Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Mol Cancer Res. 2024 Apr 2;22(4):329-336. doi: 10.1158/1541-7786.MCR-23-0749.
Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including MKI67 and EXO1. Peritoneal tumors were also enriched for proliferative gene sets, including E2F and Myc Targets. Proteomic studies found a 2.5-fold increased ratio of active-to-inactive phosphoforms of the YAP oncoprotein in peritoneal tumors, indicating downregulation of Hippo signaling.
The peritoneal microenvironment promotes growth of appendiceal tumors and expression of proliferative pathways in PDXs.
阑尾腺癌 (AA) 与其他胃肠道恶性肿瘤不同，它几乎只转移到腹腔。然而，很少有研究调查腹腔微环境与 AA 的分子相互作用。在这里，我们使用正交和侧腹植入患者来源的异种移植物 (PDX) 的多组学方法来研究腹腔微环境对 AA 的影响。植入腹腔微环境中的 AA 肿瘤往往生长得更快，Ki-67 的核表达也高于植入侧腹的相同肿瘤。比较肿瘤特异性转录组（不包括基质转录），腹腔微环境相对上调了与增殖相关的基因，包括 MKI67 和 EXO1。腹腔肿瘤还富含增殖基因集，包括 E2F 和 Myc 靶标。蛋白质组学研究发现，腹腔肿瘤中 YAP 癌蛋白的活性磷酸形式与非活性磷酸形式的比例增加了 2.5 倍，表明 Hippo 信号通路下调。
腹腔微环境促进 PDX 中阑尾肿瘤的生长和增殖途径的表达。
