J Cancer 2017; 8(8):1466-1476. doi:10.7150/jca.18466

Research Paper

Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis

Zhi-Hua Zhou1, 2, Cheng-Dong Ji1, 2, Hua-Liang Xiao3, Hai-Bin Zhao4, You-Hong Cui1, 2, Xiu-Wu Bian1, 2✉

1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China;
2. Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China;
3. Department of Pathology, Daping Hospital, Third Military Medical University, Chongqing, China;
4. Department of Pathology, The 101 Hospital of PLA, Wuxi, Jiangsu Province, China.

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Zhou ZH, Ji CD, Xiao HL, Zhao HB, Cui YH, Bian XW. Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis. J Cancer 2017; 8(8):1466-1476. doi:10.7150/jca.18466. Available from https://www.jcancer.org/v08p1466.htm

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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.

Keywords: gastric cancer, collagen fiber, immunohistochemistry, second harmonic generation, prognosis.