When mice with human tumors received doses of anti-CD47, which sets the immune system against tumor cells, the cancers shrank and disappeared. 當(dāng)患上人類腫瘤的老鼠接受一定劑量的抗CD47時，抗CD47就會使免疫系統(tǒng)抗擊腫瘤細(xì)胞，使癌癥病灶縮小，直至消失。
by Sarah C. P. Williams 胡德良 譯
| A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a "do not eat" signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. | 研究人員發(fā)現(xiàn)，一種藥物可以縮小或消除移植到老鼠身上的人類腫瘤，包括乳腺瘤、卵巢瘤、結(jié)腸瘤、膀胱瘤、腦瘤、肝臟瘤和前列腺瘤等。該療法使用的是一種抗體，這種抗體可以阻斷腫瘤細(xì)胞上正常展示出來的“不許吃我”信號，誘使免疫系統(tǒng)摧毀癌細(xì)胞。 |
| A decade ago, biologist Irving Weissman of the Stanford University School of Medicine in Palo Alto, California, discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47, he and other scientists found, is also displayed on healthy blood cells; it's a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, Weissman's lab showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, he and colleagues have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers. | 十年前，加州帕洛阿爾托市斯坦福大學(xué)醫(yī)學(xué)院的生物學(xué)家歐文·魏斯曼發(fā)現(xiàn)：比起健康細(xì)胞，白血病細(xì)胞可以產(chǎn)生更多被稱為CD47的蛋白質(zhì)。魏斯曼和其他科學(xué)家還發(fā)現(xiàn)：健康的血細(xì)胞中也有CD47；當(dāng)隨著血液循環(huán)時，CD47就成為一種標(biāo)志物，標(biāo)志著它們可以阻礙免疫系統(tǒng)將癌細(xì)胞摧毀。各種癌癥利用CD47這面旗來欺騙免疫系統(tǒng)，使免疫系統(tǒng)忽視癌細(xì)胞的存在。在過去的幾年中，魏斯曼的實驗證明：利用一種阻斷CD47的抗體，可以刺激免疫系統(tǒng)，使免疫系統(tǒng)將癌細(xì)胞當(dāng)作入侵細(xì)胞，這樣能夠治愈一些淋巴瘤和白血病病例?，F(xiàn)在，魏斯曼及同事業(yè)已證實，阻斷CD47的抗體可能遠(yuǎn)遠(yuǎn)不只是對血癌有影響。 |
| "What we've shown is that CD47 isn't just important on leukemias and lymphomas," says Weissman. "It's on every single human primary tumor that we tested." Moreover, Weissman's lab found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. | “我們所證實的是：CD47不僅僅對于白血病和淋巴瘤是關(guān)鍵的，”魏斯曼說，“它對于我們測試過的每一種人類主要腫瘤都很關(guān)鍵?！贝送?，魏斯曼的實驗還發(fā)現(xiàn)，癌細(xì)胞總是比健康細(xì)胞擁有更高水平的CD47。一種腫瘤產(chǎn)生CD47的多少可以用來預(yù)測一個病人存活的幾率有多大。 |
| To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the anti-CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types. | 為了確定阻斷CD47是否有益，科學(xué)家們將腫瘤細(xì)胞和巨噬細(xì)胞（一種免疫細(xì)胞）以及抗CD47 分子一起放在培養(yǎng)皿中。在沒有抗CD47分子的情況下，巨噬細(xì)胞就會忽視癌細(xì)胞的存在；當(dāng)抗CD47存在的時候，巨噬細(xì)胞就會吞噬并摧毀來自各種腫瘤的癌細(xì)胞。 |
| Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment -- colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped. | 接下來，研究小組將人類腫瘤移植到老鼠的腳部，因為這個部位的腫瘤監(jiān)視起來很方便。當(dāng)研究人員利用抗CD47來治療這些老鼠之后，腫瘤出現(xiàn)萎縮，并且沒有擴散到身體的其他部位。拿接受人類膀胱腫瘤移植的老鼠來說：十個沒有接受治療的老鼠，癌細(xì)胞都擴散到淋巴結(jié)；在接受抗CD47治療的十個老鼠中，只有一個老鼠的淋巴結(jié)擁有癌癥的跡象。此外，接受治療之后，移植的腫瘤通常會變小——移植到老鼠身上的結(jié)腸癌腫瘤平均萎縮到不到原來大小的三分之一。在五個接受乳腺癌腫瘤移植的老鼠中，經(jīng)抗CD47治療之后，消除了所有的癌細(xì)胞跡象，而且治療停止4個月之后，仍然沒有罹患癌癥。 |
| "We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis," says Weissman. | “我們證實，即使在腫瘤形成之后，這種抗體要么可以治愈腫瘤，要么延緩腫瘤的生長并防止轉(zhuǎn)移，”魏斯曼說。 |
| Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences. | 今天，研究小組在《美國國家科學(xué)院院刊》在線版上報道說：老鼠接受抗體治療之后，盡管巨噬細(xì)胞也攻擊表達(dá)CD47的血細(xì)胞，但是研究人員發(fā)現(xiàn)血細(xì)胞降低的情況是短暫的。事實證明，老鼠可以產(chǎn)生新的血細(xì)胞來替代治療中損失的血細(xì)胞。 |
| Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. "The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor," he notes, "and it's possible that a real tumor has additional immune suppressing effects." | 劍橋市麻省理工學(xué)院的癌癥研究人員泰勒·杰克斯稱，盡管這項新研究帶來了很大希望，但是仍然需要進行更多的研究，以便確定這些研究結(jié)果是否同樣適用于人類?！耙活w真正腫瘤的微環(huán)境比移植腫瘤的微環(huán)境要復(fù)雜得多，”他指出，“真正腫瘤可能有著另外的免疫抑制效應(yīng)?！?/span> |
| Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. "In what ways might they work together and in what ways might they be antagonistic?" Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. | 杰克斯表示，另一個問題是CD47抗體將會如何跟現(xiàn)存的治療方法形成互補：“在哪些方面可能是相輔相成的？在哪些方面可能是互相對抗的？”例如，如果化療帶來的緊張情緒會引起正常細(xì)胞比平時產(chǎn)生更多的CD47，那么除了利用化療之外再利用抗CD47就可能達(dá)不到預(yù)期效果了。 |
| Weissman's team has received a $20 million grant from the California Institute for Regenerative Medicine to move the findings from mouse studies to human safety tests. "We have enough data already," says Weissman, "that I can say I'm confident that this will move to phase I human trials." | 魏斯曼的研究小組從加州再生醫(yī)學(xué)研究所得到了2000萬美元的資助，準(zhǔn)備將研究老鼠的發(fā)現(xiàn)應(yīng)用到人類安全試驗中來?！拔覀円呀?jīng)掌握了足夠的資料，”魏斯曼說，“我對展開第一期人體試驗很有信心！” |
原著：Sarah C. P. Williams
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