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J Kleeff

Publications and source records attributed to J Kleeff.

At least 55 records · Page 3Linked to original sources
PubMed2001

Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells.

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain nonneuronal tumors with the effect based on the type of tumor. We investigated NGF and its receptors (TrkA and p75) in pancreatic cancer cells (PANC-1, MIA-PaCa-2, CAPAN-1, ASPC-1, and T3M4) by reverse transcription-PCR, Western blot analysis, NGF ELISA, and growth assays. NGF mRNA was present at comparable levels in all five pancreatic cancer cell lines. TrkA expression was relatively high in PANC-1 and MIA-PaCa-2 cells and low in CAPAN-1, ASPC-1, and T3M4 cells. p75 expression was high in PANC-1, MIA-PaCa-2, and T3M4 cells, moderate in CAPAN-1, and low in ASPC-1 cells. By ELISA assay, the intracellular NGF content in all cell lines was approximately 40 pg/10(6) cells. NGF content increased significantly in PANC-1 and MIA-PaCa-2 cells when these cells were cultured with serum-free media, whereas there was no change in the other cancer cell lines. PANC-1 and MIA-PaCa-2 cells but not the other cell lines released NGF in the culture media. Exogenous NGF stimulated the growth of PANC-1 and MIA-PaCa-2 cells, inhibited the growth of T3M4 and CAPAN-1 cells in a dose- and time-dependent manner, and did not affect the growth of ASPC-1 cells. NGF led to the phosphorylation of TrkA, mitogen-activated protein kinase (MAPK), and p38 MAPK but not stress-activated protein kinase/c-Jun NH2-terminal kinase in PANC-1 and MIA-PaCa-2 cells. In contrast, in the other pancreatic cancer cell lines none of these kinases were phosphorylated by NGF. In conclusion, the effects of NGF on pancreatic cancer cell growth are dependent on the expression levels and the balance of its TrkA and p75 receptors. NGF-induced pancreatic cancer cell growth seems to be mediated through the phosphorylation of TrkA and subsequently via MAPK. These results point to a previously unknown autocrine/paracrine pathway in pancreatic cancer, suggesting that NGF-TrkA interactions are important factors influencing cell growth and spread in this malignancy.

Blotting, Western↗
PubMed2000

Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers.

Syndecan-1 belongs to the syndecan family of cell surface transmembrane heparan-sulfate proteoglycans, which participate in cell proliferation, cell migration and cell-matrix interactions. Decreased expression of syndecan-1 has been observed in some gastrointestinal malignancies, and it is thought that high levels of syndecan-1 correlate with the maintenance of epithelial morphology and inhibition of invasiveness. In our study, we characterized the expression of syndecan-1 in normal, chronic pancreatitis and primary and metastatic human pancreatic cancer tissues, in cultured pancreatic cancer cell lines and in esophageal, gastric, colon, and liver cancers. Pancreatic cancer cell lines expressed syndecan-1 mRNA and protein at variable levels. In addition, these cells also released syndecan-1 into the culture medium. Pancreatic cancer tissues markedly over-expressed syndecan-1 mRNA in comparison with both chronic pancreatitis (2.4-fold increase, p < 0.01) and normal pancreatic samples (10.6-fold increase, p < 0.01). There was no difference in syndecan-1 mRNA expression between early and advanced tumors. By in situ hybridization and immunohistochemistry, syndecan-1 expression was evident at relatively low levels in the ductal cells and less frequently in acinar cells of the normal pancreas. In chronic pancreatitis, syndecan-1 was present at low to moderate levels in areas with atrophic acinar cells and ductular complexes. In contrast, in pancreatic cancer tissues, syndecan-1 was present at moderate to high levels in the majority of the cancer cells within the tumor mass and also in metastatic lesions of pancreatic tumors. Syndecan-1 mRNA levels in other gastrointestinal malignancies (esophageal, gastric, colon and liver cancers) were not significantly different from the levels observed in the corresponding normal samples. Together, our findings suggest that syndecan-1 expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder and that its role in pancreatic cancer seems to be different from that in other gastrointestinal malignancies.

Adenocarcinoma↗
PubMed2000

Epiregulin is Up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth.

