Thrombospondin 1 Promotes Tumor Macrophage Recruitment and Enhances Tumor Cell Cytotoxicity of Differentiated U937 Cells

Martin‐Manso, Gema; Galli, Susana; Ridnour, Lisa A.; Tsokos, Maria; Wink, David A.; Roberts, D. A.

doi:10.1158/0008-5472.can-08-0643

Cited by 109 publications

(101 citation statements)

References 45 publications

(57 reference statements)

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“…Three of the CCN1 receptors identified in these studies (LRP1, heparan sulfate proteoglycan, and a6b1 integrin) also function as TSP1 receptors, and as discussed previously, a6b1 integrin is required for TSP1 to augment phorbol esterstimulated superoxide production by macrophages (154). Therefore, different matricellular proteins may utilize convergent receptor signaling pathways to regulate ROS production.…”

Section: A Ccn1supporting

confidence: 60%

“…Further insights into TSP1 regulation of macrophage ROS signaling were obtained by investigating how TSP1 regulates macrophage killing of tumor cells (154). Treatment of interferon-c-differentiated U937 cells, monocytes, and murine macrophages with TSP1 (*10 nM) for 40-130 min (depending on cell type) augmented phorbol ester-mediated superoxide production as characterized by luminol-enhanced chemiluminescence, whereas treatment with exogenous SOD quenched the ROS signal (154).…”

Section: Tsp1 Regulation Of Rosmentioning

confidence: 99%

“…Treatment of interferon-c-differentiated U937 cells, monocytes, and murine macrophages with TSP1 (*10 nM) for 40-130 min (depending on cell type) augmented phorbol ester-mediated superoxide production as characterized by luminol-enhanced chemiluminescence, whereas treatment with exogenous SOD quenched the ROS signal (154).…”

Section: Tsp1 Regulation Of Rosmentioning

confidence: 99%

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Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Section: A Ccn1supporting

confidence: 60%

Section: Tsp1 Regulation Of Rosmentioning

confidence: 99%

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Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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“…The normalized CI is an arbitrary unit derived from electrical impedance measurement (19)(20)(21)(22). The correlation between CI and cell viability is well documented in the literature (23)(24)(25)(26). Furthermore, we also tested cell death and apoptosis in three selected tumor lines, A549, HT29, and SH-SY5Y, treated with 1 μmol/L BFBTS, the concentration approximating the IC 50 value for cell proliferation and cytotoxicity (Table 1).…”

Section: Inhibition Of Cancer Cell Proliferation and Induction Of Apomentioning

confidence: 96%

Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

et al. 2009

Molecular Cancer Therapeutics

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Bis(4-fluorobenzyl)trisulfide (BFBTS) is a synthetic molecule derived from a bioactive natural product, dibenzyltrisulfide, found in a subtropical shrub, Petiveria allieacea. BFBTS has potent anticancer activities to a broad spectrum of tumor cell lines with IC 50 values from high nanomolar to low micromolar and showed equal anticancer potency between tumor cell lines overexpressing multidrug-resistant gene, MDR1 (MCF7/adr line and KBv200 line), and their parental MCF7 line and KB lines. BFBTS inhibited microtubule polymerization dynamics in MCF7 cells, at a low nanomolar concentration of 54 nmol/L, while disrupting microtubule filaments in cells at low micromolar concentration of 1 μmol/L. Tumor cells treated with BFBTS were arrested at G 2 -M phase, conceivably resulting from BFBTS-mediated antimicrotubule activities. Mass spectrometry studies revealed that BFBTS bound and modified β-tubulin at residue Cys12, forming β-tubulin-SSfluorobenzyl. The binding site differs from known antimicrotubule agents, suggesting that BFBTS functions as a novel antimicrotubule agent. BFBTS at a dose of 25 mg/kg inhibited tumor growth with relative tumor growth rates of 19.91%, 18.5%, and 23.42% in A549 lung cancer, Bcap-37 breast cancer, and SKOV3 ovarian cancer xenografts, respectively. Notably, BFBTS was more potent against MDR1-overexpressing MCF7/adr breast cancer xenografts with a relative tumor growth rate of 12.3% than paclitaxel with a rate of 43.0%. BFBTS displays a novel antimicrotubule agent with potentials for cancer therapeutics.

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“…The normalized CI is an arbitrary unit derived from electrical impedance measurement and correlates with the cell viability (51). The growth inhibitory activity results from an induction of the cell cycle and/or apoptosis.…”

Section: Discussionmentioning

confidence: 99%

AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors

Gloesenkamp

Nitzsche²,

Ocker³

et al. 2011

Int J Oncol

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Abstract. Up-regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important role in cytostatic therapy resistance and response to hypoxia and angiogenesis. Using real-time cell proliferation assay we examined the potency of triciribine in three distinct neuroendocrine gastrointestinal tumor cell lines. Also we investigated triciribine's induction of apoptosis and effects on a broad range of cancer-associated gene products. Furthermore, we characterized the role of PTEN as a possible predictor of sensitivity to triciribine in GEP-NETs. We also looked for additive anti-neoplastic effects of triciribine when combined with conventional cytostatic drugs or other targeted drugs, affecting different molecules of the PI3K-AKT-pathway and we assessed the potency of triciribine to inhibit tumor growth in vivo, by using the chick chorioallantoic membrane assay. Treatment of insulinoma (CM) or gut neuroendocrine tumor cells (STC-1) with triciribine significantly reduced tumor cell growth by 59% and 65%, respectively. By contrast, the highly expressing PTEN carcinoid cell line BON did not respond, even at higher doses. Combinations of triciribine with classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects. Additional in vivoevaluations confirmed the anti-neoplastic potency of triciribine. Thus, our data show that inhibition the AKT-pathway potently reduces the growth of GEP-NET cells alone or in combination therapies. AKT inhibition may provide a rationale for future evaluations. IntroductionGastroenteropancreatic neuroendocrine tumors (GEP-NETs), often synonymously called carcinoids, are a very heterogeneous group of neoplasms. Originally thought of as representing a rather homogeneous group, advances in the knowledge of molecular changes within different tumor entities of the GEP-NETs led to the classification system of the WHO in 2000 (1), later supplemented with additional studies (2).With a reported incidence of 2-3:100,000 GEP-NETs are relatively rare, but the 5-year survival rate is only about 67% (3,4). For localized tumors, systemic symptoms can be absent, since often its products, excess biogenic amines and hormones, are mostly cleared by the liver. Metastasized tumors, however, have often incapacitating symptoms, e.g., for the carcinoid syndrome including diarrhea, flushing, wheezing and skin rashes.The treatment of choice in locally defined tumors is still surgical resection (5). However, at presentation, about 80% of patients have already developed liver or lymph node metastases. In the advanced stages, the medical treatment options are still poor. Currently, different chemotherapeutic regimens are used, depending amongst others on the differentiation of the tumor, including etoposide plus cisplatin or streptozotocin with 5-FU or doxorubicin (6-8). However, response rates of 0-30% are still disappointing. In well-differentiated tumors...

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Thrombospondin 1 Promotes Tumor Macrophage Recruitment and Enhances Tumor Cell Cytotoxicity of Differentiated U937 Cells

Cited by 109 publications

References 45 publications

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Natural product derivative Bis(4-fluorobenzyl)trisulfide inhibits tumor growth by modification of β-tubulin at Cys 12 and suppression of microtubule dynamics

AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors

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