Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer
Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer
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DOI：
10.1007/s11302-011-9228-9
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Robson, Simon C.
中科院分区：
文献类型：
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作者：
Kuenzli, Beat M.;Bernlochner, Maria-Isabell;Robson, Simon C.
尽管结直肠癌（CRC）的预防和管理有所改善，但不受控制的肿瘤生长并转移到远处器官仍然是一个重要的临床问题。CD39是主要的血管和免疫细胞外核苷酶，基因缺失已被证明可以延缓黑色素瘤、肺和结肠恶性肿瘤小鼠模型的肿瘤生长和血管生成。在这里，我们通过研究野生型BALB/c、人CD39转基因和CD39缺陷小鼠的原位移植和转移癌模型，来检测CD39对CRC肿瘤进展和转移的影响。我们还研究了人类结直肠癌活检中CD39和P2受体的表达模式。小鼠CD39通过内皮细胞、间质细胞和单核细胞浸润到实验性MC-26肿瘤中表达。在原发性结直肠癌模型中，尽管这些肿瘤很少转移到肝脏，但在第10天，结肠和/或直肠浆膜下的肿瘤体积在治疗组之间没有差异。在播散模型中，与CD39缺失小鼠相比，在CD39过表达转基因小鼠中，MC-26细胞系衍生的肝转移瘤生长明显更快。小鼠P2Y2 mRNA和蛋白水平均显著升高，在CD39转基因小鼠获得的较大肝转移灶中，P2X7水平也发生了变化。在临床样本中，恶性结直肠癌组织中较低水平的CD39 mRNA似乎与较长的生存期有关，并且可能与侵袭性较小的肿瘤有关。CD39对肿瘤播散的调节作用以及肿瘤中CD39、P2Y2和P2X7表达水平的差异表明嘌呤能信号参与了这些过程。我们的研究也提示基于嘌呤能的治疗在临床结直肠癌中的潜在作用。
Despite improvements in prevention and management of colorectal cancer (CRC), uncontrolled tumor growth with metastatic spread to distant organs remains an important clinical concern. Genetic deletion of CD39, the dominant vascular and immune cell ectonucleotidase, has been shown to delay tumor growth and blunt angiogenesis in mouse models of melanoma, lung and colonic malignancy. Here, we tested the influence of CD39 on CRC tumor progression and metastasis by investigating orthotopic transplanted and metastatic cancer models in wild-type BALB/c, human CD39 transgenic and CD39 deficient mice. We also investigated CD39 and P2 receptor expression patterns in human CRC biopsies. Murine CD39 was expressed by endothelium, stromal and mononuclear cells infiltrating the experimental MC-26 tumors. In the primary CRC model, volumes of tumors in the subserosa of the colon and/or rectum did not differ amongst the treatment groups at day 10, albeit these tumors rarely metastasized to the liver. In the dissemination model, MC-26 cell line-derived hepatic metastases grew significantly faster in CD39 over-expressing transgenics, when compared to CD39 deficient mice. Murine P2Y2 was significantly elevated at both mRNA and protein levels, within the larger liver metastases obtained from CD39 transgenic mice where changes in P2X7 levels were also noted. In clinical samples, lower levels of CD39 mRNA in malignant CRC tissues appeared associated with longer duration of survival and could be linked to less invasive tumors. The modulatory effects of CD39 on tumor dissemination and differential levels of CD39, P2Y2 and P2X7 expression in tumors suggest involvement of purinergic signalling in these processes. Our studies also suggest potential roles for purinergic-based therapies in clinical CRC.