{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T02:19:59Z","timestamp":1767665999164,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,8,29]],"date-time":"2020-08-29T00:00:00Z","timestamp":1598659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gastrointestinal Disorders"],"abstract":"<jats:p>Background: Angiogenesis plays an important role in colorectal cancer (CRC) tumorigenesis and metastatic progression. Methods: The present series consisted of CRC lymph node metastasis (LNM) tissue samples from 210 patients. Archival paraffin embedded LNM tissue were used to build up tissue microarray blocks and VEGF expression was immunohistochemically assessed. Results: VEGF-A and VEGF-C are overexpressed in LNM. VEGF-A was associated with patient age (p &lt; 0.001), and VEGFR-2 and VEGFR-3 with CRC relapse (p = 0.032; p = 0.030, respectively). VEGF-C positivity was associated with VEGFR-3 positivity (p = 0.031), and VEGF-D with VEGFR-2 and VEGFR-3 (p \u2264 0.001). Matching the expression in LNM with CRC, in CRC VEGF-A positivity associates with VEGF-A, VEGF-C, VEGF-D, VEGF-R2, VEGF-R3 positivity in LNM; CRC VEGF-C with VEGF-D, VEGFR-2, VEGFR-3; CRC VEGFR-2 with VEGF-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3; CRC VEGFR-3 with VEGF-A, VEGF-C, VEGF-D, VEGFR-2, VEGFR-3 in LNM. Conclusion: This study provides new information, revealing that VEGF family expression is increased in LNM. The association between the expression of VEGFR-2 and VEGFR-3 in LNM with CRC relapse reveals its impact on patient prognosis. Interesting data were found when the relationship between these proteins in primary tumor and their metastasis, were analyzed; VEGFA positivity in primary tumor is positively related to VEGF-A, VEGF-C, VEGF-D, VEGFR-2 and VEGFR-3 in their respective LNM suggesting mutual influence.<\/jats:p>","DOI":"10.3390\/gidisord2030025","type":"journal-article","created":{"date-parts":[[2020,8,30]],"date-time":"2020-08-30T06:06:22Z","timestamp":1598767582000},"page":"267-280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["VEGF Expression in Colorectal Cancer Metastatic Lymph Nodes: Clinicopathological Correlation and Prognostic Significance"],"prefix":"10.3390","volume":"2","author":[{"given":"In\u00eas","family":"Mazeda","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga 4710-057, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3526-3199","authenticated-orcid":false,"given":"Sandra F.","family":"Martins","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga 4710-057, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, Braga\/Guimar\u00e3es 4710-057, Portugal"},{"name":"Coloproctology Unit, Hospital de Braga, Braga 4710-243, Portugal"}]},{"given":"Eduardo A.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, S\u00e3o Paulo 14784-400, Brazil"}]},{"given":"Mesquita","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga 4710-057, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5779-9752","authenticated-orcid":false,"given":"Adhemar","family":"Longatto","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga 4710-057, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, Braga\/Guimar\u00e3es 4710-057, Portugal"},{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, S\u00e3o Paulo 14784-400, Brazil"},{"name":"Laboratory of Medical Investigation (LIM) 14, Faculty of Medicine, University of S\u00e3o Paulo, S\u00e3o Paulo 1246-903, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,29]]},"reference":[{"key":"ref_1","first-page":"1823","article-title":"Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature","volume":"19","author":"Des","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1002\/ijc.25516","article-title":"Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008","volume":"127","author":"Ferlay","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"ii29","DOI":"10.1093\/annonc\/mdn077","article-title":"Colon cancer: ESMO Clinical Recommendations for diagnosis, adjuvant treatment and follow-up","volume":"19","author":"Rodrigues","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"979","DOI":"10.5858\/2000-124-0979-PFICC","article-title":"Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999","volume":"124","author":"Compton","year":"2000","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Svagzdys, S., Lesauskaite, V., Pavalkis, D., Nedzelskien\u0117, I., Pranys, D., and Tamelis, A. (2009). Microvessel density as new prognostic marker after radiotherapy in rectal cancer. BMC Cancer, 9.","DOI":"10.1186\/1471-2407-9-95"},{"key":"ref_6","first-page":"272","article-title":"Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies","volume":"10","author":"Martins","year":"2011","journal-title":"WJC"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2147\/vhrm.2006.2.2.97","article-title":"Clinical implications of angiogenesis in cancers","volume":"2","author":"Pang","year":"2006","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_8","first-page":"231","article-title":"Combined perioperative plasma endoglin and VEGF-a assessment in colorectal cancer patients","volume":"47","author":"Pawlak","year":"2009","journal-title":"Folia Histochem. Cytobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/cncr.11911","article-title":"Elevated perioperative serum vascular endothelial growth factor levels in patients with colon carcinoma","volume":"100","author":"Orditura","year":"2004","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.3748\/wjg.v9.i6.1227","article-title":"Clinical significance of vascular endothelial growth factor expression and neovascularization in colorectal carcinoma","volume":"9","author":"Zheng","year":"2003","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1200\/JOP.2016.017210","article-title":"Adjuvant chemotherapy for stage II colon cancer: A clinical dilemma","volume":"13","author":"Kannarkatt","year":"2017","journal-title":"J. Oncol. Pract."