Nebuloni Manuela, Albarello Luca, Andolfo Annapaola, Magagnotti Cinzia, Genovese Luca, Locatelli Irene, Tonon Giovanni, Longhi Erika, Zerbi Pietro, Allevi Raffaele, Podestà Alessandro, Puricelli Luca, Milani Paolo, Soldarini Armando, Salonia Andrea, Alfano Massimo
L. Sacco Hospital, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy.
Department of Pathology, San Raffaele Scientific Institute, Milan, Italy.
Sci Rep. 2016 Mar 4;6:22522. doi: 10.1038/srep22522.
The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential.
来自肿瘤周围组织和结直肠癌(CRC)而非健康结肠的细胞外基质(ECM)能维持肿瘤细胞的增殖和侵袭。我们在健康、肿瘤周围组织和CRC标本的配对比较中研究了ECM的生化和物理多样性。从健康组织到肿瘤周围组织和CRC的ECM,观察到纤维的逐步线性化和组织化程度,且这与硬度和胶原蛋白交联的稳步增加相关。在肿瘤周围组织的ECM中,这些改变与血管生成增加同时出现,而在肿瘤性ECM中,它们与基质蛋白调节改变、羟基化赖氨酸和赖氨酰氧化酶含量增加有关。本研究确定肿瘤周围组织ECM硬度和交联增加,形成了适合CRC侵袭的环境,这是一种与血管生成相关的现象。结肠区域硬度增加可能代表了易发生侵袭的促结缔组织增生区域的新预测标志物,从而为监测具有侵袭潜能的腺瘤提供了新的潜在应用。