Role of urokinase (uPA) and its receptor (uPAR) in invasion and metastasis of hormone-dependent malignancies.
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.
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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
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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
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ABSTRACT: Increased expression of urokinase (uPA), a member of the serine protease family, is an effector of metastatic cascade and has been reported in various malignancies, including breast cancer. uPA overexpression in cancer tissues was correlated with a more aggressive phenotype and it is considered a strong and independent unfavorable prognostic factor in breast cancer. Using real-time PCR assay, we analyzed uPA expression of malignant and benign breast nodular lesions versus healthy tissues (normal breast and lymphocytes). We found that besides breast cancer nodule, normal mammary gland and lymphocytes overexpressed uPA too. Tissues obtained from women with benign lesions expressed homogeneous and lower uPA. In conclusion, although uPA overexpression is typical of cancer tissues, it could be considered as a feature of the whole organism affected by cancer. On the basis of these first results, uPA could be considered for further studies as a possible useful therapeutic target in breast cancer.Journal of Cancer Research and Clinical Oncology 10/2009; 136(1):157-63. DOI:10.1007/s00432-009-0694-1 · 3.01 Impact Factor