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/path.1339","article-title":"The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression","volume":"100","author":"Hanrahan","year":"2003","journal-title":"J. Pathol."},{"key":"ref_13","first-page":"55","article-title":"Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer","volume":"10","author":"Martins","year":"2013","journal-title":"Cancer Genom. Proteom."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1756-9966-29-71","article-title":"Relationship and prognostic significance of SPARC and VEGF protein expression in colon cancer","volume":"29","author":"Liang","year":"2010","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_15","first-page":"149","article-title":"The angiogenesis in colorectal carcinomas with and without lymph node metastases","volume":"49","author":"Gurzu","year":"2008","journal-title":"Rom. J. Morphol. Embryol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.otorri.2008.12.001","article-title":"Prognostic significance of angiogenesis in surgically treated supraglottic squamous cell carcinomas of the larynx","volume":"60","author":"Rodrigo","year":"2009","journal-title":"Acta Otorrinolaringol. Esp."},{"key":"ref_17","first-page":"2803","article-title":"Expression of vascular endothelial growth factor can predict event-free survival in stage II colon cancer","volume":"6","author":"Cascinu","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/modpathol.3800034","article-title":"Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in colorectal cancer","volume":"17","author":"Saad","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/dvdy.24227","article-title":"VEGFR signaling during lymphatic vascular development: From progenitor cells to functional vessels","volume":"244","author":"Secker","year":"2015","journal-title":"Dev. Dyn."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1097\/PAS.0b013e318243555b","article-title":"Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: An immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors","volume":"36","author":"Miettinen","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"29643","DOI":"10.1074\/jbc.M001029200","article-title":"Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity","volume":"275","author":"Rivard","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.exger.2005.01.009","article-title":"Expression of pulmonary VEGF family declines with age and is further down-regulated in lipopolysaccharide (LPS)-induced lung injury","volume":"40","author":"Ito","year":"2005","journal-title":"Exp. Gerontol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/j.neurobiolaging.2004.02.028","article-title":"Age-dependent VEGF expression and intraneural neovascularization during regeneration of peripheral nerves","volume":"25","author":"Pola","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_24","first-page":"2065","article-title":"VEGFR1 and NRP1 endothelial expressions predict distant relapse after radical prostatectomy in clinically localized prostate cancer","volume":"33","author":"Talagas","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_25","first-page":"3211","article-title":"The role of circulating angiogenic factors in patients operated on for localized malignant melanoma","volume":"27","author":"Bolander","year":"2007","journal-title":"Anticancer. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Berardi, R., Torniai, M., Partelli, S., Rubini, C., Pagliaretta, S., Savini, A., Polenta, V., Santoni, M., Giampieri, R., and Onorati, S. (2018). Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197035"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.it.2004.05.003","article-title":"Lymphatic vasculature: Development, molecular regulation and role in tumor metastasis and inflammation","volume":"25","author":"Saharinen","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/modpathol.3880033","article-title":"Vascular endothelial growth factor receptor-3 (VEGFR-3): A marker of vascular tumors with presumed lymphatic differentiation, including Kaposi\u2019s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas","volume":"13","author":"Folpe","year":"2000","journal-title":"Mod. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1097\/CMR.0000000000000396","article-title":"PD-1\/PD-L1 and VEGF-A\/VEGF-C expression in lymph node microenvironment and association with melanoma metastasis and survival","volume":"27","author":"Alessi","year":"2017","journal-title":"Melanoma Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e8488","DOI":"10.1097\/MD.0000000000008488","article-title":"Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer","volume":"96","author":"Chen","year":"2017","journal-title":"Medicine (Baltimore)"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Greene, F., Page, D., Fleming, I., Fritz, A., and Balch, C. (2002). AJCC Cancer Staging Manual, Springer. [7th ed.].","DOI":"10.1007\/978-1-4757-3656-4"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00428-007-0558-5","article-title":"Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas","volume":"452","author":"Pinheiro","year":"2008","journal-title":"Virchows Arch."}],"container-title":["Gastrointestinal Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2624-5647\/2\/3\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:04:36Z","timestamp":1760177076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2624-5647\/2\/3\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,29]]},"references-count":32,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["gidisord2030025"],"URL":"https:\/\/doi.org\/10.3390\/gidisord2030025","relation":{},"ISSN":["2624-5647"],"issn-type":[{"type":"electronic","value":"2624-5647"}],"subject":[],"published":{"date-parts":[[2020,8,29]]}}}