Apte M V, Park S, Phillips P A, Santucci N, Goldstein D, Kumar R K, Ramm G A, Buchler M, Friess H, McCarroll J A, Keogh G, Merrett N, Pirola R, Wilson J S
Pancreatic Research Group, Department of Gastroenterology, Bankstown-Lidcombe and Liverpool Hospitals, NSW, Sydney, Australia.
Pancreas. 2004 Oct;29(3):179-87. doi: 10.1097/00006676-200410000-00002.
Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor.
Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression.
Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77; P < 0.04; 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression.
Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.
胰腺癌预后极差，主要归因于其易于早期发生局部和远处转移。在组织病理学上，大多数胰腺癌的特征是肿瘤组织内及周围存在明显的间质/纤维反应。本研究的目的是确定：（1）人类胰腺癌中间质反应形成的细胞是否为活化的胰腺星状细胞（PSCs）；（2）胰腺癌细胞与PSCs之间是否存在相互作用，这种相互作用可能促进肿瘤的局部和远处侵袭。
通过免疫组织化学法对人胰腺癌组织连续切片进行结蛋白和胶质纤维酸性蛋白（星状细胞选择性标志物）以及α-平滑肌肌动蛋白（αSMA，活化PSCs的标志物）染色，并用天狼星红对胶原蛋白进行染色。通过形态计量学评估胶原蛋白和αSMA阳性染色程度之间的相关性。使用双重染色方法，即αSMA免疫染色和前胶原α1I mRNA原位杂交，确定间质区域胶原蛋白的细胞来源。通过将培养的大鼠PSCs暴露于对照培养基或来自2种胰腺癌细胞系（PANC-1和MiaPaCa-2）的条件培养基24小时，在体外评估胰腺癌细胞与PSCs之间可能的相互作用。通过细胞增殖和αSMA表达评估PSC活化情况。
人胰腺癌的间质区域对星状细胞选择性标志物结蛋白和GFAP（表明存在PSCs）、αSMA（表明PSCs处于活化状态）以及胶原蛋白呈强阳性染色。形态计量分析显示PSC活化程度与胶原蛋白沉积之间存在密切相关性（r = 0.77；P < 0.04；8对切片）。前胶原mRNA表达定位于间质区域的αSMA阳性细胞，表明活化的PSCs是间质区域胶原蛋白的主要来源。体外将PSCs暴露于胰腺癌细胞分泌物导致PSC活化，表现为细胞增殖和αSMA表达显著增加。
活化的PSCs存在于胰腺癌的间质反应中，并负责产生间质胶原蛋白。PSC功能受胰腺癌细胞影响。肿瘤细胞与间质细胞（PSCs）之间的相互作用可能在胰腺癌的病理生物学中起重要作用。
