Pathology, Medical Faculty Augsburg, Institute of Pathology and Molecular Diagnostics, University of Augsburg, Stenglinstraße 2, 86156, Augsburg, Germany.
Biomedical Informatics, Data Mining and Data Analytics, Faculty of Applied Computer Science and Medical Faculty, University of Augsburg, Augsburg, Germany.
Gastric Cancer. 2024 Jan;27(1):72-85. doi: 10.1007/s10120-023-01436-8. Epub 2023 Oct 24.
Recently, we presented Stroma AReactive Invasion Front Areas (SARIFA) as a new histomorphologic negative prognostic biomarker in gastric cancer. It is defined as direct contact between tumor cells and fat cells. The aim of this study was to further elucidate the underlying genomic, transcriptional, and immunological mechanisms of the SARIFA phenomenon.
To address these questions, SARIFA was classified on H&E-stained tissue sections of three cohorts: an external cohort (n = 489, prognostic validation), the TCGA-STAD cohort (n = 194, genomic and transcriptomic analysis), and a local cohort (n = 60, digital spatial profiling (whole transcriptome) and double RNA in situ hybridization/immunostaining of cytokines).
SARIFA status proved to be an independent negative prognostic factor for overall survival in an external cohort of gastric carcinomas. In TCGA-STAD cohort, SARIFA is not driven by distinct genomic alterations, whereas the gene expression analyses showed an upregulation of FABP4 in SARIFA-positive tumors. In addition, the transcriptional regulations of white adipocyte differentiation, triglyceride metabolism, and catabolism were upregulated in pathway analyses. In the DSP analysis of SARIFA-positive tumors, FABP4 and the transcriptional regulation of white adipocyte differentiation were upregulated in macrophages. Additionally, a significantly lower expression of the cytokines IL6 and TNFα was observed at the invasion front.
SARIFA proves to be a strong negative prognostic biomarker in advanced gastric cancer, implicating an interaction of tumor cells with tumor-promoting adipocytes with crucial changes in tumor cell metabolism. SARIFA is not driven by tumor genetics but is very likely driven by an altered immune response as a causative mechanism.
最近，我们提出了 Stroma AReactive Invasion Front Areas（SARIFA）作为胃癌新的组织形态学负预后生物标志物。它被定义为肿瘤细胞与脂肪细胞的直接接触。本研究旨在进一步阐明 SARIFA 现象的潜在基因组、转录和免疫学机制。
为了解决这些问题，我们在三个队列的 H&E 染色组织切片上对 SARIFA 进行分类：外部队列（n=489，预后验证）、TCGA-STAD 队列（n=194，基因组和转录组分析）和本地队列（n=60，数字空间分析（全转录组）和双重 RNA 原位杂交/免疫染色细胞因子）。
SARIFA 状态在外科队列的胃癌中被证明是独立的总生存期负预后因素。在 TCGA-STAD 队列中，SARIFA 不受明显的基因组改变驱动，而基因表达分析显示 SARIFA 阳性肿瘤中 FABP4 上调。此外，通路分析显示白色脂肪细胞分化、甘油三酯代谢和分解的转录调控上调。在 SARIFA 阳性肿瘤的 DSP 分析中，巨噬细胞中 FABP4 和白色脂肪细胞分化的转录调控上调。此外，在侵袭前沿观察到细胞因子 IL6 和 TNFα 的表达显著降低。
SARIFA 在外科晚期胃癌中被证明是一种强有力的负预后生物标志物，表明肿瘤细胞与促肿瘤脂肪细胞相互作用，肿瘤细胞代谢发生关键变化。SARIFA 不是由肿瘤遗传学驱动的，而是很可能由改变的免疫反应作为因果机制驱动的。
