Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas

Abstract

Objective The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas. Background Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis. Methods One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro.Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts. Results Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P \ 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P \ 0.001) and overall survival (P \ 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings. Conclusions The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.

Identification of a high‐risk subtype of intestinal‐type Japanese gastric cancer by quantitative measurement of the luminal tumor proportion

“…The study by Lee et al suggests that there could be a relationship between PoT and disease stage as in multivariate analysis the prognostic significance of the stroma proportion was only seen in GC patients with T3/4 disease. Furthermore, low PoT was seen in 8% of stage I patients and in up to 69% of stage III patients . While we measured PoT using a quantitative morphometric method, previous investigators simply visually estimated PoT which might explain the differences in the median PoT between studies.…”

“…However, it is necessary to point out that the three previous GC studies evaluating the prognostic value of the proportion of stroma, but also studies investigating the same in colorectal cancer and other cancers all describe that a high proportion of stroma (eg, low PoT) is related to poor survival. Our study showed the opposite for the subgroup of intestinal‐type GC.…”

“…Data from the relative stroma content at the deep invasive tumor edge in Chinese GC was used to propose a “new” staging system combining tumor‐stroma ratio and conventional TNM staging . The study in Korean GC restricted their evaluation of the tumor stroma content to areas with greatest proportion of stroma in a series of signet ring cancers reaching similar conclusions …”

“…In order to optimize patient management decisions, prognostic factors should ideally be measurable at the time of diagnosis, for example, in the diagnostic biopsy. The methodology we used in our own previous study or was used by the Italian, Chinese, and Korean investigators depends on the availability of a resected specimen to select the area of interest for stroma evaluation . It is unclear whether a similar relationship between tumor stroma content and GC patient survival can be demonstrated when measurements are performed in material from the luminal surface of the tumor.…”

Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy

“…The CAFs are known to actively promote proliferation and differentiation of tumor cells as well as support angiogenesis and metastasis by promoting matrix remodeling and epithelial to mesenchymal transition (EMT) (106–108). Even the enrichment of stroma/CAFs within the tumor tissue has a direct correlation with the tumor size and a negative impact on the clinical prognosis (109)—as observed in cases of gastric signet ring cell carcinoma—indicating the profound impact of CAFs on overall tumor biology.…”