Liver and Transplantation Centers, Beth Israel Deaconess Medical Center, Harvard University, Boston, USA,
Purinergic Signal. 2011 Jun;7(2):231-41. doi: 10.1007/s11302-011-9228-9. Epub 2011 Apr 2.
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.
尽管结直肠癌（CRC）的预防和治疗有所改善，但肿瘤的失控生长和转移性扩散到远处器官仍然是一个重要的临床关注点。在黑色素瘤、肺癌和结肠恶性肿瘤的小鼠模型中，已经证明 CD39 的基因缺失，即主要的血管和免疫细胞外核苷酸酶，可延迟肿瘤生长并减弱血管生成。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性癌症模型，测试了 CD39 对 CRC 肿瘤进展和转移的影响。我们还研究了人 CRC 活检中 CD39 和 P2 受体表达模式。鼠 CD39 表达于实验性 MC-26 肿瘤的内皮细胞、基质细胞和单核细胞浸润。在原发性 CRC 模型中，第 10 天，结肠和/或直肠浆膜下的肿瘤体积在各组之间没有差异，尽管这些肿瘤很少转移到肝脏。在播散模型中，与 CD39 缺陷小鼠相比，MC-26 细胞系衍生的肝转移在 CD39 过表达转基因小鼠中生长明显更快。在从 CD39 转基因小鼠获得的更大的肝转移中，鼠 P2Y2 的 mRNA 和蛋白水平均显著升高，并且还注意到 P2X7 水平的变化。在临床样本中，恶性 CRC 组织中 CD39 mRNA 水平较低似乎与更长的生存时间有关，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在这些过程中的参与。我们的研究还表明，基于嘌呤的治疗在临床 CRC 中可能具有潜在作用。
