。增强免疫系统对抗癌症已经被证明对其他癌症有效，如黑色素瘤。在这项研究计划中，我们的目标是找出：1)内皮细胞是否因肝脏衰老而激活，以及内皮细胞是如何改变的。2)免疫系统的哪些部分被内皮细胞吸引以响应在肝脏中的衰老发展，以及内皮细胞是否在其进入肝脏时激活免疫系统。3)当正弦形内皮细胞响应衰老时，哪些分子和信号是重要的，以及增强这些信号是否提高免疫系统响应衰老进入肝脏的能力。4)如果通过干扰内皮细胞的正常功能来阻止这种反应，这是否允许肝癌的发展。5)慢性炎症患者或其他肝癌患者的肝脏中是否出现类似的肝窦内皮细胞变化。为了实现这一点，我们将研究当同一肝脏中存在衰老细胞时，来自肝脏的内皮细胞的表现。我们的大部分研究将包括研究实验室中生长的细胞，以及手术后切除的患病人类肝脏组织。我们的研究还将包括在小鼠身上研究这些细胞，因为这是研究衰老细胞、内皮细胞和免疫系统之间复杂联系的唯一方法。这项提议将在伯明翰大学和剑桥大学的两个实验室进行，这两个实验室分别专门研究肝脏中的免疫细胞和衰老。如果我们能找出是否有可能改善免疫系统的功能，提高清除肝脏内最早形式的癌症的能力，我们就可能设计出防止未来患者患上癌症的治疗方法。

The development of cancer occurs when cells of the body accumulate damage to their DNA. This generally occurs slowly, but many patients have an increased risk of cancer development due to long-term inflammation such as liver cirrhosis or inflammatory bowel disease. This inflammation leads to damage to the DNA and activation of cancer-causing genes. At the earliest stages of cancer, prior to our current ability to detect cancer the body has defence mechanisms that suppress these cancer-causing genes and prevent cancer progressing. One such mechanism is called cellular senescence where cells of the body sense this damage and respond by irreversibly preventing that cell from reproducing itself any further. Senescent cells also signal to other cells around themselves preventing them from reproducing and attracting circulating immune cells that kill the senescent cell and the cancer-causing genes that it contains. Therefore, understanding how senescent cells are detected and killed by the immune system is important and could be a way of treating patients to prevent them getting cancer in the first place.Immune cells, which circulate in our blood, enter different parts of our body by sticking to the walls of the blood vessels when they detect a problem, such as inflammation. Within the liver the blood vessels are lined by sinusoidal endothelial cells, which can attract immune cells into the liver to kill bacteria and viruses. We know that immune cells enter the liver when cancer develops, but we do not know how this happens when cells of the liver become senescent or cancerous. Nor do we understand whether the endothelial cell is important in this process. If we could understand the processes that cause immune cells to enter the liver to kill senescent cells, then we might be able to target this pathway and prevent cancer developing in the first place through boosting the bodies natural defences. Boosting the immune system to fight cancer has already been shown to be effective in other cancers such as melanoma.In this research proposal, we aim to find out:1) whether the endothelial cell is activated by senescence in the liver and how the endothelium is altered. 2) which parts of the immune system are attracted by the endothelial cell in response to senescence developing in the liver and whether the endothelial cell activates the immune system as it enters the liver.3) which molecules and signals are important when sinusoidal endothelial cells respond to senescence and whether boosting these signals improves the ability of the immune system to enter the liver in response to senescence.4) if this response is prevented by interfering with the normal function of the endothelial cells, whether this allows liver cancer to develop.5) whether similar changes to the liver sinusoidal endothelial cell occur in the liver of patients with chronic inflammation or other patients with liver cancer.To achieve this we will study how the endothelial cells from the liver behave when senescent cells are present in the same liver. Much of our research will involve studying cells grown in a laboratory as well as diseased human liver tissue which has been removed after surgery. Our research will also involve studying these cells in mice, as this is the only way to study the complex links between senescent cells, endothelial cells and the immune system.This proposal will be carried out in two laboratories at the Universities of Birmingham and Cambridge that specialise in looking at immune cells in the liver and looking at senescence respectively.If we can find out whether it is possible to improve the functioning of the immune system and improve the ability to clear the earliest forms of cancer within the liver we might be able to design treatments that prevent patients in the future from developing cancer.