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Helmut Friess

Publications and source records attributed to Helmut Friess.

At least 91 records · Page 5Linked to original sources

Renal cancer cell metastasis into the pancreas: a single-center experience and overview of the literature.

OBJECTIVES: The pancreas is a rare target for metastasis from other primary cancers, but pancreatic metastasis play a role in the diagnostic workup of patients with pancreatic tumors, especially in patients with a history of renal cell carcinoma (RCC). METHODS: Between October 2001 and June 2004 data from 601 patients undergoing pancreatic resection were entered prospectively in a database and were analyzed for metastasis into the pancreas from RCC. RESULTS: Fifteen patients with metastasis to the pancreas from RCC were identified. One patient showed metastatic disease at time of primary diagnosis. In 8 patients, the pancreas was the only site of metastasis, whereas in 7 patients, other organs, such as the thyroid gland, the lung, or the liver, were targets of metastasis, either metachronous or simultaneous at the time of pancreatic metastasis. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 86 months (range, 0-258). Most patients were asymptomatic and diagnosed during standard tumor follow-up. So far, 14 patients remain alive with a median follow-up of 10 months. CONCLUSION: Pancreatic metastasis from RCC is rare but can occur even more than 20 years after primary tumor manifestation. Our results show that pancreatic resections for metastasis can be performed safely with a low rate of complications. Patients with a history of RCC should undergo a long-term follow-up to detect and evaluate for pancreatic metastases as well for metastasis to other organ sites.

Aged↗

Prostate stem cell antigen is a putative target for immunotherapy in pancreatic cancer.

UNLABELLED: The prostate stem cell antigen (PSCA) is a glycosylphosphatidyl-inositol (GPI)-linked cell surface antigen expressed in normal prostate and overexpressed in the majority of prostate cancers and correlates with tumor grade and disease stage. Because PSCA has been described to be up-regulated in pancreatic cancer, the purpose was to evaluate the expression of PSCA in human pancreatic cancer. Furthermore, the therapeutic efficacy of a monoclonal anti-PSCA antibody in an in vivo pancreatic cancer model was determined. METHODS: The expression of PSCA in human pancreatic cancer tissues was determined and compared with chronic pancreatitis and normal pancreas by quantitative reverse transcriptase-polymerase chain reaction. Therapeutic efficacy of the monoclonal anti-PSCA antibody 1G8 was examined in Capan-1 pancreatic tumors grown as subcutaneous grafts in athymic nude mice. RESULTS: PSCA was strongly up-regulated in human pancreatic cancer compared with chronic pancreatitis and normal pancreas. In addition, the PSCA protein was expressed on the cell surface of pancreatic cancer cells. Treatment with 1G8 significantly reduced tumor growth initiation in an in vivo pancreatic cancer xenograft model. In addition, antibody treatment of established tumors reduced tumor progression. CONCLUSIONS: These results show a potential therapeutic role for anti-PSCA antibodies in the treatment of pancreatic cancer. Furthermore, PSCA might serve as a novel marker in the diagnosis of pancreatic cancer.

Animals↗

Phosphatidylserine receptor in chronic pancreatitis: evidence for a macrophage independent role.

OBJECTIVE: This study analyzes the role of phosphatidylserine receptor (PSR) in chronic pancreatitis. SUMMARY BACKGROUND DATA: In chronic pancreatitis, destruction of parenchyma comes along with infiltration of lymphocytes and macrophages. The phosphatidylserine receptor is expressed on the surface of macrophages and is crucial for the recognition and engulfment of apoptotic cells. In the present study, we investigated the role of this receptor and its relation to apoptosis in chronic pancreatitis. METHODS: The expression and localization of PSR were analyzed by Northern blot analysis, RT-PCR, Western blot analysis and immunohistochemistry. Apoptosis was detected by the TUNEL method, and the RNA protection assay (RPA) was used to compare activation of apoptosis with PSR mRNA expression levels. In addition, the molecular data were related to clinicopathological parameters. RESULTS: PSR mRNA expression was low to absent in normal pancreatic tissue samples. In human chronic pancreatitis, increased expression of PSR mRNA was present in 12 of 29 samples (41%). Up-regulation of PSR could be confirmed by Western blot analysis. In chronic pancreatitis tissue, PSR immunoreactivity was present in all islets, in some ductal cells and in macrophages. The RNA protection assay revealed high mRNA levels of the antiapoptotic genes bcl-2 and bfl-1 (P < 0.05) in chronic pancreatitis tissues with high PSR mRNA expression. The TUNEL apoptosis in situ detection method showed positive signals in some redifferentiating acinar cells and focally in acinar cells adjacent to stromal fibroblasts in chronic pancreatitis tissue samples. The distribution pattern of PSR on pancreatic cells in chronic pancreatitis corresponded to a great extent with regions of high apoptotic activity. CONCLUSIONS: We show for the first time the presence of PSR in chronic pancreatitis on pancreatic cells other than macrophages in regions with high apoptotic activity. The coexpression and colocalization of this gene with other apoptosis mediators suggest its involvement in apoptotic processes. However, in chronic pancreatitis PSR is not only involved in phagocytosis of apoptotic cells by macrophages.

