Macrophages modulate migration and invasion of human tongue squamous cell carcinoma
Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-assoc...
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| Veröffentlicht in: | PloS one 2015-03, Vol.10 (3), p.e0120895-e0120895 |
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| creator | Pirilä, Emma Väyrynen, Otto Sundquist, Elias Päkkilä, Kaisa Nyberg, Pia Nurmenniemi, Sini Pääkkönen, Virve Pesonen, Paula Dayan, Dan Vered, Marilena Uhlin-Hansen, Lars Salo, Tuula |
| description | Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity. |
| doi_str_mv | 10.1371/journal.pone.0120895 |
| format | Article |
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Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120895</identifier><identifier>PMID: 25811194</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Animal models ; Animals ; Basale medisinske, odontologiske og veterinærmedisinske fag: 710 ; Basic medical, dental and veterinary science disciplines: 710 ; Biomarkers ; Bone morphogenetic proteins ; Carcinoma, Squamous Cell - immunology ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell adhesion ; Cell Communication ; Cell culture ; Cell Line, Tumor ; Cell Movement - immunology ; Cells, Cultured ; Coculture Techniques ; Confocal microscopy ; Cytokines - metabolism ; Dentistry ; Disease Models, Animal ; Endocytosis - immunology ; Epidermal growth factor ; Fibroblasts ; Head & neck cancer ; Heterografts ; Hospitals ; Humans ; Immunohistochemistry ; Inflammation ; Leukocyte migration ; Macrophages ; Macrophages - immunology ; Macrophages - metabolism ; Medical disciplines: 700 ; Medical prognosis ; Medical research ; Medical treatment ; Medicine ; Medisinske Fag: 700 ; Metastasis ; Mice ; Microscopy ; Mortality ; Neoplasm Invasiveness ; NF-kappa B - metabolism ; NF-κB protein ; Pathology ; Patients ; Prognosis ; Rats ; Squamous cell carcinoma ; Three dimensional models ; Tongue ; Tongue Neoplasms - immunology ; Tongue Neoplasms - metabolism ; Tongue Neoplasms - pathology ; Transforming growth factor-b ; Tumor necrosis factor-TNF ; Tumors ; VDP</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0120895-e0120895</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Pirilä 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>info:eu-repo/semantics/openAccess</rights><rights>2015 Pirilä et al 2015 Pirilä et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c781t-8adfde37829018b959ebd567dd07857fa264cab66afb82529321a21625213f2f3</citedby><cites>FETCH-LOGICAL-c781t-8adfde37829018b959ebd567dd07857fa264cab66afb82529321a21625213f2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374792/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374792/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,26567,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25811194$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Guan, Xin-Yuan</contributor><creatorcontrib>Pirilä, Emma</creatorcontrib><creatorcontrib>Väyrynen, Otto</creatorcontrib><creatorcontrib>Sundquist, Elias</creatorcontrib><creatorcontrib>Päkkilä, Kaisa</creatorcontrib><creatorcontrib>Nyberg, Pia</creatorcontrib><creatorcontrib>Nurmenniemi, Sini</creatorcontrib><creatorcontrib>Pääkkönen, Virve</creatorcontrib><creatorcontrib>Pesonen, Paula</creatorcontrib><creatorcontrib>Dayan, Dan</creatorcontrib><creatorcontrib>Vered, Marilena</creatorcontrib><creatorcontrib>Uhlin-Hansen, Lars</creatorcontrib><creatorcontrib>Salo, Tuula</creatorcontrib><title>Macrophages modulate migration and invasion of human tongue squamous cell carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.