{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T14:36:11Z","timestamp":1791988571410,"version":"4.4.0"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Objectives: The objective of this study was to assess the relationship of VEGF-C and LVD with pathoclinical factors of potential prognostic value and with the survival time of gastric cancer patients. Materials and methods: A total of 103 radically operated patients for gastric cancer who did not undergo neoadjuvant therapy were included in this study. The minimum follow-up period after surgery was 61 months. VEGF-C and lymphatic vessels were immunohistochemically determined using antibodies, including VEGF-C (c-20) sc 1881-Goat Polyclonal IgG (Santa Cruz Biotechnology) and Podoplanin D2-40 Mouse Monoclonal Antibody (ROCHE). The relationship between VEGF-C expression in gastric adenocarcinoma cells and the density of lymphatic vessels at the periphery of the primary tumor was assessed, along with the relationships of VEGF-C and LVD with selected pathoclinical parameters of gastric cancer and prognosis. Results: VEGF-C overexpression was associated with increased LVD (Mann\u2013Whitney U test, p = 0.03) and the Lauren intestinal type of cancer (Pearson\u2019s chi-square test, p &lt; 0.001). Increased LVD was more often associated with cancers located beyond the cardia (Mann\u2013Whitney U test, p = 0.04). We did not demonstrate an association of VEGF-C or LVD with OS or with prognostic features, such as pT, pN, or pTNM staging. However, in the Lauren intestinal type of cancer, VEGF-C overexpression correlated with shorter OS (log-rank, p = 0.01) and, at the level of p = 0.05 in multivariate analysis, it had an independent negative prognostic value. Conclusions: Peritumoral overexpression of VEGF-C in primary gastric cancer tumors is associated with increased LVD. The Lauren intestinal type of cancer is associated with VEGF-C overexpression. The overexpression of VEGF-C in intestinal-type gastric cancer is associated with worse prognosis.<\/jats:p>","DOI":"10.3390\/cancers17091406","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T06:38:37Z","timestamp":1745390317000},"page":"1406","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["VEGF-C and Lymphatic Vessel Density in Tumor Tissue of Gastric Cancer: Correlations with Pathoclinical Features and Prognosis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7595-7152","authenticated-orcid":false,"given":"Mariusz","family":"Szajewski","sequence":"first","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"},{"name":"Department of Oncological Surgery, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maciej","family":"Ciesielski","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"},{"name":"Department of Oncological Surgery, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4904-7059","authenticated-orcid":false,"given":"Rafa\u0142","family":"P\u0119ksa","sequence":"additional","affiliation":[{"name":"Department of Pathomorphology, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8580-536X","authenticated-orcid":false,"given":"Piotr","family":"Kurek","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micha\u0142","family":"Sta\u0144czak","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"},{"name":"Department of Oncological Surgery, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-4290","authenticated-orcid":false,"given":"Jakub","family":"Walczak","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"},{"name":"Department of Oncological Surgery, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Zieli\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Faculty of Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"},{"name":"Department of General and Oncological Surgery, Janusz Korczak Specialist Hospital, 76-200 Slupsk, Poland"},{"name":"2nd Division of Radiology, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5929-5232","authenticated-orcid":false,"given":"Wies\u0142aw Janusz","family":"Kruszewski","sequence":"additional","affiliation":[{"name":"Department of Oncological Surgery, Gdynia Oncology Centre, 81-519 Gdynia, Poland"},{"name":"Department of Oncological Surgery, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-210 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1038\/sj.bjc.6603445","article-title":"First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours","volume":"95","author":"Cao","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"468725","DOI":"10.1155\/2010\/468725","article-title":"Angiogenesis and lymphangiogenesis of gastric cancer","volume":"2010","author":"Kitadai","year":"2010","journal-title":"J. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1186\/s40001-023-01298-x","article-title":"Lymphangiogenesis in gastric cancer: Function and mechanism","volume":"28","author":"Liu","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhang, J.Y., Li, Y.Q., Zhang, M.J., and Sun, Z.J. (2025). Lymphangiogenesis orchestrating tumor microenvironment: Face changing in immunotherapy. Biochim. Biophys. Acta Rev. Cancer, 1880.","DOI":"10.1016\/j.bbcan.2025.189278"},{"key":"ref_6","first-page":"1233","article-title":"Role of tertiary lymphoid structures and B cells in clinical immunotherapy of gastric cancer","volume":"166","author":"Zhang","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era immunotherapy","volume":"19","author":"Petitprez","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","first-page":"318","article-title":"Tertiary lymphoid structures and their therapeutic implications in cancer","volume":"20","author":"Petitprez","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4549","DOI":"10.7314\/APJCP.2013.14.8.4549","article-title":"Lymphangiogenic and angiogenic microvessel density in Chinese patients with gastric carcinoma: Correlation with clinicopathologic parameters and prognosis","volume":"14","author":"Cao","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, H., Guan, R., Lei, Y., Chen, J., Ge, Q., Zhang, X., Dou, R., Chen, H., Liu, H., and Qi, X. (2015). Lymphangiogenesis in gastric cancer regulated through Akt\/mTOR-VEGF-C\/VEGF-D axis. