Stagge V, Seufferlein T, Duerschmied D, Menke A, Adler G, Beil M
Department of Internal Medicine I, University of Ulm, Germany.
Pancreas. 2001 Oct;23(3):236-45. doi: 10.1097/00006676-200110000-00003.
The extracellular matrix (ECM) plays a salient role for proliferation and differentiation of epithelial cells. It was demonstrated that cell-ECM interactions mediated through integrins control gene expression and the tissue phenotype even in malignant tumors. Alterations of the ECM are a key feature of ductal adenocarcinoma of the pancreas.
To examine the role of integrins and related signaling events for differentiation.
We established an in vitro model for ECM-induced differentiation of poorly differentiated pancreatic carcinoma cells and found that a specific pattern of ECM proteins resembling basal laminas (matrigel) induces differentiation of the PaTu-II pancreatic carcinoma cell line to a ductal phenotype. Both beta1- and beta4-integrins are required for cellular differentiation. Integrin-associated signaling events include activation of pp125 focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs). However, beta1- and beta4-integrin-mediated differentiation of PaTu-II cells was independent from FAK, ERK, and JNK activation levels. Inhibition of MAPK kinases by PD98059 led to a reduction of proliferation but did not interfere with cellular differentiation of PaTu-II cells on matrigel.
The integrin-mediated differentiation of PaTu-II cells is regulated and maintained through FAK- and MAPK-independent signal transduction pathways.
细胞外基质（ECM）在上皮细胞的增殖和分化中起着重要作用。研究表明，通过整合素介导的细胞与ECM的相互作用即使在恶性肿瘤中也能控制基因表达和组织表型。ECM的改变是胰腺导管腺癌的一个关键特征。
研究整合素及相关信号事件在分化中的作用。
我们建立了一个体外模型，用于研究ECM诱导低分化胰腺癌细胞的分化，发现一种类似于基底膜（基质胶）的特定ECM蛋白模式可诱导PaTu-II胰腺癌细胞系分化为导管表型。细胞分化需要β1和β4整合素。整合素相关的信号事件包括pp125粘着斑激酶（FAK）和丝裂原活化蛋白激酶（MAPK）如细胞外信号调节激酶（ERK）和c-Jun氨基末端激酶（JNK）的激活。然而，β1和β4整合素介导的PaTu-II细胞分化与FAK、ERK和JNK的激活水平无关。用PD98059抑制MAPK激酶可导致增殖减少，但不影响PaTu-II细胞在基质胶上的细胞分化。
PaTu-II细胞的整合素介导的分化是通过与FAK和MAPK无关的信号转导途径来调节和维持的。
