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

虽然眼睛内的癌症相对罕见，但葡萄膜黑色素瘤是迄今为止最常见的。它是由眼睛葡萄膜中黑色素细胞的恶性转化引起的。当这些肿瘤发展时，一些治疗方法可以成功地阻止它们的生长，并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，它们可以扩散到身体的其他部位，并发展为称为“转移”的继发性肿瘤。这种情况发生在大约50%的患者中，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，甚至可能在医生第一次诊断出患者患有癌症之前。葡萄膜黑色素瘤转移的两个方面是不寻常的：（i）它们几乎总是在肝脏中发展，（ii）在发展之前可能会延迟多年。本研究的最终目标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如何离开眼睛，进入血管，然后在肝脏中形成肿瘤。我们正在开发一种新的动物模型，使我们能够跟踪肿瘤细胞在体内的运动。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遗传修饰来实现的，这样它们就可以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原因导致细胞离开眼睛，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，以使肝脏肿瘤的发展。第一个事件是建立了一小部分肿瘤细胞，称为“肿瘤起始细胞”。尽管所有的肿瘤细胞都增殖，但只有“肿瘤起始细胞”的子集可以无限期地增殖，并具有形成新肿瘤的能力。因此，如果你去除了“肿瘤起始细胞”，那么剩下的肿瘤细胞最终会死亡，无需任何进一步的治疗。这被称为“肿瘤消退”。第二个事件是一种称为“中期因子”的蛋白质被释放出来，它促进了这一小部分癌症起始细胞的增殖和存活。如果癌症起始细胞缺乏“中期因子”蛋白，它们将无法存活，肿瘤将消退。我们的实验将使用方法来消除：癌症起始细胞，中期因子表达，或两者（起始细胞和中期因子）。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为治疗致命性肝转移患者确定新的靶点。

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.