《Nature》癌症复发源自免疫背叛

　　

生物通报道，加州大学医学院基因调节与信号转导实验室，Scripps研究所癌症生物学系，俄罗斯Engelhardt研究所分子生物学系分子免疫学实验室的科学家们在最新的一期Nature上发布癌症复发研究新进展文章B-cell-derived lymphotoxin promotes castration-resistant prostate cancer。

 

癌症研究多年来，各种各样的癌症治疗手段都取得了突破性的发展，遗憾的是，癌症复发仍旧是困扰全球医生和患者的问题，一旦复发患者预后情况恶劣。所以，在癌症研究领域中，寻求癌症复发机理变得十分重要。

 

在前列腺癌的治疗过程中，常常要接受大量的激素进行治疗，用于抑制睾丸激素的分泌以防止睾丸激素刺激前列腺癌细胞生长，但大量的研究发现，激素治疗的方式往往导致更为剧烈的癌症复发情况发生，并且导致更严重的后果。

 

研究人员以小鼠为模型，对这一情况进行深入的分析，结果发现，激素疗法可诱发前列腺炎症，众所周知，炎症过程会吸引大量的免疫B细胞进入炎症灶，在清除炎症有害物的过程中，免疫B细胞释放出大量的细胞因子。

 

这些炎症诱发分泌的细胞因子包括，Ikkβ，NF-kB，这些细胞因子具有促进癌细胞生长的能力。这也是长期炎症诱发癌症的机理之一。

 

所以说，当激素疗法诱发前列腺炎时，大量的细胞因子被分泌出来，重新激活已经被抑制的癌细胞。

 

科学家们发现，如果可以抑制体内细胞因子的分泌，那么试验鼠可延长寿命3-4周，相当于人类的2-3年。

（生物通 小茜）

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B-cell-derived lymphotoxin promotes castration-resistant prostate cancer

Massimo Ammirante1,4, Jun-Li Luo2,4, Sergei Grivennikov1, Sergei Nedospasov3 & Michael Karin1

 

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA

Scripps Research Institute-Florida, Department of Cancer Biology, 130 Scripps Way, Jupiter, Florida 33458, USA

Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, 119991, Moscow, Russia

These authors contributed equally to this work.

Correspondence to: Michael Karin1 Correspondence and requests for materials should be addressed to M.K. (Email: [e-mail]).

 

【Abstract】

Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma1. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality2. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months2. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice3. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth4. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer5. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells6. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment7, 8, 9, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production10. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism11. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.

 

最新PNAS解析炎症可能给肝癌的复发“火上浇油”

 

来自以色列Hadassah希伯来大学医学中心，Goldyne Savad基因疗法研究所的科学家在最新一期的PNAS上发表研究论文，解析炎症与肝癌复发的关键联系。

  

研究小组发现，慢性炎症可能是肝癌术后复发的罪魁祸首一。目前切除手术仍然是治疗实体肿瘤的主要手段，也是优选方法，因为这肝脏可以在广泛受损或切除后再生恢复功能。

  

Rinat Abramovitch及其同事发现，慢性肝炎可能促使术后细胞分裂复制，部分在手术过程中受损的细胞也会进入分裂期，这些受损的细胞（DNA可能断裂）可能已经是癌变前体细胞，受到炎症刺激后继续癌变最后分裂为癌症细胞。

  

科学家研究了一个突变的小鼠，突变基因能促进导致肝癌的慢性炎症发生。科学家发现，这种炎症导致了DNA的双链破损的增加，而这会让细胞更容易变成癌细胞。随着手术后这些分裂的细胞重新生长，它们逃避了通常会清除受损细胞的正常抗体应答。研究者认为，抑制炎症的疗法以及手术后帮助修复DNA的药物治疗方案有可能帮助预防肝癌的复发。