Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA.
Providence Regional Pathology, Portland, OR, USA.
J Pathol. 2024 Dec;264(4):411-422. doi: 10.1002/path.6356. Epub 2024 Oct 22.
The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic Kras expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell-BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.
基底膜 (BM) 是正常上皮和癌前上皮病变的主要微环境因素之一。有证据表明，BM 不仅作为肿瘤侵袭的屏障，而且在癌前阶段作为一种积极的肿瘤抑制信号底物发挥作用。然而，这些机制的分子基础尚未阐明。在这里，我们探讨了 BM 在癌前演变过程中的潜在肿瘤抑制功能，重点研究了细胞外基质受体 dystroglycan 在胰腺和胰腺疾病中的表达和功能。我们发现，dystroglycan 蛋白在正常胰腺的腺泡区表达较高，而在导管区表达较低。此外，在慢性胰腺炎和胰腺癌前和癌症演变的所有阶段（从腺泡到导管的化生到发育不良到腺癌），dystroglycan 蛋白的表达都受到强烈抑制。在小鼠胰腺中条件性敲除 dystroglycan 几乎没有表现出发育或功能缺陷的证据。然而，在致癌 Kras 表达的背景下，条件性删除 dystroglycan 的表达导致胰腺疾病的演变明显加速，包括发育不良的加速发展和存活率降低。这些数据确立了 dystroglycan 作为胰腺发育不良发展的抑制剂，并且在慢性胰腺炎和癌基因诱导转化的最早阶段被沉默。我们得出结论，dystroglycan 是癌前演变过程中 BM 肿瘤抑制功能的重要介质，其功能降低会增加癌症风险，强调细胞-BM 相互作用的动态作为早期癌症进展的重要决定因素。