Epiregulin belongs to the epidermal growth factor (EGF) family of polypeptides. Previous studies have underscored the important role of the EGF family of ligands and receptors in the pathology of pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). It is not known, however, whether epiregulin may also have a role in these diseases. Therefore, in the present study we investigated the expression and function of epiregulin in five pancreatic cancer cell lines and in PDAC and CP tissue samples. Epiregulin mRNA was present at high (MIA-PaCa-2 cells) or moderate levels (ASPC-1, CAPAN-1, and T3M4) in most cells, but was below detection levels in PANC-1 cells. All the cell lines exhibited a dose-dependent increase in growth in response to recombinant human epiregulin. Epiregulin mRNA levels were increased 2.1-fold in PDAC samples (P < 0.01) and 1.7-fold in CP samples (P < 0.01), when compared with the normal controls. There was no correlation between epiregulin mRNA levels and tumor stage or grade. By in situ hybridization, a moderate to intense epiregulin mRNA signal was present in most pancreatic cancer cells in PDAC. In contrast, only a weak (normal pancreas) to moderate (CP) signals were present in the ductal and acinar cells in CP. These findings suggest that epiregulin may contribute to the pathobiology of PDAC, and may also have a role in CP.

Adenocarcinoma↗
PubMed2000

Enhanced expression of Silencer of death domains (SODD/BAG-4) in pancreatic cancer.

Pancreatic cancers are resistant to TNF-alpha-mediated apoptosis. Silencer of death domains (SODD) binds to TNF-alpha receptor TNFR-1, and prevents spontaneous self-association of death domains and inappropriate receptor signaling. In addition, overexpression of SODD suppresses TNF-alpha-induced cell death. In this report, we demonstrate increased SODD mRNA levels in pancreatic cancer (n = 30) in comparison to normal control tissues (n = 20, P < 0.01). In situ hybridization analysis revealed SODD expression predominantly in the cancer cells within the pancreatic tumor mass. In contrast, SODD mRNA levels were not different (P > 0.05) in four other gastrointestinal cancers (liver, esophagus, stomach, colon) compared with the corresponding normal tissues. These findings indicate that in contrast to other gastrointestinal malignancies, in pancreatic cancer SODD might block TNF-alpha-mediated apoptosis which may influence the growth of pancreatic cancer cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Actinomycin D induces apoptosis and inhibits growth of pancreatic cancer cells.

Pancreatic cancer cells are usually resistant to apoptosis induced by cytotoxic drugs, by activation of surface receptors such as Fas and TNF receptor or by serum or growth factor withdrawal. Actinomycin D (actD) is an inhibitor of RNA synthesis and acts as a potent inducer of apoptosis in several cell lines. In the present study, we investigated the effects of actD on PANC-1 pancreatic cancer cells. ActD caused apoptosis in PANC-1 cells in a dose-dependent manner, as determined by cell growth assays, DNA laddering and TUNEL assays. Induction of apoptosis correlated with activation of the JNK/SAPK pathway and increased expression of Bax but not Bad or p53. PANC-1 cells were completely resistant to Fas antibody and TNF-alpha. In contrast, TRAIL decreased the growth of PANC-1 cells by 22%. Low concentrations of actD (10 ng/ml) enhanced the cytotoxic effects of all 3 cytokines. EGF, FGF-2 and IGF-I did not protect PANC-1 cells from actD-mediated apoptosis. ActD (10 ng/ml) also inhibited the growth of CAPAN-1 and T3M4 pancreatic cancer cells but not MiaPaCa-2 cells. Our observations suggest that actD may act via JNK/SAPK and Bax to promote apoptosis in PANC-1 cells and that it may inhibit the growth of other pancreatic cancer cell lines.

Antibiotics, Antineoplastic↗
PubMed2000

Pancreatic cancer--new aspects of molecular biology research.

Pancreatic ductal adenocarcinoma (PDAC) presently has an incidence of approximately 8 to 10 cases per 100,000 citizens in European countries, and the incidence has been increasing throughout the last decades. Approximately 30,000 patients die every year from PDAC in Western Europe and most of the newly diagnosed patients present with an already unresectable tumor stage. Self-sufficiency in growth signals, insensitivity to antigrowth signals, and evasion of apoptosis are hallmarks of malignant growth. In PDAC a variety of growth factors are expressed at increased levels. 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. In addition, PDACs often exhibit alterations in growth inhibitory pathways such as Smad4 mutations and Smad6 and Smad7 overexpression, and evade apoptosis through p53 mutations and aberrant expression of apoptosis regulating genes such as members of the Bcl family. Taken together, the abundance of growth promoting factors and the disturbance of growth inhibitory and apoptotic pathways give pancreatic cancer cells a distinct growth advantage which clinically results in rapid tumor progression and poor survival prognosis.

Apoptosis↗
PubMed2000

Fas and Fas-ligand expression in human pancreatic cancer.

