Recurrence after resection for ductal adenocarcinoma of the pancreas

Sperti, Cosimo; Pasquali, Claudio; Piccoli, Antônio; Pedrazzoli, Sergio

doi:10.1007/s002689900215

Cited by 400 publications

(286 citation statements)

References 36 publications

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“…This means that tissue injury accompanying surgical treatment may offer the specific environment which influences dissemination of cancer cells, if residual cancer cells are present in the resected margin or in the wound fluid. In pancreatic cancer treatment, disseminative cancer spreading and metastasis often follows surgical removal of the primary tumour (Sperti et al, 1997). We found that high levels of HGF exist in peritoneal fluid after pancreatic cancer surgery and that incubation with ascitic fluid strongly stimulates invasion of pancreatic cancer cells, yet this invasion was almost completely inhibited by an HGF-antagonist and neutralizing HGF antibody.…”

Section: Discussionmentioning

confidence: 94%

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

et al. 2001

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Summary Because of the highly aggressive behaviour, i.e. invasive, disseminative and metastatic properties, the outcome for patients with pancreatic cancer is morbid. A better understanding and interference with the malignant behaviour of pancreatic cancer may provide new directions for treatment. We report here the induction of highly motile and invasive properties in human pancreatic cancer cells by hepatocyte growth factor (HGF) and blockage of these properties by NK4, a newly identified antagonist for HGF. In all of eight human pancreatic cancer cell lines we used (AsPC-1, BxPC-3, H-48N, KP-1N, KP-2, KP-3, MIA PaCa-2 and SUIT-2 cells), the c-Met/HGF receptor was expressed at varying levels. Although weak mitogenic activity of HGF was seen only in SUIT-2 and KP-3 cells, HGF strongly stimulated migration and invasion of these pancreatic cancer cells, except for BxPC-3 and MIA PaCa-2 cells. In contrast, migration and invasion potently induced by HGF in KP-1N, KP-3 and SUIT-2 cells were inhibited by NK4. The invasion of SUIT-2 cells was also potently stimulated with the influence of cocultured pancreatic fibroblasts and by ascitic fluid obtained after pancreatic cancer resection, however, invasiveness of the cancer cells in such conditions was practically abolished by NK4. Consistently, the ascitic fluid in patients who had undergone pancreatic cancer surgery contained high levels of HGF. These findings mean that HGF is probably involved in invasion, dissemination, and metastasis of pancreatic cancer, particularly through tumour-stromal interaction and after resection of the pancreatic cancer. While competitive inhibitory effects of NK4 on HGF and cMet/receptor interaction have been demonstrated in some distinct types of human cancer cells (Date et al, 1998;Hiscox et al, 2000;Kuba et al, 2000;Parr et al, 2000), inhibitory and promising therapeutic effects of NK4 have to be evaluated in cases of highly aggressive pancreatic cancer. In the current study, cancer-stromal interaction through HGF and c-Met coupling and inhibitory effects of NK4 were investigated in human pancreatic cancer cells. The invasion of pancreatic cancer cells was potently stimulated by HGF, cocultivation with fibroblasts, and by ascitic fluid from patients who had undergone pancreatic cancer resection, but this invasion was almost completely inhibited by NK4. The potential inhibition of pancreatic cancer invasion and dissemination by NK4 was thus deemed worthy of investigation. MATERIALS AND METHODS MaterialsHuman recombinant HGF was purified from the conditioned medium of Chinese hamster ovary cells transfected with human HGF cDNA (Nakamura et al, 1989;Seki et al, 1990). Polyclonal antibody against human HGF was prepared from the serum of a rabbit immunized with human recombinant HGF and IgG was purified using protein A-Sepharose (Pharmacia Biotech, Uppsala). Anti-human HGF IgG (1 µg ml -1 ) completely neutralized the biological activities of 1 ng ml -1 human HGF. NK4 was prepared by proteolytic digestion with elastase, as described elsewher...

