A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor.

Slides:

Advertisements

Similar presentations

Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Induce Expression of CXCR4 on Human Endothelial Cells Rosalba Salcedo, Ken Wasserman,

Advertisements

A Novel Cinnamide YLT26 Induces Breast Cancer Cells Apoptosis via ROS-Mitochondrial Apoptotic Pathway in Vitro and Inhibits.

Figure 1. Herbacetin binds to AKT1/2 and suppresses each respective kinase activity. The effect of herbacetin on (A) PI3K/AKT and (B) MAPK signaling pathway.

Drug concentration (μM)

Molecular Therapy - Oncolytics

Figure 1. Herbacetin binds to AKT1/2 and suppresses each respective kinase activity. The effect of herbacetin on (A) PI3K/AKT and (B) MAPK signaling pathway.

Protein kinase B (PKB/c-akt) regulates homing of hematopoietic progenitors through modulation of their adhesive and migratory properties by Miranda Buitenhuis,

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain by Netanel A. Horowitz,

PRT , a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model by Michael P. Reilly, Uma Sinha,

Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production by Yeon-Sook Choi, Hyun-Jung.

Deregulation of SLIT2-Mediated Cdc42 Activity Is Associated with Esophageal Cancer Metastasis and Poor Prognosis Ruo-Chia Tseng, PhD, Jia-Ming Chang,

by Kesheng Dai, Richard Bodnar, Michael C. Berndt, and Xiaoping Du

Cyclooxygenase Regulates Angiogenesis Induced by Colon Cancer Cells

Immunotherapy of tumors with vaccine based on quail homologous vascular endothelial growth factor receptor-2 by Ji-yan Liu, Yu-quan Wei, Li Yang, Xia Zhao,

T3 increased J7-TRα1 cell migration and proliferation both in vitro and in vivo. T3 increased J7-TRα1 cell migration and proliferation both in vitro and.

by Rafijul Bari, Teresa Bell, Wai-Hang Leung, Queenie P

Volume 21, Issue 10, Pages (October 2013)

Inhibition of collagen-induced platelet aggregation by anopheline antiplatelet protein, a saliva protein from a malaria vector mosquito by Shigeto Yoshida,

Latency-Associated Peptide Prevents Skin Fibrosis in Murine Sclerodermatous Graft- Versus-Host Disease, a Model for Human Scleroderma Yan Zhang, Laura.

Hydrogen Sulfide Demonstrates Promising Antitumor Efficacy in Gastric Carcinoma by Targeting MGAT5 Rui Wang, Qilin Fan, Junjie Zhang, Xunan Zhang, Yuqi.

by Rizwan Masood, Megan E

Cancer-Specific Inhibitory Effects of Genetically Engineered Stem Cells Expressing Cytosine Deaminase and Interferon-β Against Choriocarcinoma in Xenografted.

Inhibition of Platelet GPIbα and Promotion of Melanoma Metastasis

Granulocyte transmigration through the endothelium is regulated by the oxidase activity of vascular adhesion protein-1 (VAP-1)‏ by Kaisa Koskinen, Petri.

Cognate recognition of the endothelium induces HY-specific CD8+ T-lymphocyte transendothelial migration (diapedesis) in vivo by Federica M. Marelli-Berg,

Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy by Mark P. Chao, Chad Tang, Russell K. Pachynski,

Nanomolar concentration of NSC606985, a camptothecin analog, induces leukemic-cell apoptosis through protein kinase Cδ–dependent mechanisms by Man-Gen.

Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression by Rosalba Salcedo, Maria Lourdes.

Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency by Joseph S. Palumbo, Kathryn E. Talmage, Hong Liu,

Inhibition of pathologic retinal neovascularization by α-defensins

Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors by Lothar Hambach, Marcel.

Apoptotic Vascular Endothelial Cells Become Procoagulant

Molecular Therapy - Nucleic Acids

by Jun Yuan, David B. Lovejoy, and Des R. Richardson

by Cunren Liu, Shaohua Yu, John Kappes, Jianhua Wang, William E

Interaction of kindlin-3 and β2-integrins differentially regulates neutrophil recruitment and NET release in mice by Zhen Xu, Jiayi Cai, Juan Gao, Gilbert.

by Michael Bezuhly, Robyn Cullen, Charles T. Esmon, Steven F

Volume 2, Issue 4, Pages (October 2002)

Inter-α inhibitor proteins maintain neutrophils in a resting state by regulating shape and reducing ROS production by Soe Soe Htwe, Hidenori Wake, Keyue.

