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H Friess

Publications and source records attributed to H Friess.

At least 163 records · Page 9Linked to original sources
PubMed1999

Bone morphogenetic protein 2 exerts diverse effects on cell growth in vitro and is expressed in human pancreatic cancer in vivo.

BACKGROUND & AIMS: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta superfamily of signaling molecules. We characterized the expression of BMP-2 and its receptors in human pancreatic tissues and pancreatic cancer cell lines and examined the effects of BMP-2 on mitogenesis. METHODS: Expression of BMP-2 and its receptors was determined by Northern blot analysis using specific complementary DNA probes. Distribution of BMP-2 in pancreatic cancers was examined by immunohistochemistry and in situ hybridization. Effects of BMP-2 on mitogenesis were assessed by monitoring cell proliferation and activation of mitogen-activated protein kinase (MAPK). RESULTS: Compared with the normal pancreas, pancreatic cancers showed a 12.5-fold (P < 0.01), 2-fold (P < 0.01), and 8-fold (P < 0.01) increase of BMP-2, BMP receptor (R)-IA, and BMPR-II messenger RNA levels, respectively. By immunohistochemistry and in situ hybridization, BMP-2 was expressed in the cancer cells within the tumor mass. There was a significant correlation between the presence of BMP-2 immunostaining in the tumors and shorter postoperative survival. Pancreatic cancer cell lines expressed variable levels of messenger RNA encoding BMP-2 and its receptors. BMP-2 stimulated the growth of two pancreatic cancer cell lines (ASPC-1 and CAPAN-1). This mitogenic effect was associated with MAPK activation and blocked by the MAPK inhibitor PD98059 in CAPAN-1 but not in ASPC-1 cells. In both cell lines, expression of wild-type Smad4 abolished the BMP-2-mediated growth stimulation. BMP-2 inhibited the growth of COLO-357 cells, an effect that was blocked by expressing a dominant negative Smad4. BMP-2 had no effect in three cell lines that underexpressed either the BMP receptors or Smad1. CONCLUSIONS: These findings indicate that BMP-2 has the capacity to act as a mitogen when Smad4 is mutated and suggest that it might play a role in the pathobiology of human pancreatic cancer.

Adolescent↗
PubMed1999

Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life.

There is overwhelming consensus that quality of life assessment is urgently required in pancreatic cancer, yet little research has been conducted. We report on the development of a disease specific questionnaire module to supplement the EORTC core cancer module, the QLQ-C30 in patients with pancreatic cancer, using EORTC quality of life study group guidelines for module development. Relevant QoL issues were generated from literature searches and interviews with health professionals and patients with pancreatic cancer. Issues were constructed into items and provisionally translated. The provisional module was pretested in patients in 8 European centres. The resulting module the QLQ-PAN26 includes 26 items related to disease symptoms, treatment side-effects and emotional issues specific to pancreatic cancer. This should ensure that the module will be sensitive to assess the small but important disease and treatment related QoL changes in pancreatic cancer. The use of the QLQ-C30 and QLQ-PAN26 will provide a comprehensive system of QoL assessment in international trials of pancreatic cancer.

Adult↗
PubMed1999

Overexpression of Smad2 and colocalization with TGF-beta1 in human pancreatic cancer.

Smad2 belongs to a family of cytoplasmic molecules that are critical components in the transforming growth factor beta (TGF-beta) signaling pathway. Upon ligand binding, the type II TGF-beta receptor (TbetaRII) heterodimerizes with and activates TGF-beta receptor type I (TbetaRI). Activated TbetaRI phosphorylates Smad2, which then heterodimerizes with Smad4, translocates into the nucleus, and subsequently effects gene transcription. Previously we have shown that pancreatic cancers overexpress TGF-betas and TbetaRII. Here, we show by northern blot analysis that Smad2 mRNA levels are significantly increased in pancreatic cancer samples in comparison with normal pancreatic tissues. By immunohistochemistry, Smad2 is present in the cancer cells of 67% of the pancreatic cancer samples. Analysis of serial sections reveals coexpression of Smad2 and TGF-beta1 in the cancer cells. Furthermore, TGF-beta1 increases steady-state levels of Smad2 mRNA in the TGF-beta1-sensitive pancreatic cancer cell line COLO-357. It is suggested that pancreatic cancer cells have the capacity to up-regulate Smad2 expression, which may lead to excessive activation of specific components of the TGF-beta-signaling pathway.

