c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation
Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is esse...
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| Veröffentlicht in: | Cancer science 2021-01, Vol.112 (1), p.243-253 |
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| creator | Chang, Tsung‐Ming Chu, Pei‐Yi Hung, Wen‐Chun Shan, Yan‐Shen Lin, Hui‐You Huang, Kuo‐Wei Chang, Jeffrey S. Chen, Li‐Tzong Tsai, Hui‐Jen |
| description | Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c‐Myc overexpression is involved in tumorigenesis. The role of c‐Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c‐Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c‐Myc overexpression. c‐Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E‐box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c‐Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c‐Myc inhibitor or VEGFC‐neutralizing chimera protein reduced lymph node metastasis in the mice with c‐Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c‐Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET.
c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET. |
| doi_str_mv | 10.1111/cas.14717 |
| format | Article |
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c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.14717</identifier><identifier>PMID: 33128283</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Animal models ; Animals ; Antibiotics ; Antibodies ; Cell Line, Tumor ; Cell, Molecular, and Stem Cell Biology ; c‐Myc ; Deoxyribonucleic acid ; DNA ; Endothelial cells ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Gene Expression Regulation, Neoplastic - physiology ; Growth factors ; Heterografts ; Humans ; Kinases ; Lymph nodes ; lymphangiogenesis ; Lymphangiogenesis - physiology ; Lymphatic Metastasis - pathology ; Lymphatic system ; Male ; Medical research ; Metastases ; Metastasis ; Mice ; Mice, Inbred NOD ; Mice, SCID ; mTOR ; Myc protein ; Neoplasia ; Neuroendocrine tumors ; Neuroendocrine Tumors - pathology ; Original ; Pancreas ; Pancreatic Neoplasms - pathology ; pancreatic neuroendocrine tumor ; Phosphorylation ; Plasmids ; Proteins ; Proto-Oncogene Proteins c-myc - metabolism ; Research centers ; Secretion ; Therapeutic targets ; TOR protein ; Transcription ; Tumorigenesis ; Up-Regulation ; Vascular endothelial growth factor ; Vascular endothelial growth factor C ; Vascular Endothelial Growth Factor C - biosynthesis ; Xenografts</subject><ispartof>Cancer science, 2021-01, Vol.112 (1), p.243-253</ispartof><rights>2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/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-c4677-b035ba32c754f5e2a543e80c8db574618b04f9dfb1eef8c32f8675ee3396f4a13</citedby><cites>FETCH-LOGICAL-c4677-b035ba32c754f5e2a543e80c8db574618b04f9dfb1eef8c32f8675ee3396f4a13</cites><orcidid>0000-0002-3236-6205 ; 0000-0003-3250-7167 ; 0000-0001-5246-5748</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/PMC7780026/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780026/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33128283$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chang, Tsung‐Ming</creatorcontrib><creatorcontrib>Chu, Pei‐Yi</creatorcontrib><creatorcontrib>Hung, Wen‐Chun</creatorcontrib><creatorcontrib>Shan, Yan‐Shen</creatorcontrib><creatorcontrib>Lin, Hui‐You</creatorcontrib><creatorcontrib>Huang, Kuo‐Wei</creatorcontrib><creatorcontrib>Chang, Jeffrey S.</creatorcontrib><creatorcontrib>Chen, Li‐Tzong</creatorcontrib><creatorcontrib>Tsai, Hui‐Jen</creatorcontrib><title>c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c‐Myc overexpression is involved in tumorigenesis. The role of c‐Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c‐Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c‐Myc overexpression. c‐Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E‐box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c‐Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c‐Myc inhibitor or VEGFC‐neutralizing chimera protein reduced lymph node metastasis in the mice with c‐Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c‐Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET.