OBJECTIVE: To investigate Fas and FasL expression in pancreatic tissues and cultured pancreatic cancer cell lines, and to assess the ability of anti-Fas antibodies to induce apoptosis. SUMMARY BACKGROUND DATA: Activation of the Fas receptor by Fas-ligand (FasL) results in apoptosis, and dysregulation of this pathway may contribute to abnormal cell proliferation. METHODS: Northern blotting and immunohistochemistry were used to compare Fas and FasL expression in normal and cancerous tissues. DNA 3'-OH end labeling was used to detect apoptotic cells. The effects of Fas activation on cell growth and signaling pathways were investigated in culture. RESULTS: Pancreatic cancers exhibited increased Fas RNA levels, whereas FasL mRNA levels were similar in both groups. Despite the colocalization of Fas and FasL in the cancer cells, an apoptotic signal was present in approximately 10% of these cells in only 2 of 16 cancer samples. Fas and FasL were coexpressed in all four cell lines, whereas Fas-associated phosphatase 1 was below the level of detection in all cell lines. Only COLO-357 cells underwent apoptosis after Fas activation. Apoptosis was associated with enhanced activation of jun kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). In the presence of actinomycin D, Fas antibody also induced apoptosis in the other three cell lines. CONCLUSIONS: These results suggest that pancreatic cancer cells are resistant to Fas-mediated apoptosis by mechanisms excluding receptor downregulation or Fas-associated phosphatase upregulation and raise the possibility that Fas-mediated apoptosis may be dependent on the activation of the JNK/p38 MAPK pathway in these cells.

Adenocarcinoma↗
PubMed2000

Expression of the multidrug-resistance 1 (MDR1) gene and prognosis in human pancreatic cancer.

Multidrug-resistance 1 (MDR1) encodes a 170 kDa transmembrane glycoprotein (P-glycoprotein), which acts as a drug-efflux pump. In the present study, we analyzed the expression of MDR1/P-glycoprotein in human pancreatic cancer and correlated the results with clinical parameters. Pancreatic cancer tissue samples were obtained from 67 patients (30 female, 37 male) who underwent surgery. Normal pancreatic tissues obtained from 15 previously healthy organ donors (4 female, 11 male) served as controls. MDR1 mRNA levels were analyzed by Northern blotting, and the exact site of MDR1 mRNA expression was determined by in situ hybridization and immunohistochemistry. Northern blot analysis indicated that in comparison with the normal pancreas, MDR1 mRNA levels were only increased 1.4-fold (p = 0.03) in the pancreatic cancer samples. However, there was a 2.9-fold (p < 0.01) increase in MDR1 mRNA levels when only the samples that exhibited increased expression (38%) were analyzed. In situ hybridization and immunohistochemical analysis showed that MDR1 was highly expressed in the cancer cells of these samples. Statistical analysis revealed that patients with high MDR1/P-glycoprotein expression had a shorter postoperative survival time compared with patients with weak to moderate expression of MDR1. On the basis of in situ hybridization, survival in the intense group was 11.6 (n = 12) versus 14.2 months (n = 42) in the mild to moderate group. On the basis of immunohistochemistry, survival in the intense group was 7.5 months (n = 10) versus 14.1 months (n = 40) in the mild to moderate group. Surprisingly, survival of patients with high expression of MDR1/P-glycoprotein was not significantly different from that of patients without detectable MDR1/P-glycoprotein expression. These findings suggest that both strong expression of MDR1/P-glycoprotein and lack of expression seem to influence tumor growth via known and yet unknown mechanisms.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Fluconazole penetration into the pancreas.

Because of antibiotic prophylaxis for necrotizing pancreatitis, the frequency of fungal superinfection in patients with pancreatic necrosis is increasing. In this study we analyzed the penetration of fluconazole into the human pancreas and in experimental acute pancreatitis. In human pancreatic tissues, the mean fluconazole concentration was 8.19 +/- 3.38 microg/g (96% of the corresponding concentration in serum). In experimental edematous and necrotizing pancreatitis, 88 and 91% of the serum fluconazole concentration was found in the pancreas. These data show that fluconazole penetration into the pancreas is sufficient to prevent and/or treat fungal contamination in patients with pancreatic necrosis.

Animals↗
PubMed1999

The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.

Transforming growth factor-beta (TGF-beta) signaling is dependent on the heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Activated TbetaRI then mediates TGF-beta signals by inducing the phosphorylation of Smad2 and/or Smad3, which separately hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of Smad2/Smad3 by activated TbetaRI is inhibited by two newly discovered members of the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are increased in human pancreatic cancer by comparison with the normal pancreas, and that by in situ hybridization, Smad7 is over-expressed in the cancer cells within the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells with a full-length Smad7 construct leads to complete loss of the growth inhibitory response to TGF-beta1, without altering TGF-beta1-mediated induction of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced anchorage-independent growth and accelerated growth in nude mice. These findings point to a previously unrecognized mechanism for selective suppression of TGF-beta-mediated growth inhibition in cancer cells that allows for continued activation of the PAI-I promoter by TGF-beta1, which may act to enhance the tumorigenicity of certain cancer cells.

