Gress T M, Müller-Pillasch F, Lerch M M, Friess H, Büchler M, Adler G
Department of Internal Medicine I, University of Ulm, Germany.
Int J Cancer. 1995 Aug 9;62(4):407-13. doi: 10.1002/ijc.2910620409.
Pancreatic cancer shows a strong desmoplastic reaction characterized by a remarkable proliferation of interstitial connective tissue (collagens type I and III, fibronectin). In this study we have analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix-degrading metalloproteinases (MMP-1, -2, -3 and -9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in pancreatic cancer and control pancreatic tissue by Northern-blot analysis and mRNA in situ hybridization. Transcripts for MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) were not detectable in pancreatic cancer and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72-kDa collagenase IV), MMP-9 (92-kDa collagenase type IV), TIMP-1 and TIMP-2 were elevated in the majority of pancreatic-cancer tissue samples as compared to control pancreatic tissue. A good correlation was seen between overexpression of these MMPs and TIMPs and the steady-state levels of transcripts coding for extracellular matrix proteins, the amount of collagen protein and the severity of the desmoplastic reaction. In situ hybridization studies localized transcripts coding for collagens type I and III to spindle-shaped stromal cells, whereas transcripts for MMP-2, MMP-9, TIMP-1 and TIMP-2 were found in both stromal and tumor cells. However, MMP-2 transcripts appeared to be more abundant in stromal cells, TIMP-1 and TIMP-2 transcripts were evenly distributed over tumor and stromal cells and relatively more MMP-9 transcripts were found in tumor cells. We conclude that, in human pancreatic cancer, MMP-2, MMP-9, TIMP-1 and TIMP-2 may be involved in processes leading to the strong desmoplastic reaction observed in these tumors. Both stromal and tumor cells appear to be the source of MMPs and TIMPs in human pancreatic cancer.
胰腺癌表现出强烈的促纤维增生反应，其特征是间质结缔组织（I型和III型胶原、纤连蛋白）显著增殖。在本研究中，我们通过Northern印迹分析和mRNA原位杂交，分析了胰腺癌组织和对照胰腺组织中编码细胞外基质成分（I型、III型和IV型胶原、层粘连蛋白、纤连蛋白）、细胞外基质降解金属蛋白酶（MMP-1、-2、-3和-9）以及金属蛋白酶组织抑制剂（TIMP-1和-2）的mRNA表达平衡。在胰腺癌组织和对照组织中未检测到MMP-1（间质胶原酶）和MMP-3（基质溶解素-1）的转录本。与对照胰腺组织相比，大多数胰腺癌组织样本中编码细胞外基质蛋白、MMP-2（72 kDa胶原酶IV）、MMP-9（92 kDa IV型胶原酶）、TIMP-1和TIMP-2的转录本稳态水平升高。这些MMPs和TIMPs的过表达与编码细胞外基质蛋白的转录本稳态水平、胶原蛋白含量以及促纤维增生反应的严重程度之间存在良好的相关性。原位杂交研究将编码I型和III型胶原的转录本定位到梭形基质细胞，而MMP-2、MMP-9、TIMP-1和TIMP-2的转录本在基质细胞和肿瘤细胞中均有发现。然而，MMP-2转录本在基质细胞中似乎更为丰富，TIMP-1和TIMP-2转录本在肿瘤细胞和基质细胞中分布均匀，而在肿瘤细胞中发现相对较多的MMP-9转录本。我们得出结论，在人类胰腺癌中，MMP-2、MMP-9、TIMP-1和TIMP-2可能参与了导致这些肿瘤中观察到的强烈促纤维增生反应的过程。在人类胰腺癌中，基质细胞和肿瘤细胞似乎都是MMPs和TIMPs的来源。