Adolescent↗

Osteonectin influences growth and invasion of pancreatic cancer cells.

OBJECTIVE: We sought to examine the expression and functional role of osteonectin in primary and metastatic pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The glycoprotein osteonectin plays a vital role in cell-matrix interactions and is involved in various biologic processes. Overexpression of osteonectin is present in malignant tumors and correlates with disease progression and poor prognosis. METHODS: Expression of osteonectin was analyzed by quantitative polymerase chain reaction and immunohistochemistry in pancreatic tissues and by enzyme-linked immunosorbent assay in the serum of patients and donors. Recombinant osteonectin and specific antisense oligonucleotides were used to examine the effects of osteonectin on induction of target genes, and on proliferation and invasiveness of pancreatic cancer cells. RESULTS: There was a 31-fold increase in osteonectin mRNA levels in PDAC and a 16-fold increase in chronic pancreatitis as compared with the normal pancreas (P < 0.01). By immunohistochemistry, faint immunoreactivity was detected in the normal pancreas. In contrast, strong staining of the cancer cells was observed in addition to extensive osteonectin immunoreactivity in surrounding fibroblasts and in the extracellular matrix. In metastatic tissues, strong immunoreactivity was observed in fibroblasts and in extracellular matrix surrounding metastatic cancer cells, whereas the signal was absent in most tumor cells. In vitro studies showed that osteonectin was able to inhibit cancer cell growth while promoting invasiveness of pancreatic tumor cells. CONCLUSION: Osteonectin is markedly overexpressed in pancreatic cancer and has the potential to increase the invasiveness of pancreatic cancer cells.

Adenocarcinoma↗

The Notch signaling pathway is related to neurovascular progression of pancreatic cancer.

OBJECTIVE: To analyze the potential role of the Notch signaling pathway in pancreatic cancer angiogenesis and invasion. BACKGROUND: Angiogenesis, pain, and early neuroinvasion are clinical features of pancreatic cancer. Blood vessels and nerves develop together and use common routes through the organism. The Notch pathway (Notch-1/4, Jagged-1/2, Delta-1) appears crucial in this process. The current study analyzed the Notch pathway in pancreatic cancer and characterized its angiogenic and invasive effects. METHODS: Five PaCa cell lines were cultured for the in vitro experiments. Real-time quantitative RT-PCR was done to quantify mRNA expression in 31 human PaCa specimens, and immunohistochemistry was used to localize protein expression within tumor specimens. Activation of the Notch signaling was done by transfection of PaCa cells with a constitutive active Notch-1 mutant (Notch-IC). Overexpression of Jagged and Delta was achieved by transfection of full-length cDNA. Spheroid assays were used to study angiogenesis and ELISAs to measure VEGF, bFGF, and angiogenin expression. Matrigel invasion assays were used to analyze tumor cell invasion. RESULTS: Notch-3 and Notch-4 mRNA were significantly (P < 0.001) overexpressed in PaCa. Immunohistochemistry revealed protein accumulation of Notch-1 as well. All ligands were significantly up-regulated. A positive immunosignal of ligands was seen in nerves, blood vessels, and ductal tumor cells. Transfection of PaCa cells with the constitutive active Notch-IC mutant and with Jagged-1 revealed increased levels for VEGF. Concomitantly, recombinant Jagged-1 increased sprouting of endothelial cells in the spheroid assay. CONCLUSION: The Notch pathway most likely regulates neurovascular development in pancreatic cancer. Activation of this signaling pathway by constitutive Notch-1 mutants and by Jagged-1 causes an angiogenic and invasive tumor phenotype. Specific blockade of Notch signaling may therefore be beneficial for patients with pancreatic cancer.

