System In Tumor Progression Research Articles

Modulators of the urokinase-type plasminogen activation system for cancer

Importance of the field: The serine protease urokinase-type plasminogen activator (uPA) and its receptor uPAR as well as two specific inhibitors, the plasminogen activator inhibitor type-1 (PAI-1) and type-2 (PAI-2), are involved in the control of extracellular matrix turnover and tumor growth. Data accumulating over the past 20 years have made increasingly clear that the uPA system has a multifunctional role in neoplastic evolution, affecting cancer cell proliferation, tumor angiogenesis, adhesion and migration.Areas covered in this review: Several therapeutic strategies inhibiting the uPA system have been or are currently being developed for suppression of tumor growth. This review examines the role of the uPA system in tumor progression and assesses the various therapeutic strategies developed to selectively exploit this system.What will the reader gain: We focus on the therapeutic developments of the last 15 years. In addition to antibodies and recombinant uPA- or uPAR-derived proteins, various antagonistic peptides as well as small molecules have been designed and synthesized that inhibit the uPA system, leading to reduced tumor progression.Take home message: The multifunctional potential of the uPA system in cancer has rendered this system an attractive novel target for anticancer therapy. A few novel tumor biology-based therapeutic strategies reported here, opening new ways for patient-optimized and individualized cancer therapy. It may be the right time to evaluate the hypothesis that the uPA system plays a pivotal role in cancer progression and that targeting this system will lead to clinical benefit in cancer patients.

Prognostic Significance of Growth Factors and the Urokinase-Type Plasminogen Activator System in Pancreatic Ductal Adenocarcinoma

To determine the diagnostic and prognostic significance of growth factors and the urokinase-type plasminogen activator (uPA) system in pancreatic ductal adenocarcinoma (PDAC) using a multigene assay. Messenger RNA (mRNA) expression of 15 genes from epidermal growth factor receptor, insulin-like growth factor (IGF), and uPA families were measured in 46 PDAC tissue samples using quantitative real-time reverse transcription-polymerase chain reaction. These results were compared with those of the uninvolved adjacent (AP) tissue and benign mucinous cystadenomas (BMC). The mRNA expression was evaluated using logistic regression and receiver operating characteristic area under the curve (ROC AUC) analyses. Their relationship with prognosis was tested by Cox regression multivariate analysis. All genes were overexpressed in most of the PDAC tissue. When compared with AP tissue, the median expression values for IGF-binding protein 3 (IGFBP-3) and uPA receptor (uPAR) was 9.8- and 9.6-fold, respectively. Expression levels of uPA, uPAR, IGF-I, and IGFBP-3 mRNA were significantly greater in PDAC than in BMC. The IGFBP-3 mRNA expression demonstrated greatest ROC AUC values for PDAC versus AP tissue (ROC AUC, 0.745; 95% confidence interval [CI], 0.65-0.86); whereas ROC AUC values were greatest for uPAR when PDAC was compared with BMC (ROC AUC, 0.846; 95% CI, 0.76-0.94). The combination of uPA, uPAR, and IGF-I significantly improved discriminatory power (ROC AUC, 0.965; 95% CI, 0.93-1.00). The IGFBP-3, uPA, plasminogen activator inhibitor-2, and International Union Against Cancer stage had a significant influence on survival, but the effect of IGFBP-3 was lost after multivariate stepwise analysis. These results indicate that there is an influence of IGF system in tumor progression from BMC to PDAC, whereas the uPA/uPAR system has the greater influence on survival in PDAC.

Mechanism and Therapeutic Reversal of Immune Suppression in Cancer

The last decades were characterized by substantial progress in our understanding of the role of the immune system in tumor progression. This raised high expectations that immunotherapy would provide a breakthrough in cancer treatment. However, these expectations have not yet materialized. It became

Involvement of TGF-beta(s)/T(beta)Rs system in tumor progression of murine mammary adenocarcinomas.

We studied the expression of TGF-beta/T(beta)R system and its biological role in tumor development, in M3 and MM3 murine mammary adenocarcinomas with different metastasizing capability and in LM3 and LMM3 derived cell lines. All the studied cells secreted TGF-beta(s) and expressed T(beta)Rs. While the proliferation of the poorly metastatic M3 cells was significantly inhibited by 4 ng/ml TGF-beta(s), the highly metastatic MM3 cells were only slightly inhibited in response to the highest dose used. LM3 and LMM3 cells, highly invasive and metastatic, were totally refractory to TGF-beta antiproliferative effect. The role of TGF-beta in modulating key proteolytic cascades in tumor progression was also studied. TGF-beta(s) enhanced metalloproteinases production in all the studied cells while induced a stimulatory net effect on plasmin system activity only in the more metastatic cells. Our results in this murine mammary tumor lineage support the concept that dissociation of TGF-beta regulated growth control versus proteolytic enzyme pathways promotes tumor dissemination.