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Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells
Purpose Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant appro...
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| Published in: | Cancer chemotherapy and pharmacology 2018-02, Vol.81 (2), p.373-385 |
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| container_end_page | 385 |
| container_issue | 2 |
| container_start_page | 373 |
| container_title | Cancer chemotherapy and pharmacology |
| container_volume | 81 |
| creator | Fedorchuk, Olexandr Susak, Yaroslav Rudyk, Mariia Senchylo, Nataliia Khranovska, Nataliia Skachkova, Oksana Skivka, Larysa |
| description | Purpose
Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of
cis
-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
Methods
Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
Results
When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
Conclusion
Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing. |
| doi_str_mv | 10.1007/s00280-017-3503-6 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1983256464</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1983256464</sourcerecordid><originalsourceid>FETCH-LOGICAL-c372t-570a27016da54fb9ebd5891078343c73a289e9e5e15039d616084825290ee6113</originalsourceid><addsrcrecordid>eNp1kL1OwzAURi0EoqXwACwoEguL4fovsUfUQqlUCQaYLTdxS4qTFDsR4u1xlIIQEpOHe77r7x6EzglcE4DsJgBQCRhIhpkAhtMDNCacUQySs0M0BsY5FhnwEToJYQsAnDB2jEZUURWzbIzmi6rq6sY1mzI3Lnk1zlXGv4WkWSd5GfBs9oS9DWVoTd0mS_tRhsR19SbJjc_LuqlMklvnwik6WhsX7Nn-naCX-7vn6QNePs4X09slzllG276MoRmQtDCCr1fKrgohFYFMMs7yjBkqlVVWWBLvUUVK0niKpCLWtTYlhE3Q1bB355v3zoZWV2XoG5jaNl3QRElGRcpTHtHLP-i26Xwd2_UUFQyIFJEiA5X7JgRv13rny6jgUxPQvWU9WNbRsu4t6zRmLvabu1Vli5_Et9YI0AEIcVRvrP_19b9bvwAbs4Rx</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1982530185</pqid></control><display><type>article</type><title>Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells</title><source>Springer Link</source><creator>Fedorchuk, Olexandr ; Susak, Yaroslav ; Rudyk, Mariia ; Senchylo, Nataliia ; Khranovska, Nataliia ; Skachkova, Oksana ; Skivka, Larysa</creator><creatorcontrib>Fedorchuk, Olexandr ; Susak, Yaroslav ; Rudyk, Mariia ; Senchylo, Nataliia ; Khranovska, Nataliia ; Skachkova, Oksana ; Skivka, Larysa</creatorcontrib><description>Purpose
Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of
cis
-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
Methods
Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
Results
When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
Conclusion
Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-017-3503-6</identifier><identifier>PMID: 29290023</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Apoptosis ; Biocompatibility ; Cancer ; Cancer Research ; Chemotherapy ; Conditioning ; Cytolysis ; Cytometry ; Cytotoxicity ; Dendritic cells ; Drug resistance ; Drugs ; Flow cytometry ; Gene expression ; Genes ; Hypoxia ; Immunology ; Immunomodulation ; Immunosuppressive agents ; In vivo methods and tests ; Lung cancer ; Lung carcinoma ; Macrophages ; Medicine ; Medicine & Public Health ; Metabolism ; Oncology ; Original Article ; Oxidative metabolism ; Phagocytosis ; Pharmacology/Toxicology ; Platinum ; Polymerase chain reaction ; Reactive oxygen species ; Sensitivity ; Toxicity ; Transcription ; Tumor cells ; Tumor necrosis factor-α ; Tumors ; Ultrasonic testing</subject><ispartof>Cancer chemotherapy and pharmacology, 2018-02, Vol.81 (2), p.373-385</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2017</rights><rights>Cancer Chemotherapy and Pharmacology is a copyright of Springer, (2017). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-570a27016da54fb9ebd5891078343c73a289e9e5e15039d616084825290ee6113</citedby><cites>FETCH-LOGICAL-c372t-570a27016da54fb9ebd5891078343c73a289e9e5e15039d616084825290ee6113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29290023$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fedorchuk, Olexandr</creatorcontrib><creatorcontrib>Susak, Yaroslav</creatorcontrib><creatorcontrib>Rudyk, Mariia</creatorcontrib><creatorcontrib>Senchylo, Nataliia</creatorcontrib><creatorcontrib>Khranovska, Nataliia</creatorcontrib><creatorcontrib>Skachkova, Oksana</creatorcontrib><creatorcontrib>Skivka, Larysa</creatorcontrib><title>Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of
