单基因修复让小鼠结直肠癌细胞转变回正常组织

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http://www.sciencedaily.com/releases/2015/06/150618134241.htm& b: J1 w3 W3 l/ B1 n9 ]# ^8 ?5 f4 T' ]
Single gene turns colorectal cancer cells back into normal tissue in mice
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6 O) y; O+ b) L) H5 X+ x1 JJune 18, 2015) L2 J( ~( X* y- d% w$ B# {
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Cell Press
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) ?! u+ `4 l1 S4 L8 Y/ t* h+ DAnti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene. Researchers found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only four days.; a# s0 H% j$ m. [. {* G
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FULL STORY
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Lab mouse (stock image). Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene, according to a study that found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only 4 days. Remarkably, tumors were eliminated within 2 weeks, and signs of cancer were prevented months later.1 P/ j2 e6 w' p+ D( {
Credit: © mgkuijpers / Fotolia/ u" `9 u2 q( e7 w/ E
Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene, according to a study published June 18th in the journal Cell. Researchers found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only 4 days. Remarkably, tumors were eliminated within 2 weeks, and signs of cancer were prevented months later. The findings provide proof of principle that restoring the function of a single tumor suppressor gene can cause tumor regression and suggest future avenues for developing effective cancer treatments.
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Colorectal cancer is the second leading cause of cancer-related death in developed countries, accounting for nearly 700,000 deaths worldwide each year. "Treatment regimes for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective, yet have remained the backbone of therapy over the last decade," says senior study author Scott Lowe of the Memorial Sloan Kettering Cancer Center.2 p; B# F7 c3 s2 l. S

- S8 @/ c% E& M# r4 p* L3 cUp to 90% of colorectal tumors contain inactivating mutations in a tumor suppressor gene called adenomatous polyposis coli (Apc). Although these mutations are thought to initiate colorectal cancer, it has not been clear whether Apc inactivation also plays a role in tumor growth and survival once cancer has already developed.
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"We wanted to know whether correcting the disruption of Apc in established cancers would be enough to stop tumor growth and induce regression," says first author Lukas Dow of Weill Cornell Medical College. This question has been challenging to address experimentally because attempts to restore function to lost or mutated genes in cancer cells often trigger excess gene activity, causing other problems in normal cells.
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4 d# T1 Z9 m, |# `. Y' B0 i; FTo overcome this challenge, Lowe and his team used a genetic technique to precisely and reversibly disrupt Apc activity in a novel mouse model of colorectal cancer. While the vast majority of existing animal models of colorectal cancer develop tumors primarily in the small intestine, the new animal model also developed tumors in the colon, similar to patients. Consistent with previous findings, Apc suppression in the animals activated the Wnt signaling pathway, which is known to control cell proliferation, migration, and survival.
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9 ]4 q( D, Y& k. U6 k0 p0 O  [When Apc was reactivated, Wnt signaling returned to normal levels, tumor cells stopped proliferating, and intestinal cells recovered normal function. Tumors regressed and disappeared or reintegrated into normal tissue within 2 weeks, and there were no signs of cancer relapse over a 6-month follow-up period. Moreover, this approach was effective in treating mice with malignant colorectal cancer tumors containing Kras and p53 mutations, which are found in about half of colorectal tumors in humans.
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: P5 j" T( x& [: j" wAlthough Apc reactivation is unlikely to be relevant to other types of cancer, the general experimental approach could have broad implications. "The concept of identifying tumor-specific driving mutations is a major focus of many laboratories around the world," Dow says. "If we can define which types of mutations and changes are the critical events driving tumor growth, we will be better equipped to identify the most appropriate treatments for individual cancers."
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3 [( M/ ^3 _/ P. e8 ^2 ]5 \) vFor their own part, Lowe and his team will next examine the consequences of Apc reactivation in tumors that progress beyond local invasion to produce distant metastases. They will also continue to investigate why Apc is so effective at suppressing colon tumor growth, with the goal of one day mimicking this effect with drug treatments.# b/ ]3 U/ `; i/ `; e" u. {, w
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"It is currently impractical to directly restore Apc function in patients with colorectal cancer, and past evidence suggests that completely blocking Wnt signaling would likely be severely toxic to normal intestinal cells," Lowe says. "However, our findings suggest that small molecules aimed at modulating, but not blocking, the Wnt pathway might achieve similar effects to Apc reactivation. Further work will be critical to determine whether WNT inhibition or similar approaches would provide long-term therapeutic value in the clinic."' e5 B( D; c5 S; e7 M% I" S; Q, P

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The above post is reprinted from materials provided by Cell Press. Note: Materials may be edited for content and length." v. y) J* M# X4 P8 F6 R

