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

Abstract

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.

Axial stretch regulates rat tail collecting lymphatic vessel contractions

“…The image z-stacks were imported in ZEN lite (Zeiss, Inc.) software to obtain 3D reconstructions. Quantitative parameters, including fiber angle and fiber straightness, were obtained using CT_FIRE software (downloaded at https://loci.wisc.edu/software/ctfire) that automatically extracts individual fibers by applying the curvelet denoising filter followed by an automated fiber extraction method 38,39 . CT_Fire uses a two-step approach i) a curvelet filter is applied to denoise the image and enhance fibers edges ii) a fiber tracking algorithm (FIRE) detects fiber boundaries and center points and calculates length of fiber, angle and straightness.…”

The role of collagen in cancer: from bench to bedside

“…The mechanisms underlying these important collagen properties are described below. Among five collagen parameters (alignment, density, width, length, and straightness), increased collagen width is the most powerful parameter for predicting cancer prognosis [175]. The elasticity of the collagen matrix is controlled by fibril bending stiffness rather than by fibril diameter or intrafibrillar crosslinking [176].…”

Stromal organization as predictive biomarker for the treatment of colon cancer with adjuvant bevacizumab; a post-hoc analysis of the AVANT trial

“…Currently, evidence is accumulating on the significance of intra-tumoral stroma organization in cancer. Alterations in collagen structures, such as fiber alignment, maturity, length, width and density, have shown to be prognostic in multiple cancer types [17][18][19][20][21][22]. A limited number of studies has so far focused on the predictive value of altered collagen structures.…”