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Section: Discussionmentioning

confidence: 94%

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

et al. 2001

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“…Rates of curative resection remain low and adjuvant therapy failure, even after curative resection, has only limited impact2, 3, 4, 5, 6. Neoadjuvant therapy has been advocated in an attempt to increase radical resections, decrease distant recurrence and improve selection of patients for surgery.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the impact of neoadjuvant therapy on patterns of recurrence in pancreatic ductal adenocarcinoma

et al. 2018

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BackgroundNeoadjuvant therapy may increase the rate of radical tumour resection in patients with pancreatic cancer. Its impact on tumour recurrence has not been investigated fully. This study aimed to assess the impact of neoadjuvant therapy on patterns of recurrence.MethodsA systematic review was performed of articles identified through the PubMed, Scopus, Embase, Ovid and Google Scholar databases that analysed the relationship between neoadjuvant therapy and recurrence published to January 2016. The main endpoint was overall tumour recurrence. Other endpoints included local recurrence, any kind of distant, hepatic, pulmonary or peritoneal metastasis.ResultsA total of 4257 citations were reviewed. Twelve observational studies comprising 1365 patients were analysed. Neoadjuvant therapy significantly reduced the risk of overall (risk ratio (RR) 0·82, 95 per cent c.i. 0·74 to 0·90; P < 0·001) and local (RR 0·42, 0·32 to 0·55; P < 0·001) recurrence. Neoadjuvant therapy did not reduce the risk of any kind of distant (RR 1·02, 0·91 to 1·14; P = 0·78), hepatic (RR 0·86, 0·68 to 1·10; P = 0·23), pulmonary (RR 0·99, 0·37 to 2·66; P = 0·98) or peritoneal (RR 0·88, 0·57 to 1·38; P = 0·58) metastasis.ConclusionNeoadjuvant therapy reduced the risk of local recurrence but not that of distant metastasis.

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“…Most patients with PDAC do not develop symptoms, such as jaundice or pain, until the tumour is already in a locally advanced or metastatic stage. Unfortunately, no curative treatment options are available for these patients, and even patients with localised disease where a curative resection is attempted frequently relapse, with mean survival ranging between 8 and 14 months (Conlon et al, 1996;Sperti et al, 1997;Trede et al, 2001). Recent advances in adjuvant therapy have achieved survival rates of 20 months , which represents an improvement, though on a low level.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions

Buchholz

Braun

Heidenblut³

et al. 2005

Oncogene

169

121

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Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumours. Both the late clinical presentation of patients, due to lack of early symptoms, as well as the rapid and aggressive course of the disease contribute to the extremely high mortality of this malignancy. Recently, a multistep progression model for PDAC integrating morphological, clinical and molecular evidence has been proposed. Putative precursor lesions, termed pancreatic intraepithelial neoplasia (PanIN), are classified into three different grades (PanIN-1 through -3) based on the degree of cellular atypia they display. We have conducted large-scale expression profiling analyses of microdissected cells from normal pancreatic ducts, PanINs of different grades and PDACs using whole-genome oligonucleotide microarrays. Verification of hybridisation results for selected genes was performed using quantitative real-time PCR and immunohistochemical analyses on PanIN tissue microarrays.Comparison of the expression profiles demonstrated that the greatest changes in gene expression occur between PanIN stages 1B and 2, suggesting that PanIN-2 may represent the first truly preneoplastic stage in PDAC progression. Our results identify a large number of potential target genes for the development of novel molecular diagnostic and therapeutic tools for the prevention and early diagnosis of PDAC and provide novel insights into the pathophysiological mechanisms involved in tumour progression in the pancreas. Oncogene (2005) 24, 6626-6636.

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Recurrence after resection for ductal adenocarcinoma of the pancreas

Cited by 400 publications

References 36 publications

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

Meta-analysis of the impact of neoadjuvant therapy on patterns of recurrence in pancreatic ductal adenocarcinoma

Transcriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions

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