cis
-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
Methods
Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
Results
When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
Conclusion
Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.</description><subject>Apoptosis</subject><subject>Biocompatibility</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Chemotherapy</subject><subject>Conditioning</subject><subject>Cytolysis</subject><subject>Cytometry</subject><subject>Cytotoxicity</subject><subject>Dendritic cells</subject><subject>Drug resistance</subject><subject>Drugs</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Hypoxia</subject><subject>Immunology</subject><subject>Immunomodulation</subject><subject>Immunosuppressive agents</subject><subject>In vivo methods and tests</subject><subject>Lung cancer</subject><subject>Lung carcinoma</subject><subject>Macrophages</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolism</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Oxidative metabolism</subject><subject>Phagocytosis</subject><subject>Pharmacology/Toxicology</subject><subject>Platinum</subject><subject>Polymerase chain reaction</subject><subject>Reactive oxygen species</subject><subject>Sensitivity</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Tumor cells</subject><subject>Tumor necrosis factor-α</subject><subject>Tumors</subject><subject>Ultrasonic testing</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kL1OwzAURi0EoqXwACwoEguL4fovsUfUQqlUCQaYLTdxS4qTFDsR4u1xlIIQEpOHe77r7x6EzglcE4DsJgBQCRhIhpkAhtMDNCacUQySs0M0BsY5FhnwEToJYQsAnDB2jEZUURWzbIzmi6rq6sY1mzI3Lnk1zlXGv4WkWSd5GfBs9oS9DWVoTd0mS_tRhsR19SbJjc_LuqlMklvnwik6WhsX7Nn-naCX-7vn6QNePs4X09slzllG276MoRmQtDCCr1fKrgohFYFMMs7yjBkqlVVWWBLvUUVK0niKpCLWtTYlhE3Q1bB355v3zoZWV2XoG5jaNl3QRElGRcpTHtHLP-i26Xwd2_UUFQyIFJEiA5X7JgRv13rny6jgUxPQvWU9WNbRsu4t6zRmLvabu1Vli5_Et9YI0AEIcVRvrP_19b9bvwAbs4Rx</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Fedorchuk, Olexandr</creator><creator>Susak, Yaroslav</creator><creator>Rudyk, Mariia</creator><creator>Senchylo, Nataliia</creator><creator>Khranovska, Nataliia</creator><creator>Skachkova, Oksana</creator><creator>Skivka, Larysa</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20180201</creationdate><title>Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells</title><author>Fedorchuk, Olexandr ; Susak, Yaroslav ; Rudyk, Mariia ; Senchylo, Nataliia ; Khranovska, Nataliia ; Skachkova, Oksana ; Skivka, Larysa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-570a27016da54fb9ebd5891078343c73a289e9e5e15039d616084825290ee6113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Apoptosis</topic><topic>Biocompatibility</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Chemotherapy</topic><topic>Conditioning</topic><topic>Cytolysis</topic><topic>Cytometry</topic><topic>Cytotoxicity</topic><topic>Dendritic cells</topic><topic>Drug resistance</topic><topic>Drugs</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Hypoxia</topic><topic>Immunology</topic><topic>Immunomodulation</topic><topic>Immunosuppressive agents</topic><topic>In vivo methods and tests</topic><topic>Lung cancer</topic><topic>Lung carcinoma</topic><topic>Macrophages</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolism</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Oxidative metabolism</topic><topic>Phagocytosis</topic><topic>Pharmacology/Toxicology</topic><topic>Platinum</topic><topic>Polymerase chain reaction</topic><topic>Reactive oxygen species</topic><topic>Sensitivity</topic><topic>Toxicity</topic><topic>Transcription</topic><topic>Tumor cells</topic><topic>Tumor necrosis