</description><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Basale medisinske, odontologiske og veterinærmedisinske fag: 710</subject><subject>Basic medical, dental and veterinary science disciplines: 710</subject><subject>Biomarkers</subject><subject>Bone morphogenetic proteins</subject><subject>Carcinoma, Squamous Cell - immunology</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Cell adhesion</subject><subject>Cell Communication</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - immunology</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Confocal microscopy</subject><subject>Cytokines - metabolism</subject><subject>Dentistry</subject><subject>Disease Models, Animal</subject><subject>Endocytosis - immunology</subject><subject>Epidermal growth factor</subject><subject>Fibroblasts</subject><subject>Head & neck cancer</subject><subject>Heterografts</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Leukocyte migration</subject><subject>Macrophages</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Medical disciplines: 700</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medical treatment</subject><subject>Medicine</subject><subject>Medisinske Fag: 700</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Microscopy</subject><subject>Mortality</subject><subject>Neoplasm Invasiveness</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Pathology</subject><subject>Patients</subject><subject>Prognosis</subject><subject>Rats</subject><subject>Squamous cell carcinoma</subject><subject>Three dimensional models</subject><subject>Tongue</subject><subject>Tongue Neoplasms - immunology</subject><subject>Tongue Neoplasms - metabolism</subject><subject>Tongue Neoplasms - pathology</subject><subject>Transforming growth factor-b</subject><subject>Tumor necrosis factor-TNF</subject><subject>Tumors</subject><subject>VDP</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>3HK</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1tv0zAUxyMEYqPwDRBEQkLw0OJL4jgvk6aJS6WhSQx4tU4cO3WV2J2dTPDtcdp0LGgPyA9x7N_5n5tPkrzEaIVpgT9s3eAttKuds2qFMEG8zB8lp7ikZMkIoo_v7U-SZyFsEcopZ-xpckJyjjEus9Pk-itI73YbaFRIO1cPLfQq7UzjoTfOpmDr1NhbCOOP0-lm6MCmvbPNoNJwM0DnhpBK1bapBC-NdR08T55oaIN6MX0XyY9PH79ffFleXn1eX5xfLmXBcb_kUOta0YKTEmFelXmpqjpnRV2jgueFBsIyCRVjoCtOchKTwUAwi1tMNdF0kbw-6O5aF8RUjyAwYwVClCIeifWBqB1sxc6bDvxv4cCI_YHzjQDfG9kqIWWlFc9IqWmeIV5BDAtjnde03nuOWmeTt6HqVC2V7T20M9H5jTUb0bhbkdEiK0oSBV4dBKQ3oTdWWOdB4BhqITjLUQTeTR68uxlU6EVnwlhasCpWeZ8YzVgZ41kkb_5BH05_ohqIGRqrXQxMjqLiPCOY46Iss0itHqDiqlVnZHxd2sTzmcH7mUFkevWrb2AIQayvv_0_e_Vzzr69x24UtP0muHYYH2KYg9mxki4Er_RdFzAS43AcqyHG4RDTcPxtwKFPd0bHaaB_ALlpB9I</recordid><startdate>20150326</startdate><enddate>20150326</enddate><creator>Pirilä, Emma</creator><creator>Väyrynen, Otto</creator><creator>Sundquist, Elias</creator><creator>Päkkilä, Kaisa</creator><creator>Nyberg, Pia</creator><creator>Nurmenniemi, Sini</creator><creator>Pääkkönen, Virve</creator><creator>Pesonen, Paula</creator><creator>Dayan, Dan</creator><creator>Vered, Marilena</creator><creator>Uhlin-Hansen, Lars</creator><creator>Salo, Tuula</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>3HK</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150326</creationdate><title>Macrophages modulate migration and invasion of human tongue squamous cell carcinoma</title><author>Pirilä, Emma ; Väyrynen, Otto ; Sundquist, Elias ; Päkkilä, Kaisa ; Nyberg, Pia ; Nurmenniemi, Sini ; Pääkkönen, Virve ; Pesonen, Paula ; Dayan, Dan ; Vered, Marilena ; Uhlin-Hansen, Lars ; Salo, Tuula</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c781t-8adfde37829018b959ebd567dd07857fa264cab66afb82529321a21625213f2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Angiogenesis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Basale medisinske, odontologiske og veterinærmedisinske fag: 