Tumor Self-Seeding by Circulating Cancer Cells

Einar K. Rofstad, Bjørn A. Graff Journal of Investigative Dermatology

Volume 21, Issue 10, Pages (October 2013)

Specific Synergy of Multiple Substrate–Receptor Interactions in Platelet Thrombus Formation under Flow Brian Savage, Fanny Almus-Jacobs, Zaverio M Ruggeri

Volume 21, Issue 5, Pages (May 2013)

Volume 15, Issue 5, Pages (May 2007)

Interleukin-18 and the Costimulatory Molecule B7-1 Have a Synergistic Anti-Tumor Effect on Murine Melanoma; Implication of Combined Immunotherapy for.

Volume 14, Issue 2, Pages (February 2001)

Volume 17, Issue 2, Pages (February 2009)

Volume 25, Issue 4, Pages (April 2017)

Volume 22, Issue 1, Pages (January 2014)

Shrimp miR-34 from Shrimp Stress Response to Virus Infection Suppresses Tumorigenesis of Breast Cancer Yalei Cui, Xiaoyuan Yang, Xiaobo Zhang Molecular.

Chie Kudo-Saito, Hiromi Shirako, Tadashi Takeuchi, Yutaka Kawakami

Ajay Gautam, Charles L. Densmore, J.Clifford Waldrep Molecular Therapy

Volume 24, Issue 1, Pages (July 2013)

Volume 21, Issue 1, Pages (January 2013)

Volume 19, Issue 12, Pages (December 2011)

Proliferation of Aml1-excised immortalized BM cells is enhanced in vitro. Proliferation of Aml1-excised immortalized BM cells is enhanced in vitro. (A)

Expression of p110γ isoform in macrophages promotes tumor growth and angiogenesis. Expression of p110γ isoform in macrophages promotes tumor growth and.

Volume 24, Issue 10, Pages (October 2016)

Molecular Therapy - Oncolytics

Effects of DPM treatment on tumor volume, tumor mass, and pulmonary metastasis at experimental end point. Effects of DPM treatment on tumor volume, tumor.

Accelerated metastasis spread in tumor-bearing mice treated with paclitaxel and anakinra. Accelerated metastasis spread in tumor-bearing mice treated with.

Primary B16F10 tumor inhibits experimental metastasis formation in the lung. Primary B16F10 tumor inhibits experimental metastasis formation in the lung.

Endogenously produced n-3 PUFAs inhibit endometrial cancer cell growth in vitro and in vivo. Endogenously produced n-3 PUFAs inhibit endometrial cancer.

Fig. 6 Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9 in vivo. Antitumor effect on tumor growth and pulmonary metastasis of CSSD-9.

SPARC is required for spontaneous metastasis

Effect of MZ treatment on lung colony formation in an experimental metastasis. Effect of MZ treatment on lung colony formation in an experimental metastasis.

Validation of KMT2D function in MM23, MM2, and MM25 PDXs

Knockdown of ROR1 increases the invasive potential of melanoma cells in vitro and in vivo. Knockdown of ROR1 increases the invasive potential of melanoma.

DHA and dietary n-3 PUFAs inhibit endometrial cancer cell growth in vitro and in xenograft models. DHA and dietary n-3 PUFAs inhibit endometrial cancer.

Presentation transcript:

A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment by Wei Zhang, Suying Dang, Tao Hong, Jian Tang, Jing Fan, Dawei Bu, Yanjie Sun, Zhugang Wang, and Thomas Wisniewski Blood Volume 120(14):2889-2898 October 4, 2012 ©2012 by American Society of Hematology

Schema of antiplatelet GPIIIa49-66 scFv Ab (A11) properties for the inhibition of tumor metastasis. Schema of antiplatelet GPIIIa49-66 scFv Ab (A11) properties for the inhibition of tumor metastasis. (A) Summary figure. Events occurring following tumor intravasation, tumor-platelet-endothelial cell binding and platelet-tumor thrombus formation, tumor-platelet embolization, angiogenesis, and extravasation. T indicates tumor cells; and AP, activated platelets. (B) Platelets promoting metastases in an experimental pulmonary metastasis B16 tumor model. (Top row) Lung specimens with metastastic colonies. Plt indicates platelet. (Bottom row) Numeric results of surface pulmonary nodules (n = 8, **P < .01). (C) Hypothesized mechanisms of A11 on the inhibition of tumor metastasis by lysing activated platelets within the tumor microenvironment. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

