Cancer CTC capture CTC clustersImmunoaffinity enrichment A B S T R A C TCirculating tumor cells, a component of the "liquid biopsy", hold great potential to transform the current landscape of cancer therapy. A key challenge to unlocking the clinical utility of CTCs lies in the ability to detect and isolate these rare cells using methods amenable to downstream characterization and other applications. In this review, we will provide an overview of current technologies used to detect and capture CTCs with brief insights into the workings of individual technologies. We focus on the strategies employed by different platforms and discuss the advantages of each. As our understanding of CTC biology matures, CTC technologies will need to evolve, and we discuss some of the present challenges facing the field in light of recent data encompassing epithelial-to-mesenchymal transition, tumor-initiating cells, and CTC clusters.
Purpose: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action.Experimental Design: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo.Results: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase-induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment.Conclusions: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma.
Heparanase is an endoglucuronidase that cleaves heparan sulfate chains of proteoglycans. In many malignancies, high heparanase expression and activity correlate with an aggressive tumor phenotype. A major consequence of heparanase action in cancer is a robust up-regulation of growth factor expression and increased shedding of syndecan-1, a transmembrane heparan sulfate proteoglycan. Substantial evidence indicates that heparanase and syndecan-1 work together to drive growth factor signaling and regulate cell behaviors that enhance tumor growth, dissemination, angiogenesis and osteolysis. Pre-clinical and clinical studies have demonstrated that therapies targeting the heparanase/syndecan-1 axis hold promise in blocking the aggressive behavior of cancer.
Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-KB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumorproduced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8. (Cancer Res 2005; 65(23): 11001-9)
Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here, we demonstrate that a HS-degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive “attachment mode” of host cells to a virus-deterring “detachment mode”. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release.
We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.
Hepatocyte growth factor (HGF) is a heparin-binding cytokine that enhances growth, motility, and angiogenesis of many tumor types, including multiple myeloma where it is often highly expressed. However, little is known regarding what controls HGF level and activity in these tumors. Evaluation of bone marrow biopsies from myeloma patients revealed a strong positive correlation between the levels of HGF and heparanase, an endoglucuronidase known to promote aggressive tumor behavior. In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF. Shed syndecan-1, whose levels in myeloma are also enhanced by heparanase expression, binds to secreted HGF. This syndecan-1-HGF complex is active as shown by its ability to stimulate paracrine signaling via c-Met, the cell surface receptor for HGF. Surprisingly, heparanase enzyme activity was not required for up-regulation of HGF expression by the tumor cells. This is in contrast to the heparanase-mediated enhanced syndecan-1 shedding, which does require activity of the enzyme. This suggests that two different functional domains within the heparanase enzyme (the enzyme active site and a separate site) contribute to events leading to enhanced HGF signaling. These findings demonstrate a novel mechanism driving the HGF pathway whereby heparanase stimulates an increase in both HGF expression and syndecan-1 shedding to enhance HGF signaling. This work also provides further mechanistic insight into the dynamic role of heparanase in driving aggressive tumor progression.Heparanase, an endo--D-glucuronidase capable of cleaving intact heparan sulfate chains from proteoglycans, is up-regulated in a wide variety of human cancers and has been associated with promoting an array of cellular events leading to enhanced tumor progression (1). In addition to its enzymatic glycosidase activity, various nonenzymatic roles of heparanase such as enhancement of AKT signaling have also been described (2). In multiple myeloma, data from in vitro and in vivo models coupled with analysis of clinical samples have identified heparanase as a promoter of tumor angiogenesis, growth, and metastasis (3-7). Together these findings indicate that heparanase is a key regulator of myeloma progression.Many of the pro-tumorigenic effects of heparanase in myeloma have been traced to heparanase-stimulated up-regulation of syndecan-1 expression and shedding (2, 4). Syndecan-1, a heparan sulfate proteoglycan, is expressed on most myeloma tumor cells and is a critical determinant of myeloma cell survival and growth (8). Heparanase stimulates the synthesis and shedding of syndecan-1 via increased expression of two sheddases, MMP-9 and uPA 3 (7). Syndecan-1 remains biologically active after it is shed from cells and can control the localization and availability of many heparin-binding growth factors (9). Using in vivo models of myeloma, our laboratory has demonstrated t...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.