Disease Progression↗

Carcinoid of the ampulla of Vater.

Endocrine neoplasms only rarely occur at the ampulla of Vater, comprising mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas). Only 105 cases are reported in the literature, most as single case reports. For many years, the neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract have been subsumed as 'carcinoids'. Instead, in the latest World Health Organization (WHO) classification published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas). Patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis. Besides endoscopic retrograde cholangiopancreatography, endosonography, computed tomography or magnetic resonance imaging may complete the staging approach of this tumor. The Kausch-Whipple procedure or pylorus-preserving pancreaticoduodenectomy is considered the treatment of choice for ampullary, well-differentiated carcinoids >2.0 cm and for ampullary neuroendocrine carcinomas. However, it should be considered that long-term survival of patients with ampullary carcinoids is also reported after local tumor excision (5-year survival rate of 90%). The dilemma is that the differentiation of neuroendocrine tumors cannot be assessed intraoperatively in most cases. Therefore, considering that the 5-year survival rate in patients with neuroendocrine carcinomas of the ampulla of Vater is very low without radical resection, neuroendocrine tumors of the ampulla of Vater without definite histological differentiation should undergo extended surgery.

Ampulla of Vater↗

Expression analysis of PMP22/Gas3 in premalignant and malignant pancreatic lesions.

PMP22 is a structural protein of Schwann cells, but it also influences cell proliferation. In the present study, quantitative RT-PCR (QRT-PCR) and immunohistochemistry were used to determine PMP22 mRNA levels and to localize PMP22 in the normal pancreas (n=20), chronic pancreatitis (CP) (n=22), pancreatic ductal adenocarcinoma (PDAC) (n=31), intraductal papillary mucinous neoplasms (IPMN) (n=9), mucinous cystic tumors (MCN) (n=4), and in a panel of PanIN lesions (n=29). PMP22 mRNA levels were significantly higher in CP (3-fold) and PDAC (2.5-fold), compared to normal pancreatic tissues. PMP22 expression was restricted to nerves in the normal pancreas, while in CP and PDAC PMP22 was also expressed in PanIN lesions and in a small percentage of pancreatic cancer cells. PMP22 was weak to absent in the tumor cells of IPMNs and MCNs. PMP22 mRNA was present at different levels in cultured pancreatic cancer cells and up-regulated by transforming growth factor (TGF)-beta1 in 2 of 8 of these cell lines. In conclusion, PMP22 expression is present in both CP and PDAC tissues. Its expression in PanIN lesions and some pancreatic cancer cells in vitro and in vivo suggests a role of PMP22 in the neoplastic transformation process from the normal pancreas to pre-malignant lesions to pancreatic cancer.

Adult↗

KAI1 inhibits anchorage-dependent and -independent pancreatic cancer cell growth.

Decreased expression of the tumor suppressor gene, KAI1, is associated with metastasis formation in pancreatic cancer. The aim of the present study was to investigate whether KAI1 influences pancreatic cancer cell growth and colony formation. A full-length KAI1 cDNA expression vector was stably transfected into Panc-1 and MiaPaCa-2 pancreatic cancer cell lines. Transfection was confirmed by Western blot analysis and immunohistochemistry. Tumor cell growth and cell cycle distribution were determined by MTT cell growth assays, colony formation assays, and flow cytometric analysis. KAI1-transfected, but not control-transfected pancreatic cancer cells displayed cytoplasmic KAI1 immunoreactivity. Cell proliferation decreased in the KAI1-transfected cells compared to parental and control cells together with a Go/G1-phase cell cycle arrest. Colony formation was reduced by 2.6- and 3.5-fold in the KAI1-transfected Panc-1 and MiaPaCa-2 pancreatic cancer cells, respectively, compared with parental cells. KAI1 blocks pancreatic cancer cell growth through cell cycle arrest and inhibits anchorage-independent cell growth. These findings support the premise that KAI1 functions as a tumor suppressor in this malignancy.

Antigens, CD↗

Combination therapy for advanced pancreatic cancer using Herceptin plus chemotherapy.

