Human Colon Cancer

结肠腺癌是世界范围内癌症死亡的主要原因，在美国每年约有50，000人死亡。需要改进结肠直肠癌（CRC）的早期检测筛查方法。如果早期发现，CRC是高度可治愈的。结肠镜检查是一种可靠和准确的筛查工具，但其高成本和侵入性导致筛查率降低。另一方面，粪便潜血试验（FOBT）侵入性较小，价格较低，甚至已被证明可以减少CRC引起的死亡;1但FOBT有限的灵敏度和特异性使其成为检测CRC的不太理想的筛查方法。许多研究人员正试图确定非侵入性筛查方法，如血液检测或粪便DNA检测，2以改善CRC的早期检测，以减少这种疾病的健康负担。以前的工作研究了测量循环，肿瘤相关的DNA或mRNA作为各种癌症的筛查，取得了一些成功。循环microRNA水平有可能作为CRC的诊断生物标志物。我们对这个主题进行了初步研究并撰写了评论。我们使用定量逆转录-聚合酶链反应来测量结肠癌患者血浆样本中的microRNA。我们发现，在102份血浆样本的队列中，循环miR-141与IV期结肠癌显著相关。采用受试者工作特征（ROC）分析评价候选血浆microRNA标志物的敏感性和特异性。我们观察到，miR-141和癌胚抗原（CEA）（一种广泛使用的CRC标记物）的组合进一步提高了检测的准确性。这些结果在中国天津采集的156份血浆样本的独立队列中得到验证。此外，我们的分析表明，高水平的血浆miR-141预测两个队列中的生存率较差，并且miR-141是晚期结肠癌的独立预后因素。因此，我们认为，血浆miR-141可能是一种新的生物标志物，补充CEA在检测结肠癌与远处转移，并在血浆中的miR-141的高水平与预后不良。我们还研究了特定基因在结肠癌小鼠模型中的功能作用，发现循环胰岛素样生长因子-1的遗传减少抑制了氧化偶氮甲烷诱导的小鼠结肠肿瘤发生。高水平的胰岛素样生长因子-1（IGF-1）与结肠癌风险的显著增加有关。此外，IGF-1在体外抑制结肠上皮细胞凋亡并刺激其增殖。不幸的是，IGF-1基因敲除小鼠有严重的发育异常，大多数不能存活，这使得研究IGF-1的基因消融如何影响结肠肿瘤发生变得困难。为了检验抑制IGF-1可预防结肠肿瘤发生的假设，我们利用了一个预先存在的小鼠模型，该模型通过Cre/loxP系统在肝脏中含有igf 1基因的缺失。这些肝脏特异性IGF-1缺陷（LID）小鼠显示循环IGF-1水平降低50 - 75%。我们进行了一项初步研究，以评估肝脏特异性IGF-1缺乏对氧化偶氮甲烷（AOM）诱导的结肠肿瘤的影响。与其野生型同窝小鼠相比，LID小鼠在结肠近端区域中具有结肠肿瘤多样性的显著抑制。我们检测了LID小鼠和野生型小鼠结肠中的增殖和凋亡标记物，以观察这些标记物是否与肿瘤发生一致。我们观察到LID小鼠结肠的增殖减少和凋亡增加。最后，我们检测了细胞因子水平，以确定IGF-1是否与炎症途径相互作用，影响结肠肿瘤发生。我们观察到与野生型同窝小鼠相比，在LID小鼠中测量的10种细胞因子中有7种的水平显著降低。这项初步研究的结果支持这一假设，即循环IGF-1水平的降低可能会阻止结肠肿瘤的发生，并影响增殖和凋亡。未来的实验将研究IGF-1受体的下游基因。

Colon adenocarcinoma is a leading cause of cancer mortality worldwid and accounts for approximately 50,000 deaths annually in the United States. There is a need to improve early detection screening methods for colorectal cancer (CRC). If detected early, CRC is highly curable. Colonoscopies are a reliable and accurate screening tool but their high cost and invasiveness lead to reduced screening rates. On the other hand, faecal occult blood tests (FOBTs) are less invasive, less expensive, have even been shown to reduce deaths caused by CRC;1 but the limited sensitivity and specificity of FOBT make it a less than ideal screening method for detecting CRC. Many researchers are trying to identify non-invasive screening methodologies, such as blood tests or faecal DNA tests,2 to improve early detection of CRC to reduce the health burden of this disease. Previous work investigated measuring circulating, tumour-associated DNA or mRNA as screens for various cancers with some success. Levels of circulating microRNAs have potential as diagnostic biomarkers for CRC. We have performed primary research and written commentaries on this topic. We used quantitative reverse transcription-polymerase chain reaction to measure microRNAs in plasma samples from colon cancer patients. We found that circulating miR-141 was significantly associated with stage IV colon cancer in a cohort of 102 plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of candidate plasma microRNA markers. We observed that combination of miR-141 and carcinoembryonic antigen (CEA), a widely used marker for CRC, further improved the accuracy of detection. These findings were validated in an independent cohort of 156 plasma samples collected at Tianjin, China. Furthermore, our analysis showed that high levels of plasma miR-141 predicted poor survival in both cohorts and that miR-141 was an independent prognostic factor for advanced colon cancer. Therefore, we propose that plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis and that high levels of miR-141 in plasma were associated with poor prognosis. We also investigated functional roles of specific genes in mouse models of colon cancer to find that genetic reduction of circulating insulin-like growth factor-1 inhibits azoxymethane-induced colon tumorigenesis in mice. High levels of insulin-like growth factor-1 (IGF-1) have been associated with a significant increase in colon cancer risk. Additionally, IGF-1 inhibits apoptosis and stimulates proliferation of colonic epithelial cells in vitro. Unfortunately, IGF-1 knockout mice have severe developmental abnormalities and most do not survive, making it difficult to study how genetic ablation of IGF-1 affects colon tumorigenesis. To test the hypothesis that inhibition of IGF-1 prevents colon tumorigenesis, we utilized a preexisting mouse model containing a deletion of the igf1 gene in the liver through a Cre/loxP system. These liver-specific IGF-1 deficient (LID) mice display a 5075% reduction in circulating IGF-1 levels. We conducted a pilot study to assess the impact of liver-specific IGF-1 deficiency on azoxymethane (AOM)-induced colon tumors. LID mice had a significant inhibition of colon tumor multiplicity in the proximal area of the colon compared to their wild-type littermates. We examined markers of proliferation and apoptosis in the colons of the LID and wild-type mice to see if these were consistent with tumorigenesis. We observed a decrease in proliferation in the colons of the LID mice and an increase in apoptosis. Finally, we examined cytokine levels to determine whether IGF-1 interacts with inflammatory pathways to affect colon tumorigenesis. We observed a significant reduction in the levels of 7 out of 10 cytokines that were measured in the LID mice as compared to wild-type littermates. Results from this pilot study support the hypothesis that reductions in circulating IGF-1 levels may prevent colon tumorigenesis and affect both proliferation and apoptosis. Future experiments will investigate downstream genes of the IGF-1 receptor.