Effect of A11 on spontaneous metastasis of LLC Effect of A11 on spontaneous metastasis of LLC. (A) It illustrates the treatment protocols in the spontaneous lung metastasis model. Effect of A11 on spontaneous metastasis of LLC. (A) It illustrates the treatment protocols in the spontaneous lung metastasis model. LLC indicates Lewis lung carcinoma. (B) Mean number of surface nodules per lung. (C) Mean volume of nodules per lung. (D) Representative histologic evidence from tumor sections of the different groups. (i-ii) 13CG2. (i) ×40; (ii) ×200. (iii-iv) A11. (iii) ×40; (iv) ×200. 13CG2 indicates control scFv Ab; n = 8, *P < .01. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

Effect of A11 on experimental metastasis of LLC Effect of A11 on experimental metastasis of LLC. (A) The (i-ii) preventive and (iii-v) therapeutic protocols in a lung metastasis model are shown. i.v. indicates intravenous injection; and LLC, Lewis lung carcinoma. Effect of A11 on experimental metastasis of LLC. (A) The (i-ii) preventive and (iii-v) therapeutic protocols in a lung metastasis model are shown. i.v. indicates intravenous injection; and LLC, Lewis lung carcinoma. (B) Mean number of surface nodules per lung in the different treatments. (C) Mean volume of nodules per lung in the different treatment groups. Ctrl. indicates control scFv Ab 13CG2; n = 8/group, **P < .001, *P < .01. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

The pathophysiologic relevance of the platelet GPIIIa49-66 epitope (GP49) on experimental lung metastases of B16 melanoma. The pathophysiologic relevance of the platelet GPIIIa49-66 epitope (GP49) on experimental lung metastases of B16 melanoma. Mice were treated as described in “Experimental lung metastasis assay.” At day 21, mice were killed. (A) Mean number of surface nodules per lung. (B) Mean volume of nodules per lung. (C) Induction of platelet count drop was determined at different time points. n = 8. *Values with significant differences. n.s. indicates no significant difference. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

Effect of A11 on early invasion of B16 melanoma cells in lung tissue. Effect of A11 on early invasion of B16 melanoma cells in lung tissue. (A) Frozen slide of lung tissue (×20) observed under a fluorescence microscope. (B) Quantitative result of adhesion of B16 in lung tissue as measurements of fluorescent intensity under a fluorescence plate reader. n = 5; *P < .01. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

Molecular mechanisms by which A11 inhibits tumor metastasis. Molecular mechanisms by which A11 inhibits tumor metastasis. (A-B) Effect of A11 on the adhesion of tumor cells to platelets in vitro. (A) The adhesion of LLCs to activated platelets as observed under fluorescence microscope. (B) The quantitative analysis of adhesion of LLC with activated platelet in the presence of various concentration of A11, as measurements of fluorescent intensity under a fluorescence plate reader. The experiment was repeated 3 times and each concentration had 4 wells. (C) Effect of A11 on the adhesion of platelets to HUVECs in vitro. The extent of adhesion was expressed as the percentage of control platelets adhering without preincubation with A11 or control scFv (13CG2). The experiment was repeated 3 times and each concentration had 4 wells. (D-E) Effect of A11 on platelet-mediated tumor cell adhesion to endothelial cell in vitro. B16 melanoma cells adhesion to HUVECs was performed as described in “Assay of tumor cells adhesion to endothelial cells.” (D) The adhesion efficiency of B16 tumor cell was observed under a fluorescence microscope. (E) Quantitative result of adhesion of B16 melanoma cells with HUVECs. (F) Effect of A11 on the destruction of already formed tumor platelet aggregates. Data and SD are given for 3 separate experiments at 0.5μM reagent in which each time point represents 5 measurements. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology

Effect of A11 on the viability of tumor cells and endothelial cells in vitro and in vivo. Effect of A11 on the viability of tumor cells and endothelial cells in vitro and in vivo. (A-C) Effect of A11 on the viability of (A) B16, (B) LLC, and (C) HUVECs as evaluated by the MTT assay. Data are mean ± SD of 3 different determinations. (D) Effect of A11 on the chemotaxis of tumor cells and HUVECs. Chemotaxis was performed in Transwell plates as described in “Transwell migration assay.” Data and SD are given for 3 independent experiment results in which each concentration represent 4 measurements. (E) Effect of A11 on the s.c. tumor growth. Tumor dimensions were measured with calipers for calculation of tumor volume. n = 5; error bars indicate SD. Wei Zhang et al. Blood 2012;120:2889-2898 ©2012 by American Society of Hematology