The HER2/neu oncogene is overexpressed in up to 70% of human pancreatic cancer specimens when compared to normal pancreatic tissue. This cell surface receptor can be targeted specifically by the neutralizing antibody Herceptin. Herceptin has been successfully used in combination with other chemotherapeutic agents in breast cancer, a cancer in which only 30% of patients harbor elevated HER2/neu levels. In the present study, we investigated the therapeutic efficacy of Herceptin in combination with gemcitabine and docetaxel. Gemcitabine is currently the standard chemotherapeutic agent used to treat pancreatic cancer. In contrast, docetaxel, a taxane, is only just being investigated in pancreatic cancer. Tumor cell resistance to taxanes is at least in part mediated by the HER2/NEU oncogene. We have previously characterized HER2/NEU expression in human pancreatic cancer cell lines and studied the anti-tumor activity of Herceptin monotherapy in vitro and in vivo. In the present study, combination therapy resulted in a dramatic improvement of animals bearing human pancreatic cancer xenografts. Furthermore, metastasis and production of ascites was lower when a combination of these three agents was used. We conclude that, as with breast cancer, the anti-tumor activity of Herceptin may be improved by combination with taxanes or gemcitabine.

Agar↗

The proteasome inhibitor MG132 induces apoptosis in human pancreatic cancer cells.

The ubiquitin-proteasome system plays a critical role in the regulation of programmed cell death. Proteasome inhibitors induce apoptosis in various cancer cells and have antitumor effects in murine tumor models. In the present study, we investigated whether the cell-permeable proteasome inhibitor MG132 (carbobenzoxyl-L-leucyl-L-leucyl-L-leucinal) reduced the growth of a human pancreatic cancer cell line through induction of apoptosis in vitro. The effects of MG132 (0.125-1.000 microM) on the growth of the human pancreatic cancer cell line BxPC-3 were analyzed by cell count and MTT assay. Apoptosis was determined by FACS analysis after annexin V and propidium iodide staining and the enrichment of intracellular nucleosomes. The proteasome inhibitor MG132 decreased cell growth of the human pancreatic cancer cell line BxPC-3 in a dose- and time-dependent manner. This effect was at least in part mediated by the induction of apoptosis. A combination therapy with standard cytotoxic agents and proteasome inhibitors could potentially be a novel therapeutic strategy in treatment of pancreatic cancer.

Apoptosis↗

Pancreatic metastasis from gastric carcinoma: a case report.

BACKGROUND: The pancreas is a rare but occasionally favored target for metastasis. Metastatic lesions in the pancreas have been described for various primary cancers, such as carcinomas of the lung, the breast, renal cell carcinoma and sarcomas. CASE PRESENTATION: We report the case of a 60-year old female with a mass in the pancreatic head four years after partial gastrectomy for gastric adenocarcinoma. The patient underwent a pancreatoduodenectomy. Pathological examination revealed metastases of the primary gastric carcinoma within the pancreatic head and in regional lymph nodes. CONCLUSIONS: Pancreatic tumors in patients with a history of non-pancreatic malignancy should always be considered to be a putative metastatic lesion at an unusual site. If the pancreas can be identified as the only site of spread, radical resection may prolong survival.

Journal Article↗

Transforming growth factor-beta pathway is activated in cholecystolithiasis.

BACKGROUND: The etiopathogenesis of cholecystolithiasis is not well defined. Primary dysmotility of the organ, due to fibrosis of the gallbladder wall or muscular dysfunction, is suggested as a crucial factor. Transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) are involved in several fibrotic disorders and play a critical role in fibrogenesis, thereby changing the physiological function of the organs. In the present study we analyzed the role of TGF-beta and its downstream target CTGF in patients with cholecystolithiasis. METHODS: Gallbladders were obtained from 16 individuals undergoing surgery for symptomatic cholecystolithiasis. Normal human gallbladder tissue samples from five individuals without any history of gallbladder disease were obtained through an organ donor transplantation program. Northern blot analysis, in situ hybridization, and immunohistochemistry were used to analyze the expression of TGF-beta1 and CTGF in the gallbladder tissue samples. RESULTS: By northern blot analysis there was an enhanced TGF-beta1 mRNA expression (eightfold increase; P < 0.04) in the cholecystolithiasis tissue samples in comparison with normal controls. There was also a concomitant increase in CTGF (41-fold increase; P < 0.01). By in situ hybridization and immunohistochemistry, CTGF mRNA was localized mainly in the mucosa layer, while intensive staining of the smooth muscle cells with TGF-beta1 and CTGF was observed. In addition, TGF-beta1 immunoreactivity was also localized in the fibroblasts and inflammatory cells. TGF-beta1 m-RNA levels showed a significant relationship with the degree of fibrosis in the tissue samples (P < 0.04, r = 0.5). CONCLUSION: Our data indicate that TGF-beta and CTGF are involved in ultrastructural tissue changes in patients with cholecystolithiasis. Activation of the "TGF-beta pathway," predominantly in the remaining mucosa and submucosal layer, indicates that extracellular matrix (ECM) synthesis with subsequent gallbladder wall fibrosis is an important step in gallbladder dysfunction in this disorder.

