Expression and Function of Receptors for Extracellular Matrix Proteins in Human Ductal Adenocarcinomas of the Pancreas

Löhr, Matthias; Trautmann, B; Göttler, Martin; Peters, Stephanie; Zauner, Ira; Maier, Anja; Klöppel, Günter; Liebe, Stefan; Kreuser, Ernst-Dieter

doi:10.1097/00006676-199604000-00007

Cited by 71 publications

(40 citation statements)

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“…In the three cell lines expressing wild-type SMAD4, including AsPC-1, MiaPaCa-2, and Panc-1, maximal migration occurs on laminin and there is a distinct absence of the a 1 b 1 integrin. These results are in agreement with previous results indicating that Panc-1 cells are negative and that BxPC-3 cells are positive for the a 1 integrin subunit by FACS analyses (Lohr et al, 1996). It is intriguing that TGFb 1 treatment of the NR4 hepatocyte cell line increased the expression of a 1 integrin subunit mRNA (Serra et al, 1994), directly correlating with our findings that cell lines with TGFb 1 -activating SMAD4 mutations express the a 1 b 1 integrin.…”

Section: Discussionsupporting

confidence: 94%

“…While expression of the a 2 integrin subunit has been demonstrated previously for most of these cell lines (Lohr et al, 1996;Sawai et al, 2001;Miyamoto et al, 2004), to our knowledge, this is the first demonstration that the CFPAC cell line is also a 2 integrin subunit positive. These results are in agreement with reports using other pancreatic cancer cell lines, including PC-2, -3, and -44, PaTu 8988S, HPAF, Capan-2, PaTu 8902, and PaTu-2 cells, which also demonstrated type I collagen adhesion and a 2 integrin subunit expression (Mollenhauer et al, 1987;Weinel et al, 1992).…”

Section: Discussionsupporting

confidence: 61%

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The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

2006

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Pancreatic cancer is characterised by a hallmark desmoplastic response that includes upregulated expression of the extracellular matrix, and type I collagen in particular. Recent studies indicate that pancreatic cancer cells stimulate type I collagen synthesis in adjacent stellate cells, and that this upregulated type I collagen expression promotes the malignant phenotype in tumour cells as defined by increased proliferation, resistance to chemically induced apoptosis, and increased tumorigenesis. The integrin specificity of this interaction between type I collagen and tumour cells was not identified, however. In the present study, we examined eight pancreatic cancer cell lines for adhesion, proliferation, and migration, on types I and IV collagen, fibronectin, laminin, and vitronectin, as well as integrin expression. Our results indicate, for the overwhelming majority of cell lines, that type I collagen promotes the strongest adhesion, proliferation, and migration relative to the other substrates tested. Utilising function-blocking monoclonal antibodies directed against particular integrin subunits in cell adhesion and migration inhibition assays, we demonstrate further that the malignant phenotype on type I collagen is mediated specifically by the a 2 b 1 integrin. These results identify a 2 b 1 integrin-mediated adhesion to type I collagen as a potential therapeutic target in the treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 61%

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

2006

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“…These observations are in good agreement with early studies on integrins and pancreatic carcinomas that reported the a6 integrin subunit to be diffusely distributed on the surface of carcinoma cells and to be present at the RNA level in pancreatic cancer cell lines and pancreatic tumor extracts. 29,30 Therefore, it is the plasma membrane-associated integrins that are expected to function in adhesion and signaling.…”

