Increased Incidence of Colon Tumors in AOM-Treated Apc1638N/+ Mice Reveals Higher Frequency of Tumor Associated Neutrophils in Colon Than Small Intestine
Increased Incidence of Colon Tumors in AOM-Treated Apc1638N/+ Mice Reveals Higher Frequency of Tumor Associated Neutrophils in Colon Than Small Intestine
复制标题
DOI：
10.3389/fonc.2019.01001
复制
发表时间：
2019-10-02
影响因子：
4.7
通讯作者：
Krug, Anne B.
中科院分区：
文献类型：
--
作者：
Metzger, Rebecca;Maruskova, Mahulena;Krug, Anne B.
结直肠癌（CRC）是最常见的癌症之一，也是死亡的主要原因。具有截短Apc种系突变的小鼠已被用作CRC的标准模型，但大多数Apc突变系在近端小肠中产生多个肿瘤，很少在结肠中产生多个肿瘤，从而排除了对结肠肿瘤微环境的详细分析。我们的目的是开发一种与人CRC具有更高相似性的模型，并与小肠肿瘤相比，表征自发发展的结肠肿瘤中的肿瘤浸润免疫细胞。因此，用氧化偶氮甲烷（AOM）重复处理Apc（1638 N/+）细胞系，实现了90%的结肠肿瘤发生率和每只小鼠4至5个结肠肿瘤。值得注意的是，AOM治疗特别增加了结肠中的肿瘤负荷，而不是小肠中的肿瘤负荷。小肠和结肠肿瘤的组织学分级和WNT信号传导活性没有显著差异，两个位置的一些病变进展为浸润性腺癌。然而，肿瘤内髓样细胞区室的特征显示结肠肿瘤中大量中性粒细胞浸润-比小肠肿瘤高6倍。此外，表达CCL 17的巨噬细胞和树突状细胞在肿瘤中积累，表明肿瘤促进免疫抑制环境的建立。因此，用AOM处理的Apc（1638 N/+）小鼠是研究免疫细胞和趋化因子对结肠癌发生的影响的合适且直接的模型。
Colorectal cancer (CRC) is one of the most common cancers and a major cause of mortality. Mice with truncating Apc germline mutations have been used as a standard model of CRC, but most of the Apc-mutated lines develop multiple tumors in the proximal small intestine and rarely in the colon precluding detailed analysis of colon tumor microenvironment. Our aim was to develop a model with higher resemblance to human CRC and to characterize tumor infiltrating immune cells in spontaneously developing colon tumors compared to small intestinal tumors. Therefore, the Apc(1638N/+) line was treated repeatedly with azoxymethane (AOM) and 90% colon tumor incidence and 4 to 5 colon tumors per mouse were achieved. Of note, AOM treatment specifically increased the tumor burden in the colon, but not in the small intestine. Histological grading and WNT-signaling activity did not differ significantly between small intestinal and colon tumors with some lesions progressing to invasive adenocarcinoma in both locations. However, characterization of the intratumoral myeloid cell compartment revealed a massive infiltration of colon tumors with neutrophils - 6-fold higher than in small intestinal tumors. Moreover, CCL17-expressing macrophages and dendritic cells accumulated in the tumors indicating the establishment of a tumor-promoting immunosuppressive environment. Thus, Apc(1638N/+) mice treated with AOM are a suitable and straightforward model to study the influence of immune cells and chemokines on colon carcinogenesis.