c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Antibodies</subject><subject>Cell Line, Tumor</subject><subject>Cell, Molecular, and Stem Cell Biology</subject><subject>c‐Myc</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Growth factors</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lymph nodes</subject><subject>lymphangiogenesis</subject><subject>Lymphangiogenesis - physiology</subject><subject>Lymphatic Metastasis - pathology</subject><subject>Lymphatic system</subject><subject>Male</subject><subject>Medical research</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>mTOR</subject><subject>Myc protein</subject><subject>Neoplasia</subject><subject>Neuroendocrine tumors</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Original</subject><subject>Pancreas</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>pancreatic neuroendocrine tumor</subject><subject>Phosphorylation</subject><subject>Plasmids</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Research centers</subject><subject>Secretion</subject><subject>Therapeutic targets</subject><subject>TOR protein</subject><subject>Transcription</subject><subject>Tumorigenesis</subject><subject>Up-Regulation</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular endothelial growth factor C</subject><subject>Vascular Endothelial Growth Factor C - biosynthesis</subject><subject>Xenografts</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp10U9rFDEYBvBQFFurh34BCfSih2nzb5KZS6EsbRUqPVS9hkz2ze6UmWSaTJS9-RH8jH4S424tVjAEEsiPhzc8CB1RckLLOrUmnVChqNpDB5SLtlKEyGfbu6pawtk-epnSHSFcila8QPucU9awhh8ga39-__FxY_EUwxhmSHjYjNPazL3FI8wmld0nHByejLcRtg8ecgzgl8HG3gOe8xgintcx5NUaf7m4ulzgPEVY5aHw4F-h584MCV4_nIfo8-XFp8X76vrm6sPi_LqyQipVdYTXneHMqlq4GpipBYeG2GbZ1UpI2nREuHbpOgrgGsuZa6SqAThvpROG8kN0tsudcjfC0oKfoxn0FPvRxI0OptdPX3y_1qvwVSvVEMJkCXj7EBDDfYY067FPFobBeAg5aSZqKShVNSv0-B96F3L05XtFKaFkW2xR73bKxpBSBPc4DCX6d3W6VKe31RX75u_pH-Wfrgo43YFv_QCb_yfpxfntLvIXg5il7w</recordid><startdate>202101</startdate><enddate>202101</enddate><creator>Chang, Tsung‐Ming</creator><creator>Chu, Pei‐Yi</creator><creator>Hung, Wen‐Chun</creator><creator>Shan, Yan‐Shen</creator><creator>Lin, Hui‐You</creator><creator>Huang, Kuo‐Wei</creator><creator>Chang, Jeffrey S.</creator><creator>Chen, Li‐Tzong</creator><creator>Tsai, Hui‐Jen</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3236-6205</orcidid><orcidid>https://orcid.org/0000-0003-3250-7167</orcidid><orcidid>https://orcid.org/0000-0001-5246-5748</orcidid></search><sort><creationdate>202101</creationdate><title>c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation</title><author>Chang, Tsung‐Ming ; Chu, Pei‐Yi ; Hung, Wen‐Chun ; Shan, Yan‐Shen ; Lin, Hui‐You ; Huang, Kuo‐Wei ; Chang, Jeffrey S. ; Chen, Li‐Tzong ; Tsai, Hui‐Jen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4677-b035ba32c754f5e2a543e80c8db574618b04f9dfb1eef8c32f8675ee3396f4a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Antibodies</topic><topic>Cell Line, Tumor</topic><topic>Cell, Molecular, and Stem Cell Biology</topic><topic>c‐Myc</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Endothelial cells</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelial Cells - pathology</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Growth factors</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Kinases</topic><topic>Lymph nodes</topic><topic>lymphangiogenesis</topic><topic>Lymphangiogenesis - physiology</topic><topic>Lymphatic Metastasis - pathology</topic><topic>Lymphatic system</topic><topic>Male</topic><topic>Medical research</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>mTOR</topic><topic>Myc protein</topic><topic>Neoplasia</topic><topic>Neuroendocrine tumors</topic><topic>Neuroendocrine Tumors - pathology</topic><topic>Original</topic><topic>Pancreas</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>pancreatic neuroendocrine tumor</topic><topic>Phosphorylation</topic><topic>Plasmids</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Research centers</topic><topic>Secretion</topic><topic>Therapeutic targets</topic><topic>TOR protein</topic><topic>Transcription</topic><topic>Tumorigenesis</topic><topic>Up-Regulation</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular endothelial growth factor C</topic><topic>Vascular Endothelial Growth Factor C - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chang, Tsung‐Ming</au><au>Chu, Pei‐Yi</au><au>Hung, Wen‐Chun</au><au>Shan, Yan‐Shen</au><au>Lin, Hui‐You</au><au>Huang, Kuo‐Wei</au><au>Chang, Jeffrey S.</au><au>Chen, Li‐Tzong</au><au>Tsai, Hui‐Jen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2021-01</date><risdate>2021</risdate><volume>112</volume><issue>1</issue><spage>243</spage><epage>253</epage><pages>243-253</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c‐Myc overexpression is involved in tumorigenesis. The role of c‐Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c‐Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c‐Myc overexpression. c‐Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E‐box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c‐Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c‐Myc inhibitor or VEGFC‐neutralizing chimera protein reduced lymph node metastasis in the mice with c‐Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c‐Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET.
c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>33128283</pmid><doi>10.1111/cas.14717</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3236-6205</orcidid><orcidid>https://orcid.org/0000-0003-3250-7167</orcidid><orcidid>https://orcid.org/0000-0001-5246-5748</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Antibiotics Antibodies Cell Line, Tumor Cell, Molecular, and Stem Cell Biology c‐Myc Deoxyribonucleic acid DNA Endothelial cells Endothelial Cells - metabolism Endothelial Cells - pathology Gene Expression Regulation, Neoplastic - physiology Growth factors Heterografts Humans Kinases Lymph nodes lymphangiogenesis Lymphangiogenesis - physiology Lymphatic Metastasis - pathology Lymphatic system Male Medical research Metastases Metastasis Mice Mice, Inbred NOD Mice, SCID mTOR Myc protein Neoplasia Neuroendocrine tumors Neuroendocrine Tumors - pathology Original Pancreas Pancreatic Neoplasms - pathology pancreatic neuroendocrine tumor Phosphorylation Plasmids Proteins Proto-Oncogene Proteins c-myc - metabolism Research centers Secretion Therapeutic targets TOR protein Transcription Tumorigenesis Up-Regulation Vascular endothelial growth factor Vascular endothelial growth factor C Vascular Endothelial Growth Factor C - biosynthesis Xenografts |
| title | c‐Myc promotes lymphatic metastasis of pancreatic neuroendocrine tumor through VEGFC upregulation |
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