Biomedical subjects

M Korc

Publications and source records attributed to M Korc.

At least 55 records · Page 3Linked to original sources

PubMed1999

Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma.

BACKGROUND: Transforming growth factor betas (TGF-betas) are multifunctional polypeptides that have been suggested to influence tumor growth. They mediate their functions via specific cell surface receptors (type I ALK5 and type II TGF-beta receptors). The aim of this study was to analyze the roles of the three TGF-betas and their signaling receptors in human hepatocellular carcinoma (HCC). METHODS: HCC tissue samples were obtained from 18 patients undergoing partial liver resection. Normal liver tissues from 7 females and 3 males served as controls. The tissues for histological analysis were fixed in Bouin's solution and paraffin embedded. For RNA analysis, freshly obtained tissue samples were snap frozen in liquid nitrogen and stored at -80 degrees C until used. Northern blot analysis was used in normal liver and HCC to examine the expression of TGF-beta1, -beta2, -beta3 and their receptors: type I ALK5 (TbetaR-I ALK5), type II (TbetaR-II), and type III (TbetaR-III). Immunohistochemistry was performed to localize the corresponding proteins. RESULTS: All three TGF-betas demonstrated a marked mRNA overexpression in HCC in comparison with normal controls, whereas the levels of all three TGF-beta receptors showed no significant changes. Intense TGF-beta1, TGF-beta2, and TGF-beta3 immunostaining was found in hepatocellular carcinoma cells and in the perineoplastic stroma with immunohistochemistry, whereas no or mild immunostaining was present in the normal liver. For TbetaR-I ALK5 and TbetaR-II, the immunostaining in both HCC and normal liver was mild to moderate, with a slightly higher intensity in the normal tissues. CONCLUSION: The upregulation of TGF-betas in HCC suggests an important role for these isoforms in hepatic carcinogenesis and tumor progression. Moreover, the localization of the immunoreactivity in both malignant hepatocytes and stromal cells suggests that TGF-betas act via autocrine and paracrine pathways in this neoplasm.

Activin Receptors, Type I↗

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

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

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

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↗

PubMed1999

Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.

PURPOSE: The reasons for the high frequency of perineural invasion and the presence of pain in pancreatic cancer are still not clear. Nerve growth factor (NGF) and its high-affinity receptor TrkA are involved in stimulating epithelial cancer cell growth and perineural invasion, as well as in pain generation in chronic benign disorders. PATIENTS AND METHODS: NGF and TrkA were examined by Northern blot analysis, in situ hybridization, and immunohistochemistry in 27 normal and 37 pancreatic cancer tissue samples. The molecular findings were correlated with the degree of perineural invasion, pain, and histopathologic tumor characteristics. RESULTS: Northern blot analysis indicated that NGF and TrkA mRNA levels were increased 2.7-fold and 5.6-fold, respectively (P <.05 and P <.05), in pancreatic cancer tissues compared with the normal pancreas tissue. As shown by in situ hybridization and immunohistochemistry, NGF was strongly present in the cytoplasm of pancreatic cancer cells. TrkA was intensely present in the perineurium of pancreatic nerves but not in the cancer cells. There was no difference in NGF and TrkA expression between early (stages I and II) and advanced (stage III) tumor stages and between well-/moderately differentiated (grades 1 and 2) and poorly differentiated (grade 3) tumors. However, tumors with high NGF/TrkA expression levels exhibited more frequent perineural invasion (P <.01). Furthermore, increased NGF/TrkA expression levels were associated with a higher degree of pain (P <. 01). CONCLUSION: Enhanced expression of the NGF/TrkA system may influence perineural invasion and may contribute to the pain syndrome in human pancreatic cancer.

Adult↗

PubMed1999

Insulin-like growth factor I improves cardiovascular function and suppresses apoptosis of cardiomyocytes in dilated cardiomyopathy.

To investigate how insulin-like growth factor I (IGF-I) modulates cardiovascular function and myocardial apoptosis in heart failure, the therapeutic effects of IGF-I were determined in a canine model of dilated cardiomyopathy. The animals were paced at 220 beats/min, and the left ventricular (LV) chamber became dilated after 2 weeks. A subset of paced dogs was treated with s.c. injections of IGF-I from week 3 to week 4. After 4 weeks of pacing, untreated paced dogs developed significant ventricular dysfunction. IGF-I-treated paced dogs showed better cardiac output, stroke volume, LV end-systolic pressure, and LV end-diastolic pressure. Moreover, pulmonary wedge pressure and systemic vascular resistance were increased in the untreated group and decreased in the IGF-I-treated group. IGF-I treatment was associated with less thinning of the ventricular wall. Compared with the controls, untreated paced dogs showed increased apoptosis of cardiac muscle cells, which was partially suppressed by IGF-I treatment. The myocardial apoptotic index was negatively related to the thickness of the ventricular wall and to cardiac output, suggesting that ventricular remodeling/dysfunction involves the occurrence of myocardial apoptosis. Due to the close resemblance between this experimental model of dilated cardiomyopathy and human heart failure, the results of this study provide evidence that IGF-I may be a potential therapeutic agent for the failing human heart.

