Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
J Surg Res. 2013 Oct;184(2):755-60. doi: 10.1016/j.jss.2013.03.035. Epub 2013 Apr 6.
Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers, including colorectal cancer (CRC). PTEN is involved in negatively regulating the phosphatidylinositol 3-kinase/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model.
Green fluorescent protein labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination.
Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared with the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs (P = 0.02).
Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and, thus, efforts to target the phosphatidylinositol 3-kinase/PTEN pathway are legitimate.
肿瘤抑制因子磷酸酶和张力蛋白同源物缺失于染色体 10（PTEN）的突变性丢失与许多癌症（包括结直肠癌（CRC））的恶性进展相关。PTEN 参与负向调节磷脂酰肌醇 3-激酶/AKT 致癌信号通路，并与转移定植过程有关。目前可用的体内模型很少用于研究 CRC 转移。本研究旨在确定在原位小鼠模型中恢复 PTEN 活性对转移的影响。
绿色荧光蛋白标记的 TENN 是一种高度转移性的人结肠癌细胞系，其 PTEN 基因突变缺失，并且 TENN 克隆（PTEN 基因恢复）肿瘤被原位植入 BALB/c 裸鼠的结肠中，并允许形成原发性和转移性肿瘤。植入后 7 周，处死小鼠并提取器官进行检查。
TENN 和 TENN 克隆细胞系均表现出 100%的原发性侵袭。然而，与显示 62%肺部和肝脏转移的亲本 TENN 细胞相比，TENN 克隆细胞的转移率降低了约 50%，只有 31.6%的肝脏转移，没有肺转移（P=0.02）。
我们的研究表明，PTEN 肿瘤抑制途径的再激活导致 CRC 转移减少 50%，而不影响原发性肿瘤的形成。重要的是，PTEN 恢复也改变了器官嗜性，从肝和肺转移到仅肝转移。这项体内研究表明，PTEN 可能特异性地作为转移抑制因子发挥作用，因此，靶向磷脂酰肌醇 3-激酶/PTEN 途径的努力是合理的。
