Midkine promotes uveal melanoma progression by stimulating ABCB5+ cancer stem cells

虽然眼部癌症相对罕见，但葡萄膜黑色素瘤是迄今为止最常见的。它是由居住在眼睛的葡萄膜束黑色素细胞的恶性转化引起的。当这些肿瘤发展时，许多治疗方法可以成功地阻止它们的生长，并且在许多情况下，保留功能性视力。然而，如果肿瘤细胞进入血管并离开眼睛，它们就会扩散到身体的其他部位，形成被称为“转移瘤”的继发性肿瘤。这种情况发生在大约50%的患者身上，不幸的是，没有成功的治疗方法。有证据表明，肿瘤细胞很早就离开了眼睛，甚至可能在医生首次诊断出患者患有癌症之前就离开了。葡萄膜黑色素瘤的转移有两个方面是不寻常的：(i)它们几乎总是在肝脏中发展，（ii）在它们发展之前可能会延迟很多年。本研究的最终目的是为肝转移患者开发新的治疗方法。为了实现这一目标，我们需要了解肿瘤细胞是如何离开眼睛，进入血管，然后在肝脏形成肿瘤的。我们正在开发一种新的动物模型，使我们能够追踪体内肿瘤细胞的运动。我们正在使用一种高灵敏度的成像仪器，可以“看到”眼睛、血管和肝脏内的肿瘤细胞。这是通过对肿瘤细胞进行基因修饰来实现的，这样它们就能表达一种可以被仪器看到的标记物。这个模型系统将使我们能够研究是什么导致细胞离开眼睛，进入血液，并最终迁移到肝脏。根据我们过去的研究，我们假设有两个重要的事件必须发生才能使肝脏肿瘤发展。第一个事件是一小部分肿瘤细胞形成，称为“肿瘤起始细胞”。尽管所有的肿瘤细胞都有增殖，但只有“肿瘤起始细胞”的子集能够无限增殖并具有形成新肿瘤的能力。因此，如果你去除“肿瘤起始细胞”，那么剩下的肿瘤细胞最终会死亡，无需进一步治疗。这被称为“肿瘤消退”。第二个事件是一种叫做“midkine”的蛋白质被释放，它促进了这一小部分致癌细胞的增殖和存活。如果致癌细胞缺乏“midkine”蛋白，它们就无法存活，肿瘤就会退化。我们的实验将使用的方法是：消除癌症启动细胞，midkine表达，或两者（启动细胞和midkine）。然后我们将在我们的模型系统中跟踪肿瘤的发展。这些研究的成功完成将确定治疗致命肝转移患者的新靶点。

While cancer within the eye is relatively rare, uveal melanoma is by far the most common. It is caused by the malignant transformation of melanocytes residing in the uveal tract of the eye. When these tumors develop, a number of treatments can successfully stop their growth and, in many cases, preserve functional vision. However, if tumor cells enter blood vessels and leave the eye, they can spread to other parts of the body and develop secondary tumors called “metastases”. This occurs in about 50% of the patients and, unfortunately, there is no successful treatment. Evidence suggests that tumor cells leave the eye early, possibly even before the doctor first diagnoses the patient with cancer. Two aspects of metastases derived from uveal melanoma are unusual: (i) they almost always develop in the liver, and (ii) there can be a delay of many years before they develop.The ultimate goal of this research is to develop new treatment methods for patients with liver metastases. In order to achieve this goal, we need to understand how the tumor cells leave the eye, enter the blood vessels, and then form tumors in the liver. We are developing a new animal model allowing us to track the movement of tumor cells within the body. We are using a highly sensitive imaging instrument that can “see” tumor cells within the eye, blood vessels, and liver. This was achieved by genetically modifying the tumor cells so they express a marker that can be seen by the instrument. This model system will allow us to study what causes the cells to leave the eye, move into the blood, and ultimately migrate into the liver.Based upon our past research, we hypothesize there are two important events that must occur in order for liver tumors to develop. The first event is that a small subset of tumor cells is established that are called “tumor initiating cells”. Even though all tumor cells proliferate, only the subset of “tumor initiating cells” can do so indefinitely and possess the ability to form new tumors. Therefore, if you remove the “tumor initiating cells”, then the remaining tumor cells would eventually die without any further treatment. This is called “tumor regression”. The second event is that a protein, called “midkine” is released that promotes the proliferation and survival of this small subset of cancer initiating cells. If the cancer initiating cells lack the “midkine” protein, they will not survive, and tumors will regress. Our experiments will use methods to eliminate: the cancer initiating cells, midkine expression, or both (the initiating cells and midkine). We will then track the tumor development in our model system. Successful completion of these studies will identify new targets for treating patients with deadly liver metastases.