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Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin.

Schafer JM, Peters DE, Morley T, Liu S, Molinolo AA, Leppla SH, Bugge TH - PLoS ONE (2011)

Bottom Line: HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both.We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis.This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.

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Tumoricidal activity of intermolecular complementing PA to human HNSCC.Nude mice bearing intradermal Cal27 (A), HN6 (B), HN12 (C), and Hep2 (D) HNSCC xenografts were injected intraperitoneally with either PBS (blue lines) or PA-U2-R200A + PA-L1-I210A + LF (red lines) at the time points indicated by the red arrows. (E) Body weight change over time in all groups. The data are expressed as mean tumor weight ± standard error of the mean; *, P<0.01. Ten mice were used per tumor and treatment group.
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pone-0020532-g002: Tumoricidal activity of intermolecular complementing PA to human HNSCC.Nude mice bearing intradermal Cal27 (A), HN6 (B), HN12 (C), and Hep2 (D) HNSCC xenografts were injected intraperitoneally with either PBS (blue lines) or PA-U2-R200A + PA-L1-I210A + LF (red lines) at the time points indicated by the red arrows. (E) Body weight change over time in all groups. The data are expressed as mean tumor weight ± standard error of the mean; *, P<0.01. Ten mice were used per tumor and treatment group.

Mentions: Cal27, Hep2, HN6, and HN12 HNSCC cell lines form solid tumors when xenografted to immunocompromized mice and were therefore suitable for assessing the efficacy of the intercomplementing toxin for HNSCC treatment in vivo. The four cell lines were transplanted intradermally to nude mice, and solid tumor nodules constituting 0.25 to 0.5 percent of the total body weight were allowed to form. The mice thereafter were treated three times per week with intraperitoneal injections of either intercomplementing toxin in combination with LF or with PBS as a control (Figure 2). Cal27, HN6, and HN12 tumors were all efficiently treated with the intercomplementing toxin, consistent with their expression of functional cell surface uPA and MMP activities in cell culture (Figure 2A-C). Average tumor sizes in toxin-treated mice ranged from 0.6 to 26 percent of the average tumor sizes of PBS-injected mice at treatment cessation. Interestingly, although Hep2 cells did not express uPA or MMP activity sufficient for intercomplementing toxin activation in culture (see above), the Hep2 tumors were treated efficiently in vivo, with the average tumor size of toxin-treated mice being just six percent of the average tumor sizes of PBS-injected mice at treatment cessation (Figure 2D). The greatest response to the intercomplementing toxin was observed with HN12-bearing mice, with 40 percent of the mice remaining tumor-free when observed for up to one year after treatment cessation.


Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin.

Schafer JM, Peters DE, Morley T, Liu S, Molinolo AA, Leppla SH, Bugge TH - PLoS ONE (2011)

Tumoricidal activity of intermolecular complementing PA to human HNSCC.Nude mice bearing intradermal Cal27 (A), HN6 (B), HN12 (C), and Hep2 (D) HNSCC xenografts were injected intraperitoneally with either PBS (blue lines) or PA-U2-R200A + PA-L1-I210A + LF (red lines) at the time points indicated by the red arrows. (E) Body weight change over time in all groups. The data are expressed as mean tumor weight ± standard error of the mean; *, P<0.01. Ten mice were used per tumor and treatment group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105081&req=5

pone-0020532-g002: Tumoricidal activity of intermolecular complementing PA to human HNSCC.Nude mice bearing intradermal Cal27 (A), HN6 (B), HN12 (C), and Hep2 (D) HNSCC xenografts were injected intraperitoneally with either PBS (blue lines) or PA-U2-R200A + PA-L1-I210A + LF (red lines) at the time points indicated by the red arrows. (E) Body weight change over time in all groups. The data are expressed as mean tumor weight ± standard error of the mean; *, P<0.01. Ten mice were used per tumor and treatment group.
Mentions: Cal27, Hep2, HN6, and HN12 HNSCC cell lines form solid tumors when xenografted to immunocompromized mice and were therefore suitable for assessing the efficacy of the intercomplementing toxin for HNSCC treatment in vivo. The four cell lines were transplanted intradermally to nude mice, and solid tumor nodules constituting 0.25 to 0.5 percent of the total body weight were allowed to form. The mice thereafter were treated three times per week with intraperitoneal injections of either intercomplementing toxin in combination with LF or with PBS as a control (Figure 2). Cal27, HN6, and HN12 tumors were all efficiently treated with the intercomplementing toxin, consistent with their expression of functional cell surface uPA and MMP activities in cell culture (Figure 2A-C). Average tumor sizes in toxin-treated mice ranged from 0.6 to 26 percent of the average tumor sizes of PBS-injected mice at treatment cessation. Interestingly, although Hep2 cells did not express uPA or MMP activity sufficient for intercomplementing toxin activation in culture (see above), the Hep2 tumors were treated efficiently in vivo, with the average tumor size of toxin-treated mice being just six percent of the average tumor sizes of PBS-injected mice at treatment cessation (Figure 2D). The greatest response to the intercomplementing toxin was observed with HN12-bearing mice, with 40 percent of the mice remaining tumor-free when observed for up to one year after treatment cessation.

Bottom Line: HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both.We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis.This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.

Show MeSH
Related in: MedlinePlus