Aged↗
PubMed1999

SR140333, a substance P receptor antagonist, influences morphological and motor changes in rat experimental colitis.

The etiology of inflammation, edema, and smooth muscle contraction characteristic of inflammatory bowel disease is not clearly understood. There is evidence that several neuropeptides, including substance P (SP), may play a role. In this study we evaluated the ability of a SP-antagonist (SR140333) to modify the course of experimental colitis induced in the rat by trinitrobenzene sulfonic acid (TNB). Colitis was induced in 24 rats using TNB applied by intrarectal enema. Twelve TNB-treated rats received SR140333, 0.1 mg/kg intraperitoneally, 30 min before the administration of TNB and every 48 hr until death. Twelve rats receiving only intrarectal 0.9% saline served as controls. Rats of each group were killed after 14 days. At day 14, the control group showed no signs of inflammation whereas the TNB-treated rats without SR140333 treatment exhibited a well-established colitis. The TNB-treated group had a higher level of inflammation, as seen histologically and by the significantly greater weight of colon strips, compared to the controls (0.30 +/- 0.09 g vs 0.13 +/- 0.03 g, P < 0.001) and to the SR140333-treated rats (0.30 +/- 0.09 g vs 0.14 +/- 0.05 g, P < 0.001). In addition, smooth muscle contractility was significantly reduced in the inflamed colons of TNB-treated rats when compared with the controls (carbachol: 42.7 +/- 20.3 vs 254.2 +/- 69.78 mg/mm2; SP: 18.5 +/- 10.02 vs 89.45 +/- 23.17 mg/mm2; KCl: 11.4 +/- 2.2 vs 98.32 +/- 33.57 mg/mm2, P < 0.01). However, SR140333-treated rats showed a recovery from inflammation and motor alterations caused by TNB (carbachol: 150.9 +/- 46.1 mg/mm2, P < 0.01; SP: 32.5 +/- 9.4 mg/mm2, P < 0.05; KCl: 125.7 +/- 36.1 mg/mm2, P < 0.01). In conclusion, treatment with SP antagonist SR140333 reduces the severity of colitis and has beneficial effects on the concomitant alterations of contractility. Thus, the blockade of substance P may represent a possibility in the treatment of intestinal inflammation.

Animals↗
PubMed1999

Molecular aspects of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. The success of its established treatment modalities is frequently limited by the advanced stage of the tumor at the time of diagnosis. Therefore, it is important to understand the mechanisms that control its growth behavior. In the present study, we review some aspects of molecular and cellular processes involved in growth control and metastatic potential of HCC. These include some growth factors and their receptors, oncogenes and tumor suppressor genes, and factors that control angiogenesis and extracellular matrix formation. These factors may be important targets for novel therapeutic approaches in the future.

Animals↗
PubMed1999

Transforming growth factor-betas and their signaling receptors are coexpressed in Crohn's disease.

OBJECTIVE: To evaluate mechanisms that contribute to tissue repair and tissue remodeling in Crohn's disease (CD). SUMMARY BACKGROUND DATA: Transforming growth factor-betas (TGF-betas) are involved in different chronic inflammatory disorders. They function by binding to two receptors, type I (TbetaR-I) subtype ALK5 and type II (TbetaR-II), which are concomitantly required for signal transduction. METHODS: Tissues were obtained from 18 patients with CD (10 female patients, 8 male patients, median age 38.7 years [range 16 to 58 years]) undergoing surgery because of CD-related complications. Tissue samples of 18 healthy organ donors (10 female subjects, 8 male subjects, median age 50.3 years [range 15 to 65 years]) served as controls. The expression and localization of TGF-beta1, TGF-beta2, TGF-beta3, TbetaR-IALK5, TbetaR-II, and TbetaR-III were studied by Northern blot analysis, in situ hybridization, and immunohistochemistry. RESULTS: On Northern blot analysis, 94% of the CD samples exhibited enhanced TGF-beta1, TGF-beta3, and TbetaR-II mRNA expression compared with controls. TGF-beta2 was increased in 72%, TbetaR-IALK5 in 72%, and TbetaR-III in 82% of the patients with CD. On in situ hybridization and immunohistochemical analysis, TGF-beta1, TbetaR-IALK5, and TbetaR-II were seen to be colocalized in the lamina propria cells and in the lymphocytes closest to the luminal surface, but also in the remaining epithelial cells, and in fibroblasts of CD tissue samples. CONCLUSIONS: The concomitant overexpression of TGF-betas and their signaling receptors in CD points to a potential role of these regulatory molecules in the pathophysiology of CD. Activation of TGF-beta-mediated pathways might promote the repair of mucosal injury by enhancing the process of reepithelization, but might also contribute to extracellular matrix generation and subsequently to intramural fibrosis and intestinal obstruction.

