Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies (Review)
ABSTRACT Despite our recent advances in characterizing the molecular basis of breast and prostate cancer and their early detection with the aid of new imaging and diagnostic techniques, these cancers continue to be the leading causes of cancer-related deaths. This limited success in achieving our ultimate goal of cancer control is due to our inability to block the production of various factors produced in the later stages of these cancers that cause this high rate of mortality. A key requirement in the complex process of tumor invasion is the ability of tumor cells to produce and recruit growth factors and proteolytic enzymes within the tumor cell environment to promote neovascularization, tumor growth and promote extracellular matrix (ECM) degradation to facilitate tumor metastasis. One such protease, urokinase (uPA), has been strongly implicated in the progression of several malignancies including breast and prostate cancer. Along with uPA, its cell surface receptor (uPAR) is also believed to be involved due to its ability to recruit uPA within the tumor cell environment. In recent years, novel in vivo models of breast and prostate cancer have been developed which have clearly demonstrated the significance of uPA and uPAR in the invasion and metastases of these hormone-dependent cancers. The availability of these in vivo models has now permitted us to evaluate the molecular, chemical and immunotherapeutic strategies targeted against the uPA/uPAR system. This review describes the mechanism of uPA actions in tumor progression and analyses the usefulness of these in vivo models to authenticate uPA/uPAR as a therapeutic target and evaluates the benefits of blocking uPA/uPAR interactions alone or in combination with currently available treatment modalities against this cancer. Based on these results, there is an urgent need to develop and optimize strategies which will ultimately allow us to control the progression of these malignancies and enhance our ability to effectively manage these patients.
- SourceAvailable from: Andreas Kjaer
[Show abstract] [Hide abstract]
- "By localized proteolytic activity, causing degradation of the extracellular matrix, uPAR facilitates cancer cells to escape the primary tumor and to be transported by the vascular and/or lymphatic system to distal sites where new metastatic lesions are established. In line with this, multiple studies have, based on immunohistochemistry on biopsies and blood-based ELISA, reported uPAR to be a strong prognostic marker for poor prognosis and metastatic disease in a number of cancers, including breast, prostate, colorectal, gastric and lung cancer         . This makes uPAR a very interesting target for non-invasive PET imaging, since this could enable a whole-body quantitative analysis of uPAR expression in both the primary tumor and metastatic lesions   . "
ABSTRACT: (64)Cu-DOTA-AE105 is a novel positron emission tomography (PET) tracer specific to the human urokinase-type plasminogen activator receptor (uPAR). In preparation of using this tracer in humans, as a new promising method to distinguish between indolent and aggressive cancers, we have performed PET studies in mice to evaluate the in vivo biodistribution and estimate human dosimetry of (64)Cu-DOTA-AE105. Five mice received iv tail injection of (64)Cu-DOTA-AE105 and were PET/CT scanned 1, 4.5 and 22h post injection. Volume-of-interest (VOI) were manually drawn on the following organs: heart, lung, liver, kidney, spleen, intestine, muscle, bone and bladder. The activity concentrations in the mentioned organs [%ID/g] were used for the dosimetry calculation. The %ID/g of each organ at 1, 4.5 and 22h was scaled to human value based on a difference between organ and body weights. The scaled values were then exported to OLINDA software for computation of the human absorbed doses. The residence times as well as effective dose equivalent for male and female could be obtained for each organ. To validate this approach, of human projection using mouse data, five mice received iv tail injection of another (64)Cu-DOTA peptide-based tracer, (64)Cu-DOTA-TATE, and underwent same procedure as just described. The human dosimetry estimates were then compared with observed human dosimetry estimate recently found in a first-in-man study using (64)Cu-DOTA-TATE. Human estimates of (64)Cu-DOTA-AE105 revealed the heart wall to receive the highest dose (0.0918mSv/MBq) followed by the liver (0.0815mSv/MBq), All other organs/tissue were estimated to receive doses in the range of 0.02-0.04mSv/MBq. The mean effective whole-body dose of (64)Cu-DOTA-AE105 was estimated to be 0.0317mSv/MBq. Relatively good correlation between human predicted and observed dosimetry estimates for (64)Cu-DOTA-TATE was found. Importantly, the effective whole body dose was predicted with very high precision (predicted value: 0.0252mSv/Mbq, Observed value: 0.0315mSv/MBq) thus validating our approach for human dosimetry estimation. Favorable dosimetry estimates together with previously reported uPAR PET data fully support human testing of (64)Cu-DOTA-AE105.Nuclear Medicine and Biology 03/2014; 41(3):290-5. DOI:10.1016/j.nucmedbio.2013.12.007 · 2.41 Impact Factor
