Stroma AReactive Invasion Front Areas (SARIFA) – a new prognostic biomarker in gastric cancer related to tumor‐promoting adipocytes

Abstract

Compared to other malignancies, there is a lack of easy-to-evaluate biomarkers for gastric cancer, which is associated with an adverse clinical outcome in many cases. Here, we present Stroma AReactive Invasion Front Areas (SARIFA) as a new histological prognostic marker. We defined SARIFA as the direct contact between a cluster of tumor glands/cells comprising at least five tumor cells and inconspicuous surrounding adipose tissue at the invasion front. A total of 480 adenocarcinomas of the stomach and the gastroesophageal junction from two different collections were classified according to SARIFA. To understand the potential underlying mechanisms, a transcriptome analysis was conducted using digital spatial profiling (DSP). It was found that 20% of the tumors were SARIFA-positive. Kappa values between the three pathologists were good in both collections: 0.74 and 0.78. Patients who presented SARIFA-positive tumors had a significantly lower overall survival in Collections A (median: 20.0 versus 44.0 months; p = 0.014, n = 160) and B (median: 15.0 versus 41.0 months; p < 0.0001, n = 320). SARIFA positivity emerged as a negative independent prognostic factor for overall survival (HR 1.638, 95% CI 1.153-2.326, p = 0.006). Using DSP, the most upregulated genes in SARIFA-positive cases were those associated with triglyceride catabolism and endogenous sterols. COL15A1, FABP2, and FABP4 were differentially expressed in positive cases. At the protein level, the expression of proteins related to lipid metabolism was confirmed. SARIFA combines low inter-observer variability, minimal effort, and high prognostic relevance, and is therefore an extremely promising biomarker related to tumor-promoting adipocytes in gastric cancer.

The Concept of Stroma AReactive Invasion Front Areas (SARIFA) as a New Prognostic Biomarker for Lipid-driven Cancers Holds True in Pancreatic Ductal Adenocarcinoma

“…The immunohistochemical expression of CD36, a multiligand translocase enabling transmembranous allocation of oxidised low-density lipoproteins, does not differ between SARIFA-positive and SARIFA-negative PDAC. These findings deviate from the analyses by Grosser et al in gastric cancers, where CD36 was more strongly expressed in SARIFA-positive tumours [9], indicating that the regulation mechanism in these two entities differs. Therefore, the uptake of fatty acid could rely on an alternative transport mechanism like extracellular vesicles [34].…”

“…This effect has been demonstrated in gastric, colorectal and prostate cancer so far. In contrast to what might be expected, the occurrence of SARIFAs did not correlate with obesity [7, 9]. In the current study, we tested the hypotheses that SARIFA classification is applicable to and prognostic in PDAC and that there are signs of enhanced lipid metabolism.…”

“…All given H&E-stained tumour slides (total 980, median 5 per case), each covering an area of approximately 220 mm 2 , were examined by two independent investigators (PG and BM) who were blinded to the clinicopathological data. A SARIFA was defined as the direct contact between at least five tumorous cells or a malignant gland and inconspicuous adipocytes at the invasion front, as described recently by our group [8, 9]. Representative images of both SARIFA-positive and SARIFA-negative cases are presented in Figure 1.…”

“…Additional immunohistochemical staining was performed to analyse and compare the expression of fatty acid metabolism–related proteins and the role of macrophages in SARIFAs, here corresponding to the results of preceding analyses on gastric carcinoma [9]. FABP4, CD36 and CD68 immunohistochemistry was performed on 30 SARIFA-positive and 30 SARIFA-negative representative cases, using 2- to 4-µm-thick, whole-slide, formalin-fixed paraffin-embedded sections.…”

“…By definition, a SARIFA is characterised as an area at the tumour invasion front where there is an absence of desmoplastic stroma reaction on malignant invasion in the surrounding inobtrusive tissue, hence leading to direct contact between tumour cells and adipocytes. Detectable on haematoxylin and eosin (H&E)–stained slides, without the necessity for additional immunohistochemistry, simple to learn, and assessable in a short period with low interobserver variability, SARIFAs can be easily implemented in routine diagnostic workflow [8, 9]. Moreover, SARIFA positivity reflects metabolic reprogramming in which tumour cells gain advantage from enhanced lipid supply.The important role of lipids in cancer became a major research line.…”