Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We p...
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| Veröffentlicht in: | Cancer science 2019-01, Vol.110 (1), p.334-344 |
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| creator | Ishii, Norihiro Araki, Kenichiro Yokobori, Takehiko Hagiwara, Kei Gantumur, Dorgormaa Yamanaka, Takahiro Handa, Tadashi Tsukagoshi, Mariko Igarashi, Takamichi Watanabe, Akira Kubo, Norio Harimoto, Norifumi Masamune, Atsushi Umezawa, Kazuo Kuwano, Hiroyuki Shirabe, Ken |
| description | Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF. |
| doi_str_mv | 10.1111/cas.13847 |
| format | Article |
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Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.13847</identifier><identifier>PMID: 30353606</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic drugs ; Antitumor agents ; Cancer therapies ; Cancer-Associated Fibroblasts - drug effects ; Cancer-Associated Fibroblasts - metabolism ; Cancer-Associated Fibroblasts - pathology ; Cell growth ; Cell Line ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Chemokines ; Chemoresistance ; Chemotherapy ; Collagen ; conophylline ; CXCL12 protein ; cytokine ; Cytokines ; Cytokines - genetics ; Cytokines - metabolism ; Deoxycytidine - administration & dosage ; Deoxycytidine - analogs & derivatives ; Female ; fibroblast ; Fibroblasts ; Fibrosis ; Gemcitabine ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Invasiveness ; Laboratories ; Ligands ; Malignancy ; Manufacturers ; Metastasis ; Mice, Inbred NOD ; Mice, SCID ; microenvironment ; Monocyte chemoattractant protein 1 ; Original ; Pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - prevention & control ; Pancreatic Stellate Cells - drug effects ; Pancreatic Stellate Cells - metabolism ; Proteins ; Radiation therapy ; stellate cell ; Stellate cells ; Stroma ; Tumor Burden - drug effects ; Tumor Burden - genetics ; Tumors ; Vinca Alkaloids - administration & dosage ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cancer science, 2019-01, Vol.110 (1), p.334-344</ispartof><rights>2018 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). 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><citedby>FETCH-LOGICAL-c5337-16d541fabd445e71f365a18aa1e06ba2a7490af617c956b1c9aadb51f1a4dfeb3</citedby><cites>FETCH-LOGICAL-c5337-16d541fabd445e71f365a18aa1e06ba2a7490af617c956b1c9aadb51f1a4dfeb3</cites><orcidid>0000-0001-6591-2439 ; 0000-0002-5696-2060</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/PMC6317962/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317962/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,1419,11569,27931,27932,45581,45582,46059,46483,53798,53800</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30353606$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishii, Norihiro</creatorcontrib><creatorcontrib>Araki, Kenichiro</creatorcontrib><creatorcontrib>Yokobori, Takehiko</creatorcontrib><creatorcontrib>Hagiwara, Kei</creatorcontrib><creatorcontrib>Gantumur, Dorgormaa</creatorcontrib><creatorcontrib>Yamanaka, Takahiro</creatorcontrib><creatorcontrib>Handa, Tadashi</creatorcontrib><creatorcontrib>Tsukagoshi, Mariko</creatorcontrib><creatorcontrib>Igarashi, Takamichi</creatorcontrib><creatorcontrib>Watanabe, Akira</creatorcontrib><creatorcontrib>Kubo, Norio</creatorcontrib><creatorcontrib>Harimoto, Norifumi</creatorcontrib><creatorcontrib>Masamune, Atsushi</creatorcontrib><creatorcontrib>Umezawa, Kazuo</creatorcontrib><creatorcontrib>Kuwano, Hiroyuki</creatorcontrib><creatorcontrib>Shirabe, Ken</creatorcontrib><title>Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Cancer therapies</subject><subject>Cancer-Associated Fibroblasts - drug effects</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Cancer-Associated Fibroblasts - pathology</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Chemokines</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Collagen</subject><subject>conophylline</subject><subject>CXCL12 protein</subject><subject>cytokine</subject><subject>Cytokines</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Female</subject><subject>fibroblast</subject><subject>Fibroblasts</subject><subject>Fibrosis</subject><subject>Gemcitabine</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Invasiveness</subject><subject>Laboratories</subject><subject>Ligands</subject><subject>Malignancy</subject><subject>Manufacturers</subject><subject>Metastasis</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>microenvironment</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Original</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - prevention & control</subject><subject>Pancreatic Stellate Cells - 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Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.
Cancer‐associated fibroblasts (CAF) are responsible for pancreatic cancer desmoplasia and promote cancer progression. This study shows that a natural compound conophylline (CnP) suppressed CAF activity, production of cancer‐promoting cytokines, and desmoplastic changes in tumors. CnP is a promising therapeutic strategy to overcome refractory pancreatic cancers through the suppression of CAF.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>30353606</pmid><doi>10.1111/cas.13847</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6591-2439</orcidid><orcidid>https://orcid.org/0000-0002-5696-2060</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6317962 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic drugs Antitumor agents Cancer therapies Cancer-Associated Fibroblasts - drug effects Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Cell growth Cell Line Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell Proliferation - genetics Chemokines Chemoresistance Chemotherapy Collagen conophylline CXCL12 protein cytokine Cytokines Cytokines - genetics Cytokines - metabolism Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Female fibroblast Fibroblasts Fibrosis Gemcitabine Gene Expression Regulation, Neoplastic - drug effects Humans Invasiveness Laboratories Ligands Malignancy Manufacturers Metastasis Mice, Inbred NOD Mice, SCID microenvironment Monocyte chemoattractant protein 1 Original Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - prevention & control Pancreatic Stellate Cells - drug effects Pancreatic Stellate Cells - metabolism Proteins Radiation therapy stellate cell Stellate cells Stroma Tumor Burden - drug effects Tumor Burden - genetics Tumors Vinca Alkaloids - administration & dosage Xenograft Model Antitumor Assays Xenografts |
| title | Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-05T07%3A05%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Conophylline%20suppresses%20pancreatic%20cancer%20desmoplasia%20and%20cancer%E2%80%90promoting%20cytokines%20produced%20by%20cancer%E2%80%90associated%20fibroblasts&rft.jtitle=Cancer%20science&rft.au=Ishii,%20Norihiro&rft.date=2019-01&rft.volume=110&rft.issue=1&rft.spage=334&rft.epage=344&rft.pages=334-344&rft.issn=1347-9032&rft.eissn=1349-7006&rft_id=info:doi/10.1111/cas.13847&rft_dat=%3Cproquest_pubme%3E2328376119%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2328376119&rft_id=info:pmid/30353606&rfr_iscdi=true |