Adult↗

The role of extended resection in pancreatic adenocarcinoma: is there good evidence-based justification?

Thus far, there are no studies concerning the radicality of pancreaticoduodenectomy which, in well-performed, randomized-controlled trials employing high standards of evidence-based medicine, show a benefit over extended lymphadenectomy. The results of the only two prospective randomized studies are not comparable and both are underpowered (level of evidence Ib). Therefore, it is still unclear whether extended lymphadenectomy for pancreatic carcinoma improves outcome. Only one study suggests a positive tendency toward increased survival rates in node-positive patients. Extended approaches including additional venous resection can be performed without a rise in the morbidity and mortality rates of patients with pancreatic carcinoma. In the future appropriately powered randomized trials of standard vs. extended resections may show the benefit of extended surgical resections. In addition, well powered trials of postoperative adjuvant therapies or preoperative neoadjuvant strategies together with surgical resections may identify more effective combinations showing a survival benefit in patients with pancreatic carcinoma.

Adenocarcinoma↗

Pancreatic tumor cells influence the composition of the extracellular matrix.

The malignant behavior of cancers depends on the microenvironmental context. We investigated compositional alterations of the extracellular matrix (ECM) in pancreatic cancer, with special emphasis on the proteoglycans decorin, lumican, and versican. Compared with normal controls (n=18), marked overexpression of these proteoglycans was observed in pancreatic cancer tissues (n=30) by quantitative RT-PCR (p<0.0001). Immunohistochemistry revealed abundance of proteoglycans in the ECM of pancreatic cancer specimens, whereas tumor cells themselves were devoid of either decorin, lumican or versican. RT-PCR confirmed pancreatic stellate cells (PSCs) as the major source of these proteins. Interestingly, TGFbeta1 and conditioned medium derived from pancreatic cancer cell lines synergistically suppressed the expression of known anti-tumor factors decorin and lumican, but stimulated the expression of pro-metastatic factor versican in cultured PSCs. These findings indicate that malignant cells can actively influence the composition of the ECM through TGFbeta1 and other soluble factors, altering their microenvironment in a tumor-favorable way.

Adenocarcinoma↗

Impact of volume and specialization for cancer surgery.

BACKGROUND/AIMS: The so-called volume/outcome relationship postulates that a higher caseload and specialization results in an improved outcome. The existence of such a relationship, however, is still debated in the literature. The objective of this review is to discuss the available data on this relationship in surgical oncology. METHODS: A Medline analysis was performed using the following terms: volume, outcome, cancer, and surgery. The bibliography of each relevant article was screened for further studies. RESULTS: For most malignancies a volume/outcome relationship was demonstrated in recent years. Components of this improved outcome are decreased perioperative morbidity and mortality, higher quality of life after surgery, improved economic outcome, and a better long-term prognosis for patients with cancer. The magnitude of this relationship, however, varies greatly among different malignancies. The exact reason for the volume/outcome relationship is still unknown. CONCLUSION: Concentrating high-risk procedures in high-volume hospitals might prevent thousands of perioperative deaths per year. This concept seems feasible for rare and high-risk diseases; however, it is unclear what threshold should be used for the definition of a high-volume provider. For common and low-risk diagnoses, it seems more realistic to educate the medical community in order to improve the outcome for the patients.

Clinical Competence↗

Glypican-1 antisense transfection modulates TGF-beta-dependent signaling in Colo-357 pancreatic cancer cells.

The heparan sulfate proteoglycan glypican-1 is essential as a co-receptor for heparin binding growth factors, such as HB-EGF and FGF-2, in pancreatic cancer cells. In the present study, the role of glypican-1 in the regulation of TGF-beta signaling was investigated. Colo-357 pancreatic cancer cells were stably transfected with a full-length glypican-1 antisense construct. Cell growth was determined by MTT and soft agar assays. TGF-beta1 induced p21 expression and Smad2 phosphorylation were analyzed by immunoblotting. PAI-1 promoter activity was determined by luciferase assays. Down-regulation of glypican-1 expression by stable transfection of a full-length glypican-1 antisense construct resulted in decreased anchorage-dependent and -independent cell growth in Colo-357 pancreatic cancer cells and attenuated TGF-beta1 induced cell growth inhibition, Smad2 phosphorylation, and PAI-1 promoter activity. There was, however, no significant difference in TGF-beta1 induced p21 expression and Smad2 nuclear translocation. In conclusion, glypican-1 is required for efficient TGF-beta1 signaling in pancreatic cancer cells.

