11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis
Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Ang...
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| Veröffentlicht in: | PloS one 2023-03, Vol.18 (3), p.e0255709 |
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| creator | Davidson, Callam T Miller, Eileen Muir, Morwenna Dawson, John C Lee, Martin Aitken, Stuart Serrels, Alan Webster, Scott P Homer, Natalie Z M Andrew, Ruth Brunton, Valerie G Hadoke, Patrick W F Walker, Brian R |
| description | Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P |
| doi_str_mv | 10.1371/journal.pone.0255709 |
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Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0255709</identifier><identifier>PMID: 36940215</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism ; 11β-Hydroxysteroid dehydrogenase ; Actin ; Adenocarcinoma ; Angiogenesis ; Animal models ; Animals ; Antibodies ; Antigens ; Biology and Life Sciences ; Breast cancer ; CD3 antigen ; Cell culture ; Cell proliferation ; Collagen (type I) ; Corticosterone ; Diabetic retinopathy ; Diet ; Extracellular matrix ; Female ; Fibrosis ; Gene sequencing ; Glucocorticoids ; Glucocorticoids - metabolism ; Hydroxysteroids ; Immune system ; Immunohistochemistry ; Inflammation ; Inflammatory response ; Liver ; Liver cancer ; Medicine and Health Sciences ; Metastases ; Mice ; Muscles ; Myocardial infarction ; Neoplasms ; Neovascularization, Pathologic ; Nitrogen ; Pancreatic cancer ; Pancreatic carcinoma ; Second harmonic generation ; Smooth muscle ; Solid tumors ; Squamous cell carcinoma ; Tumors</subject><ispartof>PloS one, 2023-03, Vol.18 (3), p.e0255709</ispartof><rights>Copyright: © 2023 Davidson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>2023 Davidson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Davidson et al 2023 Davidson et al</rights><rights>2023 Davidson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3919-15e1374da12fec1b7ee060be6009f948897cc1bca1acb469ae4b0fa7497f634f3</cites><orcidid>0000-0002-2416-1648 ; 0000-0001-5835-3886 ; 0000-0003-4867-4568</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027213/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027213/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36940215$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Davidson, Callam T</creatorcontrib><creatorcontrib>Miller, Eileen</creatorcontrib><creatorcontrib>Muir, Morwenna</creatorcontrib><creatorcontrib>Dawson, John C</creatorcontrib><creatorcontrib>Lee, Martin</creatorcontrib><creatorcontrib>Aitken, Stuart</creatorcontrib><creatorcontrib>Serrels, Alan</creatorcontrib><creatorcontrib>Webster, Scott P</creatorcontrib><creatorcontrib>Homer, Natalie Z M</creatorcontrib><creatorcontrib>Andrew, Ruth</creatorcontrib><creatorcontrib>Brunton, Valerie G</creatorcontrib><creatorcontrib>Hadoke, Patrick W F</creatorcontrib><creatorcontrib>Walker, Brian R</creatorcontrib><title>11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.</description><subject>11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism</subject><subject>11β-Hydroxysteroid dehydrogenase</subject><subject>Actin</subject><subject>Adenocarcinoma</subject><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>CD3 antigen</subject><subject>Cell culture</subject><subject>Cell proliferation</subject><subject>Collagen (type 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R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2023-03-01</date><risdate>2023</risdate><volume>18</volume><issue>3</issue><spage>e0255709</spage><pages>e0255709-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Glucocorticoids inhibit angiogenesis by activating the glucocorticoid receptor. Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reduces tissue-specific glucocorticoid action and promotes angiogenesis in murine models of myocardial infarction. Angiogenesis is important in the growth of some solid tumours. This study used murine models of squamous cell carcinoma (SCC) and pancreatic ductal adenocarcinoma (PDAC) to test the hypothesis that 11β-HSD1 inhibition promotes angiogenesis and subsequent tumour growth. SCC or PDAC cells were injected into female FVB/N or C57BL6/J mice fed either standard diet, or diet containing the 11β-HSD1 inhibitor UE2316. SCC tumours grew more rapidly in UE2316-treated mice, reaching a larger (P<0.01) final volume (0.158 ± 0.037 cm3) than in control mice (0.051 ± 0.007 cm3). However, PDAC tumour growth was unaffected. Immunofluorescent analysis of SCC tumours did not show differences in vessel density (CD31/alpha-smooth muscle actin) or cell proliferation (Ki67) after 11β-HSD1 inhibition, and immunohistochemistry of SCC tumours did not show changes in inflammatory cell (CD3- or F4/80-positive) infiltration. In culture, the growth/viability (assessed by live cell imaging) of SCC cells was not affected by UE2316 or corticosterone. Second Harmonic Generation microscopy showed that UE2316 reduced Type I collagen (P<0.001), whilst RNA-sequencing revealed that multiple factors involved in the innate immune/inflammatory response were reduced in UE2316-treated SCC tumours. 11β-HSD1 inhibition increases SCC tumour growth, likely via suppression of inflammatory/immune cell signalling and extracellular matrix deposition, but does not promote tumour angiogenesis or growth of all solid tumours.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36940215</pmid><doi>10.1371/journal.pone.0255709</doi><orcidid>https://orcid.org/0000-0002-2416-1648</orcidid><orcidid>https://orcid.org/0000-0001-5835-3886</orcidid><orcidid>https://orcid.org/0000-0003-4867-4568</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism 11β-Hydroxysteroid dehydrogenase Actin Adenocarcinoma Angiogenesis Animal models Animals Antibodies Antigens Biology and Life Sciences Breast cancer CD3 antigen Cell culture Cell proliferation Collagen (type I) Corticosterone Diabetic retinopathy Diet Extracellular matrix Female Fibrosis Gene sequencing Glucocorticoids Glucocorticoids - metabolism Hydroxysteroids Immune system Immunohistochemistry Inflammation Inflammatory response Liver Liver cancer Medicine and Health Sciences Metastases Mice Muscles Myocardial infarction Neoplasms Neovascularization, Pathologic Nitrogen Pancreatic cancer Pancreatic carcinoma Second harmonic generation Smooth muscle Solid tumors Squamous cell carcinoma Tumors |
| title | 11β-HSD1 inhibition does not affect murine tumour angiogenesis but may exert a selective effect on tumour growth by modulating inflammation and fibrosis |
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