Adolescent↗
PubMed1999

Connective tissue growth factor is a regulator for fibrosis in human chronic pancreatitis.

OBJECTIVE: To evaluate the parameters that mediate fibrogenesis in chronic pancreatitis (CP). BACKGROUND: Connective tissue growth factor (CTGF), which is regulated by transforming growth factor beta (TGF-beta), has recently been implicated in skin fibrosis and atherosclerosis. In the present study, the authors analyzed the concomitant presence of TGF-beta1 and its signaling receptors-TGF-beta receptor I, subtype ALK5 (TbetaR-I(ALK5)), and TGF-beta receptor II (TbetaR-II)-as well as CTGF and collagen type I in the pancreatic tissue of patients undergoing surgery for chronic pancreatitis. PATIENTS AND METHODS: CP tissue samples were obtained from 40 patients (8 women, 32 men) undergoing pancreatic resection. Tissue samples of 25 previously healthy organ donors (12 women, 13 men) served as controls. The expression of TGF-beta1, TbetaR-I(ALK5), TbetaR-II, CTGF, and collagen type I was studied by Northern blot analysis. By in situ hybridization and immunohistochemistry, the respective mRNA moieties and proteins were localized in the tissue samples. RESULTS: Northern blot analysis showed that CP tissue samples exhibited concomitant enhanced mRNA expression of TGF-beta1 (38-fold), TbetaR-II (5-fold), CTGF (25-fold), and collagen type I (24-fold) compared with normal controls. In addition, TbetaR-I(ALK5) mRNA was increased in 50% of CP tissue samples (1.8-fold). By in situ hybridization, TGF-beta1, TbetaR-I(ALK5), and TbetaR-II mRNA were often seen to be colocalized, especially in the ductal cells and in metaplastic areas where atrophic acinar cells appeared to dedifferentiate into ductal structures. In contrast, CTGF was located in degenerating acinar cells and principally in fibroblasts surrounding these areas. Moreover, CTGF mRNA expression levels correlated positively with the degree of fibrosis in CP tissues. CONCLUSION: The concomitant overexpression of CTGF, collagen type I, TGF-beta1, and its signaling receptors in CP suggests that these proteins contribute to enhanced extracellular matrix synthesis and accumulation, resulting finally in the fibrogenesis observed in CP.

Adult↗
PubMed1999

Nerve growth factor and its high-affinity receptor in chronic pancreatitis.

OBJECTIVE: To study the mechanisms that are involved in nerve growth and contribute to pain generation in chronic pancreatitis (CP). SUMMARY BACKGROUND DATA: Chronic pancreatitis is a painful disease associated with characteristic nerve changes, including an increase in nerve number and diameter. The mechanisms that influence nerve growth are not known. Nerve growth factor (NGF) and its high-affinity tyrosine kinase receptor A (TrkA) are involved in neural development and survival and growth of central and peripheral nerves. METHODS: Nerve growth factor and TrkA were investigated by Northern blot analysis, in situ hybridization, and immunohistochemical staining in the pancreases of 24 patients with CP, and the findings were correlated with clinical parameters. RESULTS: By Northern blot analysis, NGF and TrkA mRNA expression were increased in 42% (13.1-fold) and 54% (5.5-fold) of the CP samples (p < 0.01), respectively. In situ hybridization revealed that in CP, enhanced NGF mRNA expression was present in metaplastic ductal cells, in degenerating acinar cells, and in acinar cells dedifferentiating into tubular structures. TrkA mRNA was intensely present in the perineurium. Further, enhanced NGF and TrkA mRNA signals were also present in intrapancreatic ganglia cells in CP samples. Immunohistochemistry confirmed the in situ hybridization findings. Analysis of the molecular findings with clinical parameters revealed a significant relation (p < 0.05) between NGF mRNA levels and pancreatic fibrosis (r = 0.64) and acinar cell damage (r = 0.74) and between TrkA mRNA and pain intensity (r = 0.84). CONCLUSION: Activation of the NGF/TrkA pathway occurs in CP. It might influence neural morphologic changes and the pain syndrome in this disorder.