Cell Division↗

Desmoplastic reaction influences pancreatic cancer growth behavior.

Connective tissue growth factor (CTGF), which is regulated by transforming growth factor-ss (TGFss), has recently been implicated in the pathogenesis of fibrotic diseases and tumor stroma. Inasmuch as generation of desmoplastic tissue is characteristic for pancreatic cancer, it is not known whether it gives pancreatic cancer cells a growth advantage or is a reaction of the body to inhibit cancer cell progression. In the present study we analyzed the expression and localization of CTGF and evaluated whether it influences the prognosis of pancreas cancer. Tissue samples were obtained from 25 individuals (6 women, 19 men) undergoing pancreatic resection for pancreatic cancer. Tissue samples from 13 previously healthy organ donors (5 women, 8 men) served as controls. Expression of CTGF was studied by Northern blot analysis. In situ hybridization and immunohistochemistry localized the respective mRNA moieties and proteins in the tissue samples. Northern blot analysis revealed that pancreatic cancer tissue samples exhibited a 46-fold increase in CTGF mRNA expression ( p < 0.001) over that of normal controls. In vitro studies confirmed that pancreatic stellate cells are the major source of CTGF mRNA expression and revealed a large variance in basal and TGFss-induced CTGF expression in cultured pancreatic cancer cells. This could also be confirmed by in situ hybridization, indicating that CTGF mRNA signals were located principally in fibroblasts, with only weak signals in the cancer cells. High CTGF mRNA levels in the tissue samples correlated with better tumor differentiation ( p < 0.03). In addition, patients whose tumors exhibited high CTGF mRNA levels (> onefold increase above normal controls) lived significantly longer than those whose tumors expressed low CTGF mRNA levels (none to onefold) ( p < 0.04 multivariate analysis). Our present data indicate that CTGF, as a downstream mediator of TGFss, is overexpressed in connective tissue cells and to a lesser extent in pancreatic cancer cells. Because patients with high CTGF mRNA expression levels have a better prognosis, our findings indicate that the desmoplastic reaction provides a growth disadvantage for pancreatic cancer cells.

Adenocarcinoma↗

Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action.

PURPOSE: The aim of this study was to investigate the expression and significance of decorin in pancreatic cancer. EXPERIMENTAL DESIGN: Decorin expression in normal pancreas and excised tumors was examined by real-time quantitative PCR, Western blot analysis, and immunohistochemistry. Reverse transcription-PCR was used to analyze cultures of pancreatic cancer and stellate cells. Growth-inhibitory effects of decorin in vitro were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, Western blot, and fluorescence-activated cell-sorting analysis. RESULTS: Pancreatic cancer was characterized by striking overexpression of decorin mRNA in tumor tissues (9-fold by real-time quantitative PCR; 44 patients versus 18 healthy donors; P < 0.01). Strong decorin immunostaining was observed in the extracellular matrix of pancreatic cancer tissue, whereas tumor cells were devoid of decorin. Double staining for anti-smooth muscle actin and decorin and reverse transcription-PCR analysis of primary cultures revealed pancreatic stellate cells as the putative source of decorin. Human recombinant decorin was able to suppress growth of pancreatic cancer cells in vitro through p21 mediated G(1)-S block of the cell cycle. However, in contrast to the previously described chemotherapy-potentiating capacity of decorin, this proteoglycan attenuated the cytostatic action of carboplatin and gemcitabine toward pancreatic cancer cells. CONCLUSIONS: Decorin might exert an antiproliferative effect toward pancreatic cancer cells, thus playing a role in a host stromal reaction aimed at sequestering and inhibiting growing malignant cells. However, in clinical settings, the importance of collagen-associated decorin as a moderate antitumor modality would be undermined by its ability to attenuate the efficiency of chemotherapeutics. Considering the general failure of adjuvant therapies in pancreatic cancer, the role of decorin in this process warrants further investigation.

Adult↗