factor-α</topic><topic>Tumors</topic><topic>Ultrasonic testing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fedorchuk, Olexandr</creatorcontrib><creatorcontrib>Susak, Yaroslav</creatorcontrib><creatorcontrib>Rudyk, Mariia</creatorcontrib><creatorcontrib>Senchylo, Nataliia</creatorcontrib><creatorcontrib>Khranovska, Nataliia</creatorcontrib><creatorcontrib>Skachkova, Oksana</creatorcontrib><creatorcontrib>Skivka, Larysa</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Databases</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fedorchuk, Olexandr</au><au>Susak, Yaroslav</au><au>Rudyk, Mariia</au><au>Senchylo, Nataliia</au><au>Khranovska, Nataliia</au><au>Skachkova, Oksana</au><au>Skivka, Larysa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>81</volume><issue>2</issue><spage>373</spage><epage>385</epage><pages>373-385</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Purpose
Tumor cell resistance to platinum-based chemotherapeutic agents is one of the major hurdles to successful cancer treatment with these drugs, and is associated with alterations in tumor cell immune evasion and immunomodulatory properties. Immunocyte targeting is considered as a relevant approach to fight drug-resistant cancer. In this study, immunological hallmarks of
cis
-DDP-resistant Lewis lung carcinoma cells (LLC/R9) were investigated.
Methods
Immunological features of LLC/R9 cells cultured in vitro in normoxic and hypoxic conditions as well as of those that were grown in vivo were examined. The expression of immunologically relevant genes was evaluated by RT-PCR. Tumor cell susceptibility to the macrophage contact tumoricidal activity and NK-mediated cytolysis was investigated in MTT test. TNF-α-mediated tumor cell apoptosis as well as macrophage phagocytosis, oxidative metabolism, and CD206 expression after the treatment with conditioned media from normoxic and hypoxic tumor cells were studied by flow cytometry. Flow cytometry was also used to characterize dendritic cell maturity.
Results
When growing in vitro, LLC/R9 were characterized by slightly increased immunosuppressive cytokine gene expression. Transition to in vivo growth was associated with the enhancement of transcription of these genes in tumor cells. LLC/R9 cells had lowered sensitivity to contact-dependent macrophage-mediated cytotoxicity and to the TNFα-mediated apoptosis in vitro. Conditioned media from hypoxic LLC/R9 cells stimulated reactive oxygen species generation and CD206 expression in non-sensitized macrophages. Acquisition of drug resistance by LLC/R9 cells was associated with their increased sensitivity to NK-cell-mediated cytolysis. Meanwhile, the treatment of LLCR/9-bearing animals with generated ex vivo and loaded with LLC/R9 cell-lysate dendritic cells (DCs) resulted in profoundly enhanced tumor metastasizing.
Conclusion
Decreased sensitivity to macrophage cytolysis, polarizing effect on DCs maturation along with increased susceptibility to NK-cell cytotoxic action promote extensive local growth of chemoresistant LLC/R9 tumors in vivo, but hamper their metastasizing.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>29290023</pmid><doi>10.1007/s00280-017-3503-6</doi><tpages>13</tpages></addata></record> |
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| subjects | Apoptosis Biocompatibility Cancer Cancer Research Chemotherapy Conditioning Cytolysis Cytometry Cytotoxicity Dendritic cells Drug resistance Drugs Flow cytometry Gene expression Genes Hypoxia Immunology Immunomodulation Immunosuppressive agents In vivo methods and tests Lung cancer Lung carcinoma Macrophages Medicine Medicine & Public Health Metabolism Oncology Original Article Oxidative metabolism Phagocytosis Pharmacology/Toxicology Platinum Polymerase chain reaction Reactive oxygen species Sensitivity Toxicity Transcription Tumor cells Tumor necrosis factor-α Tumors Ultrasonic testing |
| title | Immunological hallmarks of cis-DDP-resistant Lewis lung carcinoma cells |
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