Adult↗
PubMed1999

Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas.

OBJECTIVE: To compare growth factor receptor expression in papilla of Vater cancer and pancreatic cancer. SUMMARY BACKGROUND DATA: Cancer of the papilla of Vater has a much better prognosis than pancreatic cancer. Earlier symptoms may result in earlier diagnosis, but different biologic growth behaviors and genetic alterations might also be explanations. PATIENTS AND METHODS: Surgical specimens from papilla of Vater cancers (24 patients) and pancreatic cancers (80 patients), normal papilla of Vater tissues (20 patients), and normal pancreatic tissues (24 patients) were frozen and fixed. The authors compared the expression of the epidermal growth factor receptor (EGFR) and c-erbB2 and c-erbB3 by Northern blot, in situ hybridization, and immunohistochemistry. RESULTS: In papilla of Vater cancer, Northern blots showed comparable EGFR and c-erbB2 mRNA expression but significantly lower c-erbB3 mRNA levels than in normal papilla. In pancreatic cancer, mRNA expression was enhanced compared with normal controls for EGFR (4-fold), c-erbB2 (2.5-fold), and c-erbB3 (5.2-fold). In situ hybridization confirmed this and showed mRNA expression only in cancer cells. EGFR immunohistochemical staining scores were comparable in papilla of Vater cancer (1.17 +/- 0.22) and normal papilla (1.42 +/- 0.25). Staining scores for c-erbB2 (2.72 +/- 0.40 vs. 3.89 +/- 0.37) and c-erbB3 (2.78 +/- 0.35 vs. 3.89 +/- 0.53) were slightly lower than controls in papilla of Vater cancer. In pancreatic cancer, immunostaining scores for EGFR, c-erbB2, and c-erbB3 were significantly higher than controls. CONCLUSION: Members of the EGFR family show similar or lower expression in papilla of Vater cancer than in normal controls. In pancreatic cancer, these receptors are upregulated. This supports the hypothesis that papilla of Vater cancer and pancreatic cancer have biologic differences that may contribute to the different growth of these tumors.

Adult↗
PubMed1999

Alteration of fibroblast growth factor and receptor expression after acute pancreatitis in humans.

After an episode of acute pancreatitis (AP) in humans, the pancreas exhibits varying degrees of fibrosis, acinar cell regeneration, and the formation of tubular complexes. The mechanisms underlying these changes are unknown. By using Northern blot analysis and immunohistochemistry, we assessed the expression and distribution of fibroblast growth factors (FGFs) and their receptor in human pancreatic tissues obtained from patients with AP. By comparison with the normal pancreas, acidic FGF (aFGF) and FGF-receptor 1 (FGFR-1, flg), mRNA levels were significantly decreased in human pancreatic tissues, which were obtained approximately 8 days after onset of AP. In the normal pancreas, acidic FGF, basic FGF, and FGFR-1 immunoreactivity was present at low to moderate levels in a heterogeneous pattern in the cytoplasm of acinar and ductal cells. Two patterns of immunoreactivity were observed in the AP group. In regions that have undergone necrosis, there was complete loss of aFGF, bFGF, and FGFR-1 immunostaining. In contrast, in the regenerating areas, aFGF and bFGF were readily evident in exocrine-type cells, in association with a marked increase in FGFR-1 immunoreactivity. These findings indicate that FGF/receptor expression is altered after AP, and raise the possibility that FGFs may be involved in the process of pancreatic exocrine regeneration during recovery from AP.

Acute Disease↗
PubMed1999

Ligand induced upregulation of the type II transforming growth factor (TGF-beta) receptor enhances TGF-beta responsiveness in COLO-357 cells.