( n* M1 x2 s/ W1 P! cJournal Reference:, h( h, p; m: d7 B+ h6 s  {3 B9 w
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Lukas E. Dow, Kevin P. O’Rourke, Janelle Simon, Darjus F. Tschaharganeh, Johan H. van Es, Hans Clevers, Scott W. Lowe. Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer. Cell, 2015; 161 (7): 1539 DOI: 10.1016/j.cell.2015.05.033
8 l' i! f1 E. t4 n3 i& z7 }. a单基因修复让小鼠结直肠癌细胞转变回正常组织7 Z$ m! c! H3 k$ j

$ @  }) P6 y+ a! D% _4 W( p& X抗癌的常规策略是杀死肿瘤细胞。然而，最近的研究发现癌细胞可能通过重新激活一个基因被诱导变回正常的组织细胞，相关报道发表在6月18的Cell杂志上。研究人员发现，在小鼠结直肠癌细胞中维持正常水平的人类结肠癌抑制基因四天，可以让肿瘤细胞停止生长，重新建立正常的肠道功能。需要注意的是，肿瘤是在2周内消除的，癌症的迹象数月后消失。该发现不仅为相关原理探索提供线索，即恢复单个肿瘤抑制基因的功能可能会使肿瘤消退，也有助于未来开发有效的癌症治疗方法。
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在发达国家中结直肠癌是死亡率第二高的癌症，每年导致全球约70万人的死亡。senior study author Scott Lowe of the Memorial Sloan Kettering Cancer Center说：”目前对于晚期结直肠癌主要采取的手段是组合化疗，但这些药物大多数是高毒但低效的，但这种主流治疗措施已经被沿用十几年了。
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. {' y" P* s  ?2 O- q' B) n高达90％的结肠直肠肿瘤细胞中存在（adenomatous polyposis coli）APC基因突变，导致基因活性丧失，这是一个抑癌基因。虽然知道这些突变可能引发结肠直肠癌，但尚未明确APC的失活在肿瘤形成后的维持和生长中所起的作用。 first author Lukas Dow of Weill Cornell Medical College说：“我们想知道在已经形成的癌症细胞中恢复APC的活性是否可以阻止肿瘤的生长并诱导细胞恢复”这个问题在实验上是非常具有挑战性的，因为在癌细胞中试图恢复功能丢失或突变的基因活性往往会引发其他基因的活性，导致正常细胞出现其他的问题。为了克服这一难题，Lowe和他的团队使用精确的遗传修饰技术可逆地破坏APC活度，建立新的结直肠癌小鼠模型。以往绝大多数的结大肠癌动物模型出现肿瘤的部位主要小肠，但新的动物模型在结肠也出现肿瘤，类似于患者中的现象。与以前的研究结果相识，抑制APC活性会激活动物的Wnt信号通路，众所周知这个信号通路控制细胞的增殖，迁移和存活。5 i& U7 q7 O8 }, C# u

3 R5 ~) p8 Q3 m6 u当APC重新被激活后，Wnt信号恢复到正常水平，肿瘤细胞停止增殖，肠细胞恢复正常功能。在2周内肿瘤消退，消失或重新融入到正常组织中，并且超过6个月小鼠肿瘤没有复发迹象。此外，这种方法可以有效治疗小鼠中含有Kras 和 p53突变的恶性结直肠癌，这两个突变被发现存在于越一半的人类结直肠癌患者中。
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虽然APC重新不太可能用于其他类型的癌症研究，但相关的实验方法可以被广泛应用。 Dow说：“世界各地许多实验室的一大研究重点是发现各种肿瘤的特异性基因突变，如果我们可以发现特定肿瘤中哪些关键基因的突变导致了肿瘤的生长，我们将能够针对特定癌症制定最合适的治疗方法。”
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对于他们的研究，Lowe和他的团队下一步将研究APC重新激活对转移肿瘤的作用。同时他们也将继续研究APC抑制结直肠肿瘤生长的机理，希望将来可以用于临床治疗。
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Lowe 说“目前直接恢复病人结直癌细胞APC的活性是不切实际，过去的研究也表明，彻底阻断Wnt信号可能会对正常肠道细胞产生严重的毒副作用。
/ \, r4 U- Z. e8 s6 {然而，我们的研究结果表明，使用小分子进行调节而不是抑制Wnt信号通路，可能可以达到类似APC重新激活的效果。下一步的工作将是至关重要的，需要确定抑制WNT或类似的方法是否具有用于长期临床治疗的价值。”+ c5 a0 R0 O( I) {0 A. }
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