710</topic><topic>Basic medical, dental and veterinary science disciplines: 710</topic><topic>Biomarkers</topic><topic>Bone morphogenetic proteins</topic><topic>Carcinoma, Squamous Cell - 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metabolism</topic><topic>NF-κB protein</topic><topic>Pathology</topic><topic>Patients</topic><topic>Prognosis</topic><topic>Rats</topic><topic>Squamous cell carcinoma</topic><topic>Three dimensional models</topic><topic>Tongue</topic><topic>Tongue Neoplasms - immunology</topic><topic>Tongue Neoplasms - metabolism</topic><topic>Tongue Neoplasms - pathology</topic><topic>Transforming growth factor-b</topic><topic>Tumor necrosis factor-TNF</topic><topic>Tumors</topic><topic>VDP</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pirilä, Emma</creatorcontrib><creatorcontrib>Väyrynen, Otto</creatorcontrib><creatorcontrib>Sundquist, Elias</creatorcontrib><creatorcontrib>Päkkilä, Kaisa</creatorcontrib><creatorcontrib>Nyberg, Pia</creatorcontrib><creatorcontrib>Nurmenniemi, Sini</creatorcontrib><creatorcontrib>Pääkkönen, Virve</creatorcontrib><creatorcontrib>Pesonen, Paula</creatorcontrib><creatorcontrib>Dayan, Dan</creatorcontrib><creatorcontrib>Vered, Marilena</creatorcontrib><creatorcontrib>Uhlin-Hansen, Lars</creatorcontrib><creatorcontrib>Salo, Tuula</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>NORA - Norwegian Open Research Archives</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pirilä, Emma</au><au>Väyrynen, Otto</au><au>Sundquist, Elias</au><au>Päkkilä, Kaisa</au><au>Nyberg, Pia</au><au>Nurmenniemi, Sini</au><au>Pääkkönen, Virve</au><au>Pesonen, Paula</au><au>Dayan, Dan</au><au>Vered, Marilena</au><au>Uhlin-Hansen, Lars</au><au>Salo, Tuula</au><au>Guan, Xin-Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Macrophages modulate migration and invasion of human tongue squamous cell carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-03-26</date><risdate>2015</risdate><volume>10</volume><issue>3</issue><spage>e0120895</spage><epage>e0120895</epage><pages>e0120895-e0120895</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25811194</pmid><doi>10.1371/journal.pone.0120895</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-03, Vol.10 (3), p.e0120895-e0120895 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1667003308 |
| source | MEDLINE; NORA - Norwegian Open Research Archives; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiogenesis Animal models Animals Basale medisinske, odontologiske og veterinærmedisinske fag: 710 Basic medical, dental and veterinary science disciplines: 710 Biomarkers Bone morphogenetic proteins Carcinoma, Squamous Cell - immunology Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Cell adhesion Cell Communication Cell culture Cell Line, Tumor Cell Movement - immunology Cells, Cultured Coculture Techniques Confocal microscopy Cytokines - metabolism Dentistry Disease Models, Animal Endocytosis - immunology Epidermal growth factor Fibroblasts Head & neck cancer Heterografts Hospitals Humans Immunohistochemistry Inflammation Leukocyte migration Macrophages Macrophages - immunology Macrophages - metabolism Medical disciplines: 700 Medical prognosis Medical research Medical treatment Medicine Medisinske Fag: 700 Metastasis Mice Microscopy Mortality Neoplasm Invasiveness NF-kappa B - metabolism NF-κB protein Pathology Patients Prognosis Rats Squamous cell carcinoma Three dimensional models Tongue Tongue Neoplasms - immunology Tongue Neoplasms - metabolism Tongue Neoplasms - pathology Transforming growth factor-b Tumor necrosis factor-TNF Tumors VDP |
| title | Macrophages modulate migration and invasion of human tongue squamous cell carcinoma |
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