Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors

Chlenski, Alexandre; Guerrero, Lisa J.; Peddinti, Radhika; Spitz, Jared A; Leonhardt, Payton; Yang, Qiwei; Tian, Yufeng; Salwen, Helen R.; Cohn, Susan L.

doi:10.1186/1476-4598-9-138

Cited by 51 publications

(53 citation statements)

References 36 publications

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“…Furthermore, staining for blood vessels and pericytes was also significantly reduced with pracinostat treatment in vivo, compared with controls. Perivascular smooth muscle cells are essential for vascular integrity, by providing physiologic and mechanical support for blood vessels (42). Untreated bladder xenografts showed a significantly higher number of blood vessels and pericytes than pracinostattreated tumor samples (Fig.…”

Section: Discussionmentioning

confidence: 96%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchoragedependent growth capacities. Pracinostat also induced growth arrest at the G 0 -G 1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer.

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Section: Discussionmentioning

confidence: 96%

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Sooraj

Cain

et al. 2016

Molecular Cancer Therapeutics

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“…1 B and C). SPARC has contextdependent pro-and antiangiogenic effects (42); in HUVECs, SPARC appears to repress invasion and angiogenesis (43). Knockdown of WNK1 in both HUVECs and HDMECs did not affect amounts of the WNK1 downstream kinases OSR1 and SPAK ( Fig.…”

Section: Wnk1mentioning

confidence: 95%

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Dbouk

Weil

Perera

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The with no lysine (K) (WNK) family of enzymes is best known for control of blood pressure through regulation of the function and membrane localization of ion cotransporters. In mice, global as well as endothelial-specific WNK1 gene disruption results in embryonic lethality due to angiogenic and cardiovascular defects. WNK1−/− embryos can be rescued by endothelial-specific expression of a constitutively active form of the WNK1 substrate protein kinase OSR1 (oxidative stress responsive 1). Using human umbilical vein endothelial cells (HUVECs), we explored mechanisms underlying the requirement of WNK1-OSR1 signaling for vascular development. WNK1 is required for cord formation in HUVECs, but the actions of the two major WNK1 effectors, OSR1 and its close relative SPAK (STE20/SPS1-related proline-, alanine-rich kinase), are distinct. SPAK is important for endothelial cell proliferation, whereas OSR1 is required for HUVEC chemotaxis and invasion. We also identified the zinc-finger transcription factor Slug in WNK1-mediated control of endothelial functions. Our study identifies a separation of functions for the WNK1-activated protein kinases OSR1 and SPAK in mediating proliferation, invasion, and gene expression in endothelial cells and an unanticipated link between WNK1 and Slug that is important for angiogenesis.endothelium | angiogenesis | migration | EMT | Slug

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“…Use of SPARC knockout (Sparc -/-) mice revealed that SPARC suppresses syngeneic and oncogenedriven tumors (9,(11)(12)(13)(14) through regulation of matrix deposition and through antiinflammatory, antiangiogenic, antiproliferative, and proapoptotic effects, while SPARC has been found to be upregulated in the stroma (9,15). SPARC exerts autocrine and paracrine inhibition of cancer cell proliferation through cell-cycle arrest (8,9,13,16,17) and suppression of survival signaling (7,11,12,18,19), cancer cell adhesion, and invasion (8,11,12,17,18).…”

Section: Introductionmentioning

confidence: 99%

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

Said¹,

Frierson²,

Sänchez‐Carbayo³

et al. 2013

J. Clin. Invest.

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Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in Sparc-deficient mice and their wild-type littermates, we found that loss of SPARC accelerated the development of urothelial preneoplasia (atypia and dysplasia), neoplasia, and metastasis and was associated with decreased survival. SPARC reduced carcinogen-induced inflammation and accumulation of reactive oxygen species as well as urothelial cell proliferation. Loss of SPARC was associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with concomitant increased activation of urothelial and stromal NF-κB and AP1 in vivo and in vitro. Syngeneic spontaneous and experimental metastasis models revealed that tumorand stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization. In human bladder tumor tissues, the frequency and intensity of SPARC expression were inversely correlated with disease-specific survival. These results indicate that SPARC is produced by benign and malignant compartments of bladder carcinomas where it functions to suppress bladder carcinogenesis, progression, and metastasis.

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Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors

Cited by 51 publications

References 36 publications

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK

Loss of SPARC in bladder cancer enhances carcinogenesis and progression

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