The effects of transforming growth factor (TGF)-beta 1 on type I and type II TGF-beta receptor (T beta RI and T beta RII) expression were examined in five pancreatic cancer cell lines. In contrast to its actions in COLO-357, a TGF-beta-sensitive pancreatic cancer cell line, TGF-beta 1 did not significantly alter TGF-beta receptor expression in either the TGF-beta-sensitive BXPC-3 and PANC-1 cells or in the TGF-beta-resistant CAPAN-1 and T3M4 cells. Neutralizing anti-T beta RII antibodies blocked TGF-beta 1-dependent signaling in COLO-357 cells but exhibited an attenuated effect in COLO-357 cells preincubated with TGF-beta 1 for 48 h. Basal T beta RII expression levels were comparable in all five cell lines examined. In contrast, COLO-357 cells and BX-PC-3 cells expressed relatively high basal levels of T beta RI. However, COLO-357 cells harbored a normal Smad4 gene, whereas BX-PC-3 cells exhibited a complete deletion of this gene. We conclude that the TGF-beta 1-induced T beta RII upregulation serves to enhance TGF-beta 1 responsiveness in COLO-357 cells, and that this upregulation requires the presence of adequate levels of T beta RI and T beta RII, and a functional Smad4 gene product. Our findings also indicate that TGF-beta 1 may inhibit pancreatic cancer cell growth via a Smad4-independent pathway.

Cell Division↗
PubMed1999

Stable transfection of a glypican-1 antisense construct decreases tumorigenicity in PANC-1 pancreatic carcinoma cells.

Glypican-1 belongs to a family of glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycans (HSPGs) that affect cell growth, invasion, and adhesion. Cell-surface HSPGs are believed to act as co-receptors for heparin-binding mitogenic growth factors. It was reported that glypican-1 is strongly expressed in human pancreatic cancer, and that it may play an essential role in regulating growth-factor responsiveness in pancreatic carcinoma cells. In this study we investigated the effects of decreased glypican-1 expression in PANC-1 pancreatic cancer cells. To this end, PANC-1 cells were stable transfected with a full-length glypican-1 antisense construct. The glypican- antisense transfected clones displayed markedly reduced glypican- protein levels and a marked attenuation of the mitogenic responses to heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor-2 (FGF2), heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and hepatocyte growth factor (HGF). In addition, glypican-1 antisense-expressing PANC-1 cells exhibited a significantly reduced ability to form tumors in nude mice in comparison with parental and sham-transfected PANC-1 cells. These data suggest that glypican-1 plays an important role in the responses of pancreatic cancer cells to heparin-binding growth factors, and documents for the first time that its expression may enhance tumorigenic potential in vivo.

Animals↗
PubMed1999

Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer.

Transforming growth factor-betas (TGF-betas) bind to the type II TGF-beta receptor (TbetaRII), which then heterodimerizes with the type I TGF-beta receptor (TbetaRI), thereby initiating a signaling cascade. TGF-betas are overexpressed in pancreatic cancer, and this overexpression is associated with more aggressive disease. Although TbetaRII also is overexpressed in pancreatic ductal adenocarcinoma cells in vivo, the biologic significance of this overexpression is not completely known. Therefore in this study, we characterized TbetaRII expression by Northern blot analysis in 32 normal and 42 cancerous pancreatic tissues and correlated the survival of the cancer patients with TbetaRII messenger RNA (mRNA) levels. Northern blot analysis revealed that, by comparison with the normal controls, TbetaRII expression was increased in 19 (45%) of 42 cancer samples. Densitometric analysis of all the pancreatic tissues revealed a 3.4-fold increase (p < 0.01) in TbetaRII mRNA levels in the cancer tissues by comparison with normal controls. There was a strong correlation between the expression of TbetaRII and the levels of two invasion-promoting genes, plasminogen-activator-inhibitor-1 (PAI-1) and matrix-metalloproteinase-9 (MMP9). Log-rank analysis of the Kaplan-Meier survival curves indicated that patients whose tumors overexpressed TbetaRII had a significantly shorter survival period than did patients whose cancers expressed low levels of TbetaRII. It is suggested that TbetaRII overexpression may be a marker that correlates with disease progression in pancreatic ductal adenocarcinoma.

Adolescent↗
PubMed1999

Evaluation of laser doppler flowmetry for the study of benign and malignant gastric blood flow in vivo.

