阐明炎症和结肠癌转移之间的密切关联

  发表在国际杂志Gastroenterology上的一项研究论文中，来自亚利桑那州立大学的研究人员通过研究首次揭示了炎症如何触发结肠癌细胞扩散到其它器官或发生转移，该研究或可帮助研究人员寻找靶向药物来预防和治疗结肠癌。
  研究者DuBois说道，我们很早就知道一些看似简单的事情，比如服用阿司匹林或其他抗炎性药物对于降低结直肠癌具有有益的效应，但是一些非阿司匹林的非类固醇性抗炎药物往往会引发严重的心血管副作用，因此我们需要开发新型的靶向药物。本文研究为开发新型有效的结直肠癌疗法及筛选技术提供了一定技术；当前几乎有一半恶性结直肠癌患者在接受治疗后的5年内都会死亡，其中一个原因就是癌症已经产生了化疗耐受性，但有些研究证据却显示炎症和炎症介质或许在肿瘤转移过程中扮演着重要角色。
  本文研究中，研究者揭示了结肠癌肿瘤如何“欺骗”宿主，利用炎性介值将癌症干细胞扩散到机体其它器官中，研究者发现，促炎性介导子前列腺素E2和结直肠癌癌症干细胞的水平增加直接相关；而癌症是一种由多种不同细胞类型组成的混合体，某些细胞，比如癌症干细胞则被认为是癌症开始、生长、恶化及复发的罪魁祸首。
  前列腺素E2是一种含量丰富的促炎性生物活性脂质，其主要存在于多种癌症中，比如肺癌、头颈癌、乳腺癌等，当在癌症中发现较高水平的前列腺素E2，就意味着患者会表现出预后不良；正常情况下前列腺素E2可以起到机体救援的作用，其可以吸引免疫细胞，刺激多种途径来愈合伤口；但在癌症中，癌细胞会使得前列腺素E2长期存在，就好象伤口永远不会愈合一样，以便产生多种癌症干细胞来促进癌症进展及转移。
  本文研究中研究者发现，当前列腺素E2结合癌细胞表面的受体4时（EP4），其就会诱发信号级联反应促进癌症干细胞更新、分化们最终对化疗产生耐受性。而研究者利用多种方法，即利用人类组合和小鼠模型来开展研究，首先他们从结肠癌患者机体中提取样本，并且纯化癌症干细胞，当利用前列腺素E2处理癌症干细胞时研究者发现，相比不利用前列腺素E2处理的细胞而言，处理后的癌症干细胞的转移特性是前者的1000倍。
  此外，研究者在人类结肠癌组织样本中也发现了前列腺素E2水平的升高及癌症干细胞水平的增加，当研究者通过添加抑制EP4受体的药物来阻断前列腺素E2的信号通路时，就可以有效降低结肠息肉及癌症干细胞的产生，进而阻断癌症的转移；研究者指出，如果可以靶向作用并且消除结肠癌患者机体的癌症干细胞，那么就可以开发出一种新型疗法来治疗患者并且改善其治疗预后。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice
Gastroenterology        doi: 10.1053/j.gastro.2015.07.064
Wang D1, Fu L1, Sun H1, Guo L1, DuBois RN2.
BACKGROUND & AIMS:
Inflammation may contribute to formation, maintenance, and expansion of cancer stem cells (CSCs), which have the capacity for self-renewal, differentiation, and resistance to cytotoxic agents. We investigated the effects of the inflammatory mediator prostaglandin E2 (PGE2) on colorectal CSC development and metastasis in mice and the correlation between levels of PGE2 and CSC markers in human colorectal cancer (CRC) specimens.
METHODS:
Colorectal carcinoma specimens and matched normal tissues were collected from patients at the Mayo Clinic (Scottsdale, AZ) and analyzed by mass spectrometry and quantitative PCR. Human primary CRC cells and mouse tumor cells were isolated using microbeads and flow cytometry and analyzed in sphere-formation and flow cytometry assays. LS-174T cells were sorted by flow cytometry (for CD133+CD44+ and CD133-CD44- cells) and also used in these assays. NSG mice were given cecal or subcutaneous injections of LS-174T or human primary CRC cells. ApcMin/+ mice and NSG mice with orthotopic cecal tumors were given vehicle (controls), PGE2, celecoxib, or/and Ono-AE3-208. PGE2 downstream signaling pathways were knocked down with small hairpin RNAs, expressed from lentiviral vectors in LS-174T cells, or blocked with inhibitors in human primary CRC cells.
RESULTS:
Levels of PGE2 correlated with colonic CSC markers (CD133, CD44, LRG5, and SOX2 mRNAs) in human colorectal carcinoma samples. Administration of PGE2 to ApcMin/+ mice increased tumor stem cells and tumor burden, compared with controls. NSG mice given PGE2 had increased numbers of cecal CSCs and liver metastases, compared with controls, after intracecal injection of LS-174T or human primary CRC cells. Alternatively, celecoxib, an inhibitor of prostaglandin-endoperoxide synthase 2 (PTGS2 or COX2), reduced polyp numbers in ApcMin/+ mice, liver metastasis in NSG mice with orthotopic tumors, and numbers of CSCs in ApcMin/+ and NSG mice. Inhibitors or knockdown of PGE receptor 4 (PTGER4 or EP4), PI3K p85α, ERK1, or nuclear factor (NF)-κB reduced PGE2-induced sphere formation by and expansion of LS-174T and/or human primary CRC cells. Knockdown of ERK1 or PI3K p85α also attenuated PGE2-induced activation of NF-κB in LS-174T cells. An EP4 antagonist reduced the ability of PGE2 to induce CSC expansion in orthotopic tumors and to accelerate formation of liver metastases. Knockdown experiments showed that NF-κB was required for PGE2 induction of CSCs and metastasis in mice.
CONCLUSIONS:
PGE2 induces CSC expansion by activating NF-κB, via EP4-PI3K and EP4-MAPK signaling, and promotes formation of liver metastases in mice. The PGE2 signaling pathway might therefore be targeted therapeutically to slow colorectal cancer progression.