Collagen components in the tumor microenvironment substantially influence cancer pathogenesis and progression. Nevertheless, in gastric cancer, collagen status and its prognostic role remain unclear. Using picrosirius red staining and immunohistochemistry, we found that collagen deposition was significantly increased in gastric cancer when compared with non-neoplastic tissues, and in cancer stroma, more immature collagen components were present, suggesting a qualitative change. Furthermore, the morphology of collagen fibers could be weakly, moderately or strongly changed in gastric cancer; when weakly or moderately changed, they appeared similar to normal collagen fibers, except for a higher linearization and density; when strongly changed, they were thicker and less eosinophilic, sharply differently from their normal counterparts. In addition, we found abundant myofibroblasts and elevated expression of lysyl oxidase-like 2 (the enzyme that mediates crosslinking of collagen molecules) in cancer stroma, which might contribute to the increased collagen deposition and crosslinking. Last, five collagen architectural parameters (alignment, density, width, length and straightness) were analyzed with second harmonic generation imaging, a highly specific technology for detection of collagen fibers, and our data indicated that all the parameters were significantly increased in the tumor microenvironment. Of the five parameters, collagen width was the most powerful parameter in predicting 5-year overall survival, and increased collagen width was associated with reduced survival. The prognostic value of collagen width was superior to traditional clinicopathological parameters, and this was validated in two unrelated gastric cancer cohorts that contained 225 and 151 patients. Collectively, the collagen status (content, maturity, morphology and architecture) was profoundly reorganized in the tumor microenvironment of gastric cancer, and collagen width could serve as a valuable prognostic indicator.

5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a‑mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer.

GMS can serve as a useful prognostic factor for gastric cancer, and according to GMS, the tumor microenvironment in this cancer type may be partially classified as inflammatory or desmoplastic microenvironment that possesses different pathobiological features.

Double immunohistochemical staining could improve accuracy of perineural invasion detection in gastric cancer, particularly in the diffuse type. Moreover, perineural invasion predicts a poor outcome in gastric cancer, but it cannot provide more information than traditional clinicopathologic variables.

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