Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
The Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
J Cancer Res Clin Oncol. 2021 Nov;147(11):3333-3341. doi: 10.1007/s00432-021-03753-w. Epub 2021 Sep 2.
Colorectal cancer (CRC) is the third most common malignancy worldwide, but the key driver to distant metastases is still unknown. This study aimed to elucidate the link between immunosurveillance and organotropism of metastases in CRC by evaluating different gene signatures and pathways.
CRC patients undergoing surgery at the Department of General, Visceral and Transplantation Surgery at the Ludwig-Maximilian University Hospital Munich (Munich, Germany) were screened and categorized into M0 (no distant metastases), HEP (liver metastases) and PER (peritoneal carcinomatosis) after a 5-year follow-up. Six patients of each group were randomly selected to conduct a NanoString analysis, which includes 770 genes. Subsequently, all genes were further analyzed by gene set enrichment analysis (GSEA) based on seven main cancer-associated databases.
Comparing HEP vs. M0, the gene set associated with the Toll-like receptor (TLR) cascade defined by the Reactome database was significantly overrepresented in HEP. HSP90B1, MAPKAPK3, PPP2CB, PPP2R1A were identified as the core enrichment genes. The immunologic signature pathway GSE6875_TCONV_VS_FOXP3_KO_TREG_DN with FOXP3 as downstream target was significantly overexpressed in M0. RB1, TMEM 100, CFP, ZKSCAN5, DDX50 were the core enrichment genes. Comparing PER vs. M0 no significantly differentially expressed gene signatures were identified.
Chronic inflammation might enhance local tumor growth. This is the first study identifying immune related gene sets differentially expressed between patients with either liver or peritoneal metastases. The present findings suggest that the formation of liver metastases might be associated with TLR-associated pathways. In M0, a high expression of FOXP3 + tumor infiltrating lymphocytes (TILs) seemed to prevent at least in part metastases. Thus, these correlative findings lay the cornerstone to further studies elucidating the underlying mechanisms of organotropism of metastases.
结直肠癌（CRC）是全球第三大常见恶性肿瘤，但远处转移的关键驱动因素仍不清楚。本研究旨在通过评估不同的基因特征和途径，阐明 CRC 中免疫监视与转移器官趋向性之间的联系。
在德国慕尼黑路德维希-马克西米利安大学医院普外科、内脏和移植外科（慕尼黑）接受手术的 CRC 患者在接受手术后进行了筛查，并在 5 年随访后分为 M0（无远处转移）、HEP（肝转移）和 PER（腹膜癌病）。每组各随机选择 6 名患者进行 NanoString 分析，该分析包括 770 个基因。随后，根据七个主要癌症相关数据库，通过基因集富集分析（GSEA）进一步分析所有基因。
HEP 与 M0 相比，Reactome 数据库定义的 Toll 样受体（TLR）级联相关的基因集在 HEP 中明显过表达。HSP90B1、MAPKAPK3、PPP2CB、PPP2R1A 被鉴定为核心富集基因。GSE6875_TCONV_VS_FOXP3_KO_TREG_DN 免疫特征途径，其下游靶标为 FOXP3，在 M0 中明显过表达。RB1、TMEM 100、CFP、ZKSCAN5、DDX50 为核心富集基因。与 M0 相比，PER 与 M0 之间没有发现明显差异表达的基因特征。
慢性炎症可能增强局部肿瘤生长。这是第一项确定肝转移或腹膜转移患者之间差异表达的免疫相关基因集的研究。本研究结果表明，肝转移的形成可能与 TLR 相关途径有关。在 M0 中，高表达 FOXP3+肿瘤浸润淋巴细胞（TIL）似乎至少部分阻止了转移的发生。因此，这些相关发现为进一步阐明转移器官趋向性的潜在机制奠定了基础。
