Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Marchioninistr.15, 81377, Munich, Germany.
Cancer Lett. 2024 Apr 28;588:216769. doi: 10.1016/j.canlet.2024.216769. Epub 2024 Mar 2.
Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP and α-SMA, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-β expression in nearby tumor cells. Then, TGF-β promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis.
癌症相关成纤维细胞 (CAFs) 在多种癌症中发挥着重要作用。然而，肿瘤基质在非功能性胰腺神经内分泌肿瘤 (NF-PanNETs) 中的作用往往被忽视。分析 CAFs 的异质性可以揭示 NF-PanNETs 中恶性表型的原因。在这里，我们发现基质比例高的患者预后较差，尤其是浸润性基质（基质和肿瘤细胞呈现浸润性生长模式且无规则边界）的患者。此外，特征为 FAP 和 α-SMA 的肌成纤维 CAFs (myCAFs) 与肿瘤细胞空间上更接近，并促进 EMT 和肿瘤生长。有趣的是，只有空间上更接近 myCAFs 的肿瘤细胞才会发生 EMT。我们进一步阐明，myCAFs 会刺激附近肿瘤细胞中 TGF-β 的表达。然后，TGF-β 促进了相邻肿瘤细胞的 EMT，并促进了肿瘤细胞中 myCAFs 标志物基因的表达，导致远处转移。我们的研究结果表明，myCAFs 导致 EMT 的空间异质性，从而导致 NF-PanNETs 的肝转移。本研究的结果可能为预防肝转移提供了可能的靶点。
