Induction of platelet‐derived growth factor A and B chains and over‐expression of their receptors in human pancreatic cancer

Ebert, Matthias P.; Yokoyama, Munehiro; Friess, Helmut; Kobrin, Michael S.; Büchler, Markus W.; Korc, Murray

doi:10.1002/ijc.2910620507

Cited by 112 publications

(86 citation statements)

References 20 publications

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“…Recently, several molecular alterations which are induced by TGF-b1 in pancreatic cancer cells in vitro have been identified. Thus, the induction of PDGFs and cyclin D1 in pancreatic cancer cells by TGF-b1 has been reported (Ebert et al, 1995;Kornmann et al, 1999). Our current study may further help to understand how this growth factor may contribute to pancreatic cancer pathogenesis, despite its growth inhibitory effect on pancreatic cancer cells in vitro.…”

Section: Discussionmentioning

confidence: 58%

“…While we and others have identified a high frequency of growth factor overexpression in pancreatic cancer, the molecular mechanisms of growth factor mediated pancreatic tumorigenesis remain largely unknown (Korc et al, 1992;Ebert et al, 1995;Fujimoto et al, 1998;Löhr et al, 2001). TGF-b1, the most prominent and well characterized member of the large TGF-b superfamily, is highly expressed in pancreatic cancers (Friess et al, 1993).…”

Section: Discussionmentioning

confidence: 86%

“…However, the exact molecular mechanisms of its pathogenesis remain largely unknown. We and others have reported the frequent overexpression of oncogenes and growth factors, such as EGF, FGF, VEGF and PDGF in pancreatic cancers along with the overexpression of their respective receptors (Korc et al, 1992;Ebert et al, 1995;Kornmann et al, 1997;Fujimoto et al, 1998). Furthermore, growth factors of the TGF-b superfamily are also overexpressed in this tumour and TGF-b1 overexpression is associated with poor survival in these patients (Friess et al, 1993).…”

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confidence: 83%

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Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

et al. 2002

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PTEN is a candidate tumour suppressor gene and frequently mutated in multiple cancers, however, not in pancreatic cancer.Recently, it has been demonstrated that PTEN expression is regulated by TGF-b1. Using TGF-b1 transgenic mice (n=7) and wildtype littermates (n=6), as well as pancreatic tissues obtained from organ donors (n=10) and patients with pancreatic cancer (n=10), we assessed the expression of PTEN by means of immunohistochemistry and semiquantitative PCR analysis. In addition, PANC-1 cells were treated with TGF-b1 in vitro and the levels of PTEN mRNA were determined in these cells. In human pancreatic cancers PTEN mRNA levels were significantly decreased (P50.05). In addition, in the pancreas of TGF-b1 transgenic mice the expression of PTEN was significantly reduced (P50.01), as compared to wildtype littermates and incubation of PANC-1 cells with TGF-b1 decreased PTEN mRNA levels after 24 h. Inasmuch as TGF-b1 decreases PTEN expression in human pancreatic cancer cells and human pancreatic cancers overexpress TGF-b1, the reduced expression of PTEN in pancreatic cancer may be mediated by TGF-b1 overexpression. Thus, although PTEN is not mutated in pancreatic cancers, the reduction of its expression may give pancreatic cancer cells an additional growth advantage.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 86%

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confidence: 83%

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Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

et al. 2002

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“…neoplastic cells and interstitial cells) contributing to the overexpression of growth factors inducing desmoplasia in pancreatic cancer has remained obscure. It is generally believed that the cancerous component secretes the growth factors that give rise to this host reaction (Korc et al, 1992;Friess et al, 1993;Yamanaka et al, 1993;Ebert et al, 1995;Gold, 1999;Wenger et al, 1999). However, as haematopoietic cells including lymphocytes, macrophages and granulocytes are also capable of secreting growth factors (Roberts and Sporn, 1988;Grotendorst et al, 1989;Leonardi et al, 2000), we hypothesised that infiltrated haematopoietic cells in addition to cancer cell itself could be a source of growth factors that result in induction of desmoplasia.…”

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confidence: 93%

“…In various malignancies including pancreatic cancer, overexpression of these growth factors is frequently observed (Korc et al, 1992;Friess et al, 1993;Yamanaka et al, 1993;Ebert et al, 1995;Gold, 1999;Wenger et al, 1999) and has been associated with a significant decrease in the survival and advanced tumour stage . Comprehensive analysis, however, concerning the growth factors that have the strongest impact on the induction of the desmoplastic reaction has never been reported; furthermore, as to which one of the cellular component (i.e.…”