Section: Discussionmentioning

confidence: 99%

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

et al. 2007

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Pancreatic adenocarcinomas are highly invasive cancers for reasons that are currently unclear. Here we sought to determine if the proinvasive integrin a6b4 may be related to pancreatic adenocarcinoma tumor progression. Expression of integrin a6b4 was analyzed via immunohistochemistry for the b4 subunit in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) lesions, pancreatic adenocarcinomas and chronic pancreatitis. In normal pancreatic ducts, integrin a6b4 was noted only at the cell's basal interface with the basement membrane. In pancreatic adenocarcinomas, 92% (104/113) demonstrated overexpression of integrin a6b4 and altered localization to the cytoplasm and membranous regions. This pattern of expression was observed in all PanIN lesions as early as PanIN-1A, and was evident in lesions that were juxtapositioned to normal epithelium. In contrast, 93% (13/14) of chronic pancreatitis samples resembled the staining pattern of normal pancreas. When cancer was present in areas of chronic pancreatitis, this altered expression of a6b4 integrin identified the cancer. We conclude that integrin a6b4 is expressed only on the basal surface of ductal cells in normal pancreas and chronic pancreatitis. During pancreatic adenocarcinoma progression, the a6b4 integrin is dramatically overexpressed and displays altered localization at the earliest stages of PanIN, thus representing an early event in pancreatic adenocarcinoma progression. Keywords: pancreatic intraepithelial neoplasia (PanINs); immunohistochemistry; precursor lesion; integrins; pancreatic cancer; chronic pancreatitis Pancreatic carcinoma is the fourth leading cause of cancer death in the US and has the highest death to incidence ratio of all cancers. 1 Poor prognosis of pancreatic cancer patients relates to a high incidence of tumor cell invasion and metastasis. Treatment options are limited and patients succumb to the disease shortly after diagnosis unless eligible for tumor resection. 2 Of those patients that undergo resection, only 15-20% will survive to 5 years. 1 Over 90% of pancreatic cancers are adenocarcinomas that are thought to arise from proliferative premalignant pancreatic intraepithelial neoplasia (PanIN) of the ductal epithelium. PanIN lesions start as low cuboidal epithelial cells that become columnar due to increased mucin production. Cells then present with nuclear atypia and enhanced proliferation, which lead to luminal shedding and/ or invasion into the stroma. 3 These morphological alterations correlate with increased genetic abnormalities such as the activation of K-ras, loss of tumor suppressors (eg p16, p53 and DPC4) and upregulation of telomerases. 4 Although PanIN-1A and PanIN-1B are considered early cancer precursor lesions, molecular studies have shown that PanIN-2 and PanIN-3 lesions represent a distinct step toward invasive carcinoma. 5 Moreover, PanIN lesions can be found in patients with chronic pancreatitis 6 and these patients have an increased risk of developing pancreatic cancer. 7,8 Infiltrating duct-like and tubul...

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“…This cell line has been extensively characterized by us and others. 17,[32][33][34] The cell line carries mutations in codon 12 of the ras oncogene and mutations in exon 5/6 of the p53 tumour suppressor gene while RB1 is wild-type. PaCa-44 cells were grown in RPMI with 10% FCS supplemented with penicillin and streptomycin (Gibco).…”

Section: Establishment and Treatment Of Preformed Pancreatic Tumours mentioning

confidence: 99%

Targeted chemotherapy by intratumour injection of encapsulated cells engineered to produce CYP2B1, an ifosfamide activating cytochrome P450

et al. 1998

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The prognosis of pancreatic adenocarcinoma is poor and agent ifosfamide to toxic metabolites. Administration of current treatment ineffective. A novel treatment strategy is ifosfamide to tumour-bearing mice that were recipients of described here using a mouse model system for pancreatic implanted encapsulated cells results in partial or even comcancer. Cells that have been genetically modified to plete tumour ablation. These results suggest that in situ express the cytochrome P450 2B1 enzyme are encapsuchemotherapy with genetically modified cells in an lated in cellulose sulphate and implanted into pre-estabimmunoprotected environment may prove useful for lished tumours derived from human pancreatic cells. application in man. Cytochrome P450 2B1 converts the chemotherapeutic

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Expression and Function of Receptors for Extracellular Matrix Proteins in Human Ductal Adenocarcinomas of the Pancreas

Cited by 71 publications

References 0 publications

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

The α2β1 integrin mediates the malignant phenotype on type I collagen in pancreatic cancer cell lines

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

Targeted chemotherapy by intratumour injection of encapsulated cells engineered to produce CYP2B1, an ifosfamide activating cytochrome P450

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