BACKGROUND: Tumour vascularisation is a determinant of the development of metastases. AIMS: To measure blood flow in normal stomach and gastric adenocarcinomas by laser Doppler flowmetry and correlate blood flow with vascularisation after immunohistochemical staining of resected specimens for CD31 and von Willebrand factor. PATIENTS: Twenty two undergoing resection for gastric adenocarcinoma and 10 undergoing cholecystectomy. RESULTS: Mean (SD) gastric blood flow was 208 (35) perfusion units (PU) in patients undergoing cholecystectomy and 190 (75) PU in the undiseased part of the stomach in patients with gastric adenocarcinoma. Gastric blood flow was higher in the border of gastric adenocarcinomas (322 (120) PU, p<0.01 v normal stomach) but lower in the centre (74 (27) PU, p<0.01 v normal stomach and tumour border). Blood flow was higher in tumours staged T>/=3 than in those staged T<3. Blood vessel density in normal stomach was 41 (8) stained cells/field viewed and was 1. 9-3.4 times higher in gastric adenocarcinomas. CONCLUSION: Laser Doppler flowmetry is a valuable tool for studying the pathophysiological alterations of malignant blood flow in the human stomach in vivo.

Adenocarcinoma↗
PubMed1999

Group II and IV phospholipase A(2) are produced in human pancreatic cancer cells and influence prognosis.

BACKGROUND: Phospholipase A(2) (PLA(2)) is involved in regulating biosynthesis of arachidonic acid and its metabolites. There are three major structurally different forms of PLA(2): group I, also called pancreatic PLA(2) (PLA(2)-I); group II, referred to as secretory non-pancreatic or synovial or platelet PLA(2) (PLA(2)-II); group IV, referred to as cytosolic PLA(2) (PLA(2)-IV). AIMS: To examine PLA(2)-I, PLA(2)-II, and PLA(2)-IV in normal and pancreatic cancer tissues. Patients-PLA(2) was studied in 58 pancreatic adenocarcinomas, obtained from 25 women and 33 men undergoing pancreatic resection. Normal organ donor pancreas served as control. METHODS: The enzymes were analysed by northern blot, in situ hybridisation, and immunohistochemistry. The molecular findings were correlated with clinical variables of the patients. RESULTS: Northern blot analysis of total RNA showed enhanced PLA(2) group II and IV mRNA expression in 52% and 55% of the pancreatic cancer samples respectively compared with the normal controls (p = 0.0013 and p = 0.0025). On immunohistochemical analysis, intense PLA(2)-I immunoreactivity was seen in acinar cells, but not in ductal cells, in the normal pancreas. In pancreatic cancer cells, PLA(2)-I immunostaining was absent. PLA(2)-II immunostaining was visible only in some acinar and ductal cells in the normal pancreas, whereas in pancreatic cancer increased PLA(2)-II immunoreactivity was present in 65% of the cancer samples. On in situ hybridisation, weak PLA(2)-IV mRNA signals were detected in acinar and ductal cells of normal samples; these signals were present to a much greater extent in pancreatic cancer cells. The presence of PLA(2)-II in pancreatic cancer was associated with a higher degree of fibrosis (p<0.01). Furthermore, there was a significant correlation between the enhanced expression of PLA(2)-II and longer survival after surgery (p<0.03), but not of PLA(2)-IV and longer postoperative survival. CONCLUSION: These data suggest that PLA(2)-II and PLA(2)-IV are upregulated in human pancreatic cancer, and that upregulation of PLA(2)-II in pancreatic cancer covariates negatively with cancer cell growth.

Adenocarcinoma↗
PubMed1999

Molecular aspects of pancreatic cancer and future perspectives.

Pancreatic cancer has one of the worst prognoses of all human malignancies and the molecular mechanisms underlying this aggressive disease have been extensively investigated in the past years. Tyrosine kinase growth factor receptors and their ligands act to influence tumor cell growth, differentiation, invasion, metastasis, and angiogenesis. In pancreatic cancer a variety of these growth factor receptors and ligands are expressed at increased levels and this overexpression influences the clinical course of the disease. For example, the concomitant presence of the EGF receptor and its ligands EGF, TGF-alpha, and/or amphiregulin is associated with enhanced tumor aggressiveness and shorter survival periods following tumor resection. Furthermore, the growth inhibitory effects of the TGF-beta superfamily of serine-threonine kinase receptors and their ligands are often blocked in pancreatic cancer cells. In addition to these alterations, mutations of the p53 tumor-suppressor gene, the K-ras proto-oncogene, and the Smad4 gene are frequently present in these tumors. Taken together, the abundance of growth-promoting factors, the disturbance of growth inhibitory pathways, and the presence of gene mutations combine to give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival.

ErbB Receptors↗