Animals↗

PubMed1999

Characterization of cytokeratin 20 expression in pancreatic and colorectal cancer.

Cytokeratin 20 belongs to the epithelial subgroup of the intermediate filament family. Because of its restricted range of expression in humans, it has become an important tool for detecting and identifying metastatic cancer cells by immunohistochemistry and by PCR analysis. Despite its widespread diagnostic use in colorectal cancer and occasional use in pancreatic cancer, little is known about the expression of CK 20 in these tumors in vivo. Therefore, in the present study we characterized CK 20 expression in pancreatic and colorectal cancer by comparison with its expression in the normal pancreas and colon. Tissue samples from 24 patients with pancreatic cancer and from 41 patients with colorectal cancer were examined for CK 20 expression by Northern blot analysis, immunohistochemistry, and in situ hybridization. CK 20 expression was observed in the cancer cells of both cancer types. A subgroup of the pancreatic cancers exhibited a 3.2-fold increase in CK 20 mRNA by comparison with respective normal controls. In contrast, colon cancers underexpressed CK 20 mRNA by comparison with the respective controls. In the normal tissues, CK 20 immunoreactivity was relatively faint and sparse in the pancreatic ductal cells but intense and abundant in the apical portions of the colonic mucosa. CK 20 immunoreactivity was also evident in the ductal cells from the chronic pancreatitis-like lesions adjacent to the cancer cells. Furthermore, distant metastases from pancreas carcinomas exhibited strong CK 20 immunoreactivity. It is concluded that CK 20 is overexpressed in pancreatic cancer and that it can serve as an excellent marker for metastatic pancreatic cancer.

Colorectal Neoplasms↗

PubMed1998

The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer.

Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recognition, growth, and adhesion. In vitro studies suggest that cell-surface HSPGs act as coreceptors for heparin-binding mitogenic growth factors. Here we show that the glycosylphosphatidylinositol- (GPI-) anchored HSPG glypican-1 is strongly expressed in human pancreatic cancer, both by the cancer cells and the adjacent fibroblasts, whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1. Stable expression of a form of glypican-1 engineered to possess a transmembrane domain instead of a GPI anchor conferred resistance to the inhibitory effects of PI-PLC on growth factor responsiveness. Furthermore, transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. We propose that glypican-1 plays an essential role in the responses of pancreatic cancer cells to certain mitogenic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder.

Adolescent↗

PubMed1998

Transfection of the type I TGF-beta receptor restores TGF-beta responsiveness in pancreatic cancer.

Transforming growth factor-beta (TGF-beta) signaling is initiated following heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Both receptors are required for TGF-beta responsiveness. In the present study, we characterized the actions of TGF-beta1 in T3M4 human pancreatic cancer cells, which express low levels of TbetaRI and high levels of TbetaRII. Cells were transiently transfected with p3TP-Lux, a TGF-beta-responsive luciferase reporter gene construct. TGF-beta1 was without effect in parental T3M4 cells, but caused a time- and dose-dependent increase in luciferase activity in T3M4 cells co-transfected with a TbetaRI cDNA expression vector. Co-transfection of TbetaRI with a truncated Smad4 cDNA that is known to block TGF-beta-dependent signaling, abrogated the TbetaRI-induced increase in luciferase activity. Sequencing of the TbetaRI and the Smad4 genes in T3M4 cells did not reveal any mutations. These findings indicate that one mechanism for TGF-beta resistance in pancreatic cancer is due to a quantitative decrease in TbetaRI expression.

Activin Receptors, Type I↗

PubMed1998

Enhanced expression of the insulin receptor substrate-2 docking protein in human pancreatic cancer.

Insulin receptor substrate-2 (IRS-2) is a multisite docking protein implicated in mitogenic signaling after activation of the insulin and insulin-like growth factor (IGF)-I receptors. In the present study, we characterized IRS-2 expression and function in human pancreatic cancer. IRS-2 mRNA and protein were expressed in ASPC-1 and COLO-357 human pancreatic cancer cell lines. Insulin, IGF-I, and IGF-II enhanced the growth of both cell lines, stimulated tyrosine phosphorylation of IRS-2, and increased IRS-2-associated phosphatidylinositol (PI) 3-kinase activity. The mitogenic effects of insulin, IGF-I, and IGF-II were markedly attenuated by the PI 3-kinase inhibitor LY 294002. Northern blot analysis of total RNA extracted from normal and cancerous tissues revealed that IRS-2 mRNA levels were increased in the cancer tissues (P = 0.032). In the normal pancreas, IRS-2 immunoreactivity was present at low levels in some ductal and acinar cells and at moderate levels in a heterogeneous pattern in all of the endocrine islets. In the pancreatic cancers, IRS-2 was abundant in the ductal-like cancer cells. These findings indicate that IRS-2 is overexpressed in human pancreatic cancer and suggest that it may contribute to enhanced mitogenic signaling via the PI 3-kinase pathway, thereby leading to excessive growth stimulation in this malignancy.

Colonic Neoplasms↗