Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts
<p>Abstract</p> <p>Background</p> <p>Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-<it>O</it>-sulfation state. HSPGs bind to numerous growth factor ligands including fibrobl...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-08-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/10/427 |
| _version_ | 1818919336700542976 |
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| author | Peterson Sarah M Iskenderian Andrea Cook Lynette Romashko Alla Tobin Kristen Jones Michael Norton Angela Gómez-Yafal Alicia Heartlein Michael W Concino Michael F Liaw Lucy Martini Paolo GV |
| author_facet | Peterson Sarah M Iskenderian Andrea Cook Lynette Romashko Alla Tobin Kristen Jones Michael Norton Angela Gómez-Yafal Alicia Heartlein Michael W Concino Michael F Liaw Lucy Martini Paolo GV |
| author_sort | Peterson Sarah M |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-<it>O</it>-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth <it>in vivo</it>.</p> <p>Methods</p> <p>We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. <it>In vitro </it>studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using <it>in vivo </it>xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. <it>In vivo </it>studies were statistically analyzed using Student's t test.</p> <p>Results</p> <p><it>In vitro</it>, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular density within the tumors. By contrast, transient exogenous treatment of MDA-MB-231 xenografts with rhSulf2 was not sufficient to inhibit or reverse tumor growth.</p> <p>Conclusion</p> <p>These data indicate that <it>in vivo </it>progression of human breast cancer xenografts can be inhibited with sulfatase expression, and therapeutic effect requires constant delivery at the tumor site. Our results support a direct effect of sulfatases on tumor growth or invasion, rather than an effect in the stromal compartment.</p> |
| first_indexed | 2024-12-20T01:04:15Z |
| format | Article |
| id | doaj.art-e6955f3168a140e0a95768edca7a471e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-20T01:04:15Z |
| publishDate | 2010-08-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-e6955f3168a140e0a95768edca7a471e2022-12-21T19:58:54ZengBMCBMC Cancer1471-24072010-08-0110142710.1186/1471-2407-10-427Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenograftsPeterson Sarah MIskenderian AndreaCook LynetteRomashko AllaTobin KristenJones MichaelNorton AngelaGómez-Yafal AliciaHeartlein Michael WConcino Michael FLiaw LucyMartini Paolo GV<p>Abstract</p> <p>Background</p> <p>Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-<it>O</it>-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth <it>in vivo</it>.</p> <p>Methods</p> <p>We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. <it>In vitro </it>studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using <it>in vivo </it>xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. <it>In vivo </it>studies were statistically analyzed using Student's t test.</p> <p>Results</p> <p><it>In vitro</it>, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular density within the tumors. By contrast, transient exogenous treatment of MDA-MB-231 xenografts with rhSulf2 was not sufficient to inhibit or reverse tumor growth.</p> <p>Conclusion</p> <p>These data indicate that <it>in vivo </it>progression of human breast cancer xenografts can be inhibited with sulfatase expression, and therapeutic effect requires constant delivery at the tumor site. Our results support a direct effect of sulfatases on tumor growth or invasion, rather than an effect in the stromal compartment.</p>http://www.biomedcentral.com/1471-2407/10/427 |
| spellingShingle | Peterson Sarah M Iskenderian Andrea Cook Lynette Romashko Alla Tobin Kristen Jones Michael Norton Angela Gómez-Yafal Alicia Heartlein Michael W Concino Michael F Liaw Lucy Martini Paolo GV Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts BMC Cancer |
| title | Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts |
| title_full | Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts |
| title_fullStr | Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts |
| title_full_unstemmed | Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts |
| title_short | Human Sulfatase 2 inhibits <it>in vivo </it>tumor growth of MDA-MB-231 human breast cancer xenografts |
| title_sort | human sulfatase 2 inhibits it in vivo it tumor growth of mda mb 231 human breast cancer xenografts |
| url | http://www.biomedcentral.com/1471-2407/10/427 |
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