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confidence: 99%

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

et al. 2004

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Pancreatic cancer is often associated with an intense production of interstitial collagens, known as the desmoplastic reaction. To understand more about desmoplasia in pancreatic cancer, the expression of mRNA for type I and III collagens and potent desmoplastic inducing growth factors transforming growth factor-b (TGF-b), connective tissue growth factor (CTGF), acidic and basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) A and C and epidermal growth factor (EGF) was analysed by quantitative RT-PCR. Expression of both collagens in 23 frozen primary pancreatic cancer nodules was significantly higher than that in 15 nonneoplastic pancreatic tissues. The expressions of mRNAs for TGF-b, acidic FGF, basic FGF and PDGF C were likewise higher in surgical cancer nodules, while that of CTGF, PDGF A and EGF were not. Among these growth factors, the expression of TGF-b mRNA showed the most significant correlation with that of collagens (Po0.0001). By immunohistochemistry, TGF-b showed faint cytoplasmic staining in cancer cells. In contrast, isolated cells, mainly located on the invasive front surrounding cancerous nests, were prominently and strongly stained. These TGF-b-positive cells contained a segmented nucleus, were negative for anti-macrophage (CD68) and positive for anti-granulocyte antibodies, indicating their granulocytic nature. In conclusion, TGF-b seemed to play a major role among the various growth factors in characteristic overproduction of collagens in pancreatic cancer. Moreover, the predominant cells that express TGF-b were likely to be infiltrated granulocytes (mostly are neutrophils) and not pancreatic cancer cells.

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Molecular pathology of primary and metastatic ductal pancreatic lesions

Ruggeri

Huang

Berger

et al. 1997

Cancer

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BACKGROUND The molecular pathology underlying the development and progression of ductal pancreatic adenocarcinoma is poorly understood relative to that of other major cancers in industrialized societies. The frequency, nature, and distribution of p53 abnormalities, their temporal relationship to the metastatic and clinicopathologic phenotypes of sporadic and familial pancreatic cancer, and their consequent effects on the genetics and expression of critical wild‐type p53‐regulated genes (mdm‐2 and p21/WAF‐1) warrant examination in pancreatic adenocarcinoma. This molecular and immunochemical study of the p53, mdm‐2, and p21/WAF‐1 genes and gene products examined the largest series of nonneoplastic, neoplastic, and metastatic ductal pancreatic lesions reported to date in relation to clinicopathologic profile. METHODS Histologically confirmed specimens of primary (n = 136) and metastatic (n = 23) sporadic and familial ductal pancreatic adenocarcinoma lesions were subjected to immunochemical analyses of p53 expression in which a panel of 3 antibodies was utilized. A panel of nonneoplastic but histologically abnormal pancreatic lesions (n = 77) from individuals with varied histories of cigarette smoking were subjected to similar immunohistochemical examinations. In addition, 3 specimens from patients with chronic pancreatitis, 2 specimens of normal fetal pancreata, and 16 specimens of normal adult pancreata were examined as control tissues. Suitable frozen and archival microdissected tumor lesions were evaluated for mutations in exons 4‐9 of the p53 gene by single strand conformation polymorphism (SSCP) and dideoxy sequencing analyses in which two distinct sets of outer and nested intron‐based amplification primers were used for each exon. A subset of 25 tumor specimens and 18 tumor‐derived cell lines for which the p53 mutation status was known were examined for amplification and/or overexpression of the mdm‐2 gene; amplification was determined by Southern hybridization and overexpression by immunohistochemical and Western blot analyses. Similarly, mutations in the coding region of p21/WAF‐1 gene were examined by SSCP and DNA sequence analyses, and steady‐state expression of the p21/WAF‐1 protein was assessed by Western blot analysis in these subsets of tumors and tumor‐derived cell lines. RESULTS Positive ductal nuclear p53 immunostaining was demonstrated in 56% of primary tumors and 54% of metastatic lesions. The frequency did not differ significantly between sporadic and familial lesions, and immunostaining was not observed in ductal, acinar, or islet cell elements of normal pancreata or histologically abnormal benign pancreatic lesions from cigarette smokers. A total of 70% of tumor samples revealed reproducible SSCP abnormalities for p53; 42% of these were found in exons 7 and 8. DNA sequence analysis of cases with greater than 35% epithelial cellularity (n = 25) revealed 17 missense mutations, 12 of which were transitions. Seventy‐five percent of these transitions were of G:C→A:T type. A total of 22% of ...

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Induction of platelet‐derived growth factor A and B chains and over‐expression of their receptors in human pancreatic cancer

Cited by 112 publications

References 20 publications

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

Molecular pathology of primary and metastatic ductal pancreatic lesions

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