Zhou Zhi-Hua, Ji Cheng-Dong, Xiao Hua-Liang, Zhao Hai-Bin, Cui You-Hong, Bian Xiu-Wu
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China.
J Cancer. 2017 Jun 1;8(8):1466-1476. doi: 10.7150/jca.18466. eCollection 2017.
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.
肿瘤微环境中的胶原蛋白成分对癌症的发病机制和进展有重大影响。然而,在胃癌中,胶原蛋白状态及其预后作用仍不清楚。通过使用天狼星红染色和免疫组织化学方法,我们发现与非肿瘤组织相比,胃癌中的胶原蛋白沉积显著增加,并且在癌基质中存在更多不成熟的胶原蛋白成分,提示存在质的变化。此外,胃癌中胶原纤维的形态可能发生轻度、中度或重度改变;轻度或中度改变时,它们除了线性化程度和密度较高外,看起来与正常胶原纤维相似;重度改变时,它们更粗且嗜酸性更弱,与正常对应物明显不同。另外,我们发现癌基质中有丰富的肌成纤维细胞以及赖氨酰氧化酶样2(介导胶原分子交联的酶)表达升高,这可能导致胶原蛋白沉积和交联增加。最后,使用二次谐波产生成像(一种检测胶原纤维的高度特异性技术)分析了五个胶原结构参数(排列、密度、宽度、长度和直线度),我们的数据表明所有参数在肿瘤微环境中均显著增加。在这五个参数中,胶原宽度是预测5年总生存期最有力的参数,胶原宽度增加与生存期缩短相关。胶原宽度的预后价值优于传统的临床病理参数,这在两个分别包含225例和151例患者的不相关胃癌队列中得到了验证。总体而言,胃癌肿瘤微环境中的胶原蛋白状态(含量、成熟度、形态和结构)发生了深刻重组,胶原宽度可作为一个有价值的预后指标。