Tumor cell binding to components of the basement membrane is well known to trigger intracellular signaling pathways. Signaling ultimately results in the modulation of gene expression, facilitating metastasis. Type IV collagen is the major structural component of the basement membrane and is known to be a polyvalent ligand, possessing sequences bound by the ␣ 1  1 , ␣ 2  1 , and ␣ 3  1 integrins, as well as cell surface proteoglycan receptors, such as CD44/chondroitin sulfate proteoglycan (CSPG). The role of ␣ 2  1 integrin and CD44/CSPG receptor binding on human melanoma cell activation has been evaluated herein using triple-helical peptide ligands incorporating the ␣1(IV)382-393 and ␣1(IV)1263-1277 sequences, respectively. Gene expression and protein production of matrix metalloproteinases-1 (MMP-1), -2, -3, -13, and -14 were modulated with the ␣ 2  1 -specific sequence, whereas the CD44-specific sequence yielded significant stimulation of MMP-8 and lower levels of modulation of MMP-1, -2, -13, and -14. Analysis of enzyme activity confirmed different melanoma cell proteolytic potentials based on engagement of either the ␣ 2  1 integrin or CD44/CSPG. These results are indicative of specific activation events that tumor cells undergo upon binding to select regions of basement membrane collagen. Based on the present study, triple-helical peptide ligands provide a general approach for monitoring the regulation of proteolysis in cellular systems.Melanoma is one of the most rapidly increasing malignancies in the world in both young and old patients, with over 50,000 newly diagnosed patients each year (1). 1 Mortality from cancer is frequently due to metastasis, given that surgical excision of the primary tumor considerably enhances the prognosis of a patient and prolongs survival (2). Metastasis is a complex series of finely coordinated events that results in cancer cells circulating in lymph and blood vascular systems to invade remote tissues and establish secondary sites of tumor growth (3). Extravasation of the tumor cell into secondary tissues requires alterations in cellular behaviors, resulting from specific adhesion to components of the basement membrane. Tumor cells respond to each of the various components of the ECM, 2 including the collagens; noncollagenous glycoproteins, such as fibronectin and laminin; and proteoglycans, such as decorin and syndecan (4). These interactions are known to occur through several families of cell surface receptors, including the integrins and cell surface proteoglycans.Integrins are heterodimeric proteins composed of one ␣ and one  subunit and are the best described of the cell surface adhesion molecules. To date, there are 18 different ␣ subunits and 8 distinct  subunits identified that combine to form at least 24 heterodimers (5-7). Although the specific integrin expression profile can fluctuate with tumor type and stage of progression, highly metastatic melanoma cells are known to up-regulate expression of, and ␣ 6  4 integrins while down-regulating the expression ...
Identification of the biochemical pathways involved in the transformation from primary to metastatic melanoma is an area under intense investigation. A 2DE proteomics approach has been applied herein to the matched patient primary and metastatic melanoma cell lines WM-115 and WM-266-4, respectively, to better understand the processes that underlie tumor progression. Image analysis between samples aligned 470 common gel spots. Quantitative gel analysis indicated 115 gel spots of greater intensity in the metastatic line compared with the primary one, leading to the identification of 131 proteins via database searching of nano-LC-ESI-Q-TOF-MS/MS data. This more than tripled the number of proteins previously shown to be of higher abundance during melanoma progression. Also observed were 22 gel spots to be of lesser intensity in the metastatic line with respect to the primary one. Of these gel spots 15 proteins could be identified. Numerous proteins from both groups had not been reported previously to participate in melanoma progression. Further analysis of one protein, cyclophilin A, confirmed that this protein is expressed at higher levels in metastatic melanoma compared with primary melanoma and normal fibroblasts. Overall, this study expands our knowledge of protein modulation during melanoma stages, and suggests new targets for inhibitor development.
Digoxin-like immunoreactive factor (DLIF) and ouabain-like factor (OLF) are the mammalian counterparts to the plant-derived cardiotonic steroids digoxin and ouabain. Compelling evidence indicates that the cardiotonic steroids may have anticancer properties. Recent evidence indicates that low (nanomolar) concentrations of DLIF selectively induce cell death in transformed cells, while sparing normal cells, and is even more potent than the plant-derived compounds. The discovery that these endogenous molecules may play a role in the regulation of cancer cell proliferation provides a potentially new paradigm for the physiologic role of DLIF and OLF. In addition, the possible use of digoxin itself as a therapeutic agent in cancer has been explored, and evidence suggests that its conversion to dihydrodigoxin may be involved in regulating anticancer activity. The mechanism(s) for the pro-apoptotic property of these compounds is not known. In this brief review, we will discuss the proposed mechanism of action of digoxin, ouabain, DLIF, and OLF as anticancer compounds and discuss the effects that metabolic conversion to their dihydro-derivatives may have on this activity. From the perspective of therapeutic drug monitoring, these findings suggest some potential new challenges in the need to measure concentrations of digoxin and dihydrodigoxin as well as their endogenous counterparts DLIF and OLF in serum.
Objective: To determine result reproducibility, and performance of the BD Onclarity™ HPV Assay (Onclarity) on the BD Viper™ LT platform using both contrived and clinical specimens. Methods: Reproducibility was assessed in BD SurePath™ LBC media (SurePath) using contrived panels (HPV16+, 18+, or 45+) or clinical specimens (HPV16+, 18+, 31+, 33/58+, 45+, 52+, or HPV-). In addition, specimens from 3,879 individuals from the Onclarity trial were aliquoted prior to or following cytology processing and tested for HPV. Finally, specimens were collected using either the Cervex-brush® or Cytobrush® (or Cytobrush/spatula) for comparison of HPV results. Results: Contrived specimens showed >95% concordance with expected results and pooled clinical specimens had standard deviation and coefficient of variation values ranging from 0.87 to 1.86 and 2.9% to 5.6%, respectively. For pre-cytology and post-cytology aliquot analyses, specimens showed >98.0% overall agreement and mean differences in Ct score for HPV ranging from -0.07 to 0.31. Positivity rates were close between the Cervex-brush and Cytobrush/spatula for all age groups tested. Conclusions: Onclarity results are reproducible and reliable, regardless of sample collection before or after the cytology aliquot. Onclarity performs well regardless of the method of specimen collection (Cervex-brush or Cytobrush/spatula) for cervical cancer screening.
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