Adolescent↗
PubMed1999

Growth factors and cytokines in pancreatic carcinogenesis.

Pancreatic cancer is a deadly disease challenging basic and clinical researchers alike in characterizing its pathobiology and finding better treatment options. A number of molecular alterations including gene mutations such as k-ras, p53, and Smad4 and aberrant expression of a variety of genes have been identified in recent years. This review focuses on two families of growth factors and growth factor receptors which are representative for the molecular alterations observed in pancreatic cancer: the transforming growth factor-beta superfamily of serine-threonine kinase receptors and their ligands, which usually act as negative growth regulators, and the epidermal growth factor receptor family and their ligands, which have the potential to act as growth promoters in pancreatic cancer. In addition, we will discuss the role of the cytokines TNF-alpha, IFN-gamma, and IL-6 and its effects on pancreatic cancer cell proliferation in vitro and in vivo. Pancreatic cancer cell biology consists of complex interactions of various factors, and a better understanding of the molecular pathogenesis of this disorder might lead to better treatment strategies in the near future.

Animals↗
PubMed1999

Detection and localization of Mip-3alpha/LARC/Exodus, a macrophage proinflammatory chemokine, and its CCR6 receptor in human pancreatic cancer.

Macrophage Proinflammatory Human Chemokine-3alpha (Mip-3alpha/LARC/Exodus) belongs to a large family of chemotactic cytokines, which participate in directing inflammatory cell migration and in modulating angiogenesis. Mip-3alpha signals through a recently identified G-protein linked 7-transmembrane receptor, CCR6. In this study, we have characterized the expression of Mip-3alpha and CCR6 in 12 normal and 16 cancerous human pancreatic tissues and in 4 cultured pancreatic cancer cell lines, and assessed the effects of Mip-3alpha on growth and invasion of these cell lines. Pancreatic cancer tissues markedly overexpressed Mip-3alpha in comparison with normal pancreatic samples. By in situ hybridization Mip-3alpha and CCR6 mRNA moieties were present in cancer cells within the tumors. In addition, Mip-3alpha was abundant in the macrophages infiltrating the tumor mass. Mip-3alpha and its receptor CCR6 were expressed in all 4 tested pancreatic cancer cell lines. Mip-3alpha stimulated the growth of one cell line, enhanced the migration of another cell line, and was without effect in the other 2 cell lines. Together, our findings suggest that Mip-3alpha has the potential to act via autocrine and paracrine mechanisms to contribute to the pathobiology of human pancreatic cancer.

Adolescent↗
PubMed1999

Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer.

Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells.

Adolescent↗
PubMed1999

Id-1 and Id-2 are overexpressed in pancreatic cancer and in dysplastic lesions in chronic pancreatitis.

Id proteins antagonize basic helix-loop-helix proteins, inhibit differentiation, and enhance cell proliferation. In this study we compared the expression of Id-1, Id-2, and Id-3 in the normal pancreas, in pancreatic cancer, and in chronic pancreatitis (CP). Northern blot analysis demonstrated that all three Id mRNA species were expressed at high levels in pancreatic cancer samples by comparison with normal or CP samples. Pancreatic cancer cell lines frequently coexpressed all three Ids, exhibiting a good correlation between Id mRNA and protein levels, as determined by immunoblotting with highly specific anti-Id antibodies. Immunohistochemistry using these antibodies demonstrated the presence of faint Id-1 and Id-2 immunostaining in pancreatic ductal cells in the normal pancreas, whereas Id-3 immunoreactivity ranged from weak to strong. In the cancer tissues, many of the cancer cells exhibited abundant Id-1, Id-2, and Id-3 immunoreactivity. Scoring on the basis of percentage of positive cells and intensity of immunostaining indicated that Id-1 and Id-2 were increased significantly in the cancer cells by comparison with the respective controls. Mild to moderate Id immunoreactivity was also seen in the ductal cells in the CP-like areas adjacent to these cells and in the ductal cells of small and interlobular ducts in CP. In contrast, in dysplastic and atypical papillary ducts in CP, Id-1 and Id-2 immunoreactivity was as significantly elevated as in the cancer cells. These findings suggest that increased Id expression may be associated with enhanced proliferative potential of pancreatic cancer cells and of proliferating or dysplastic ductal cells in CP.

Adolescent↗
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

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↗