[Show abstract] [Hide abstract]
- "CEBPB and PLAU were the only predicted markers for early detection of CRC in the IBD. The PLAU gene encodes plasminogen activator, a serine protease involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation . The CEBPB gene is an important transcriptional activator that plays a role in the regulation of acute-phase reaction, inflammation and hemopoiesis , . "
ABSTRACT: Significantly expressed genes extracted from microarray gene expression data have proved very useful for identifying genetic biomarkers of diseases, including cancer. However, deriving a disease related inference from a list of differentially expressed genes has proven less than straightforward. In a systems disease such as cancer, how genes interact with each other should matter just as much as the level of gene expression. Here, in a novel approach, we used the network and disease progression properties of individual genes in state-specific gene-gene interaction networks (GGINs) to select cancer genes for human colorectal cancer (CRC) and obtain a much higher hit rate of known cancer genes when compared with methods not based on network theory. We constructed GGINs by integrating gene expression microarray data from multiple states - healthy control (Nor), adenoma (Ade), inflammatory bowel disease (IBD) and CRC - with protein-protein interaction database and Gene Ontology. We tracked changes in the network degrees and clustering coefficients of individual genes in the GGINs as the disease state changed from one to another. From these we inferred the state sequences Nor-Ade-CRC and Nor-IBD-CRC both exhibited a trend of (disease) progression (ToP) toward CRC, and devised a ToP procedure for selecting cancer genes for CRC. Of the 141 candidates selected using ToP, ∼50% had literature support as cancer genes, compared to hit rates of 20% to 30% for standard methods using only gene expression data. Among the 16 candidate cancer genes that encoded transcription factors, 13 were known to be tumorigenic and three were novel: CDK1, SNRPF, and ILF2. We identified 13 of the 141 predicted cancer genes as candidate markers for early detection of CRC, 11 and 2 at the Ade and IBD states, respectively.PLoS ONE 06/2013; 8(6):e65683. DOI:10.1371/journal.pone.0065683 · 3.23 Impact Factor
[Show abstract] [Hide abstract]
- "A note of caution comes from some studies which have demonstrated potential tumorgenic effects of tempol. Tempol caused post-transcriptional activation of the urokinase receptor (Lejeune et al., 2006) which is associated with progression of human prostate cancer (Rabbani & Xing, 1998). Rats subjected to severe exercise showed DNA strand breaks that were enhanced by oral tempol (200 μmol · kg -1 · d -1 ) (Wierzba et al., 2006). "
ABSTRACT: Tempol is a redox-cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability. It has been studied extensively in animal models of oxidative stress. Tempol has been shown to preserve mitochondria against oxidative damage and improve tissue oxygenation. Tempol improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia, reduced the weight gain and prevented diastolic dysfunction and heart failure in fat-fed models of the metabolic syndrome. Tempol protected many organs, including the heart and brain, from ischemia/reperfusion damage. Tempol prevented podocyte damage, glomerulosclerosis, proteinuria and progressive loss of renal function in models of salt and mineralocorticosteroid excess. It reduced brain or spinal cord damage after ischemia or trauma and exerted a spinal analgesic action. Tempol improved survival in several models of shock. It protected normal cells from radiation while maintaining radiation sensitivity of tumor cells. Its paradoxical pro-oxidant action in tumor cells accounted for a reduction in spontaneous tumor formation. Tempol was effective in some models of neurodegeneration. Thus, tempol has been effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage and many of the diseases associated with aging. Indeed, tempol given from birth prolonged the life span of normal mice. However, presently tempol has been used only in human subjects as a topical agent to prevent radiation-induced alopecia.Pharmacology [?] Therapeutics 02/2010; 126(2):119-45. DOI:10.1016/j.pharmthera.2010.01.003 · 7.75 Impact Factor