《生物学通讯》：癌症干细胞疗法新进展

资讯来源：University of Copenhagen

编辑翻译：菁菁

译文校对：奇奇

本文献于2021年5月首次发表在最新的《生物学通讯》（Communications Biology),介绍了关于干细胞疗法的新进展。

得益于科罗拉多大学癌症中心的研究人员所做的工作，癌症医生可能很快就会拥有一种用于治疗黑色素瘤和其他类型癌症的新武器。

免疫系统由一个个细胞系统组成，总是忙于应对即将到来的威胁。当细胞缺乏时，免疫系统的性能就会受到影响。

例如，在化疗后的癌症患者中可以看到这一情况。化疗靶向患者体内的所有细胞，包括骨髓中的干细胞。这些细胞原本可以发育成新的免疫细胞，但在化疗后受到损伤。这意味着免疫系统在对抗新感染时会缺乏细胞。

有些药物可以从骨髓中提取干细胞，以便于在治疗后重新移植给患者。这些干细胞发育成新的免疫细胞，从而使身体能够再次对抗即将到来的威胁。但以前，我们缺乏对这些药物作用机制的详细了解。

现在，哥本哈根大学的研究人员在小鼠身上进行的一项研究展示了该药物如何在细胞水平上发挥作用。研究人员应用和测试了两种药物。书面研究显示一种药物更为有效，而测试结果则支持另一种药物更加有效。这一发现可能不仅有助于改善干细胞移植，也可能有助于未来的药物改进。

哥本哈根大学生物医学科学系的博士Astrid Sissel Jorgensen说：“我们已经测试了两种用于干细胞移植的药物，它们似乎具有相同的效果。它们的作用是阻断受体，使骨髓将干细胞释放到血液中。不过，新研究表明它们的作用并不局限于阻断受体。这两种细胞中的一种还会影响细胞中的其他信号通路。简而言之，这使它比另一种药物更为有效。”

她还说：“我们过去认为，我们所要做的就是阻断受体，而这两种药物具有相同的效果。现在看来，其中一种还有更多的作用。”

研究人员测试的药物通过充当CXCR4受体拮抗剂来动员干细胞。这意味着它们能够抑制或降低受体的活性。有几种药物靶向该受体，包括了抑制HIV复制的药物。

“这些药物不仅会阻断受体的正常信号传导。我们测试过的两种药物中的一种还会影响其他一些细胞通路，甚至使受体退回细胞并从表面消失，”研究的通讯作者Mette Rosenkilde教授解释说。研究结果表明，这两种药物中的一种会使骨髓释放更多的干细胞进入血液。

这种关于药物如何以不同方式影响细胞通路的信息，被称为偏向性信号。这让其中一种药物在实践中比理论上更有效。

据研究人员称，关于偏向性信号的新知识挑战了当前对这些药物的看法。

“研究结果直接影响了我们对干细胞移植药物的看法。从长远来看，它也可能影响我们对未来药物的看法，以及如何设计新药以达到最佳效果。两者都与干细胞动员有关，也用于治疗 HIV 感染，其中这种特殊受体起着主要作用，”Mette Rosenkilde说。 

英语原文

Stem cell drugs surprise researchers, could lead to better drugs in the future

Your immune system is always busy fighting incoming threats. It consists of a system of cells, and when there is a shortage of cells, it affects the performance of the immune system.

This is seen, for example, in cancer patients following chemotherapy. This is because chemotherapy targets all the cells in your body, including the stem cells in your bone marrow, which were meant to develop into new immune cells. This means that the immune system then lacks cells to fight new infections.

There are drugs that can harvest stem cells from the bone marrow, so that they can be returned to the patients after treatment. They then develop into new immune cells, enabling the body to once again fight incoming threats. But previously, we lacked detailed knowledge of how these drugs worked.

Now, a study conducted in mice by researchers at the University of Copenhagen demonstrates how the medicine works at the cell level—and, surprisingly, how one of the two applied and tested drugs is more effective than the other, despite the fact that the other drug, on paper, appears to be the most effective of the two. This discovery may not just help improve stem cell transplantation; it may also lead to improved drugs in the future.

"We have tested two drugs for stem cell transplantation which appear to have the same effect. What they do is block a receptor, causing the bone marrow to release stem cells into the blood. What the new study shows, though, is that they do not just block the receptor; one of the two drugs also affects other signaling pathways in the cell. And in short, that makes it more effective than the other of the two drugs," says Ph.D. Student Astrid Sissel Jørgensen from the Department of Biomedical Sciences at the University of Copenhagen.

"We used to believe that all we had to do was block the receptor, and that the two drugs had the same effect. It now appears that there is more to it," she says.

The drugs tested by the researchers mobilize stem cells by acting as CXCR4 receptor antagonists. This means that they inhibit or reduce activity of the receptor. Several drugs target this receptor, including drugs inhibiting HIV replication.

"The drugs not only block the receptor's normal signaling. One of the two drugs we have tested also affect some of the other cell pathways and even make the receptor withdraw into the cell and disappear from the surface," explains Professor Mette Rosenkilde, who is the corresponding author of the study. The study results reveal that one of the two drugs makes the bone marrow release more stem cells into the blood.

This knowledge about how drugs affect cell pathways differently is also known as biased signaling. And it is things like these that make one of the drugs more effective in practice than on paper.

According to the researchers, the new knowledge on biased signaling challenges our current view of these drugs.

"The results of our study directly influence our view of drugs used for stem cell transplantation. In the long term, though, it may also affect our view of future drugs, and how new drugs should be designed to have the best possible effect, both in connection with stem cell mobilization, but also for treating HIV infections, where this particular receptor also plays a main role," says Mette Rosenkilde.

参考文献

Astrid S. Jørgensen et al, Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization, Communications Biology (2021).

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