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1109-0"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3748\/wjg.v10.i6.783","article-title":"Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis","volume":"10","author":"Yan","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Vimalraj, S., Hariprabu, K.N.G., Rahaman, M., Govindasami, P., Perumal, K., Sekaran, S., and Ganapathy, D. (2023). Vascular endothelial growth factor-C and its receptor-3 signaling in tumorigenesis. 3 Biotech, 13.","DOI":"10.1007\/s13205-023-03719-4"},{"key":"ref_13","first-page":"586","article-title":"Overexpression of both VEGF-A and VEGF-C in gastric cancer correlates with prognosis, and silencing of both is effective to inhibit cancer growth","volume":"6","author":"Wang","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1152\/physrev.00005.2002","article-title":"Vascular growth factors and lymphangiogenesis","volume":"82","author":"Jussila","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, X.-L., Fang, J.-P., Tang, R.-Y., and Chen, X.-M. (2010). Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: A retrospective study of 123 cases. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-299"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1159\/000336807","article-title":"Expression of vascular endothelial growth factor C correlates with lymphatic vessel density and prognosis in human gastroesophageal junction carcinoma","volume":"35","author":"Yang","year":"2012","journal-title":"Onkologie"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.21873\/anticanres.17273","article-title":"Predictive Biomarkers of Lymph Node Metastasis in Early Gastric Cancer: A Reference of Clinicopathological Characteristics, Protein Expression, Epstein-Barr Virus Status, and Microsatellite Instability","volume":"44","author":"Byeon","year":"2024","journal-title":"Anticancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.7314\/APJCP.2012.13.7.3089","article-title":"Prognostic value of vascular endothelial growth factor expression in resected gastric cancer","volume":"13","author":"Liu","year":"2012","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s10120-012-0216-8","article-title":"High density of peritumoral lymphatic vessels measured by D2-40\/podoplanin and LYVE-1 expression in gastric cancer patients: An excellent prognostic indicator or a false friend?","volume":"16","author":"Kielan","year":"2013","journal-title":"Gastric Cancer"},{"key":"ref_21","first-page":"1823","article-title":"Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer","volume":"5","author":"Yonemura","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9473","DOI":"10.1007\/s11033-012-1812-8","article-title":"Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: A meta-analysis","volume":"39","author":"Peng","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"40","DOI":"10.14715\/cmb\/2024.70.1.6","article-title":"Comparative study on the expression of Pax3, Rad51 and VEGF-C in esophageal gastric junction adenocarcinoma and distal gastric adenocarcinoma","volume":"70","author":"Pan","year":"2024","journal-title":"Cell. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S285","DOI":"10.1016\/S0753-3322(05)80047-2","article-title":"Cyclooxygenase-2 expression is associated with VEGF-C and lymph node metastases in gastric cancer patients","volume":"59","author":"Zhang","year":"2005","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2016). TNM Classification of Malignant Tumours, Wiley-Blackwell. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1046\/j.1365-2168.1998.00940.x","article-title":"Classification of adenocarcinoma of the oesophagogastric junction","volume":"85","author":"Siewert","year":"1998","journal-title":"Br. J. Surg."},{"key":"ref_27","first-page":"125","article-title":"Simple quantitation of immunohistochemical staining positivity in microscopy for histopathology routine","volume":"11","author":"Klipponen","year":"1992","journal-title":"Acta Stereol."},{"key":"ref_28","first-page":"401","article-title":"Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma","volume":"143","author":"Weidner","year":"1993","journal-title":"Am. J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"218","DOI":"10.4143\/crt.2009.41.4.218","article-title":"No association of vascular endothelial growth factor-A (VEGF-A) and VEGF-C expression with survival in patients with gastric cancer","volume":"41","author":"Lee","year":"2009","journal-title":"Cancer Res. Treat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/modpathol.3880543","article-title":"Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi\u2019s sarcoma and a subset of angiosarcomas","volume":"15","author":"Kahn","year":"2002","journal-title":"Mod. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1245\/s10434-009-0707-y","article-title":"Increased intratumoral lymphatic vessel density correlates with lymph node metastasis in early gastric carcinoma","volume":"17","author":"Lee","year":"2010","journal-title":"Ann. Surg. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1756-9966-30-14","article-title":"Expressions of COX-2 and VEGF-C in gastric cancer: Correlations with lymphangiogenesis and prognostic implications","volume":"30","author":"Gou","year":"2011","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","first-page":"3911","article-title":"Intratumoral lymphangiogenesis and prognostic significance of VEGFC expression in gastric cancer","volume":"34","author":"Ikeda","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.21037\/jgo-22-651","article-title":"Identification of candidate biomarkers associated with gastric cancer prognosis based on an integrated bioinformatics analysis","volume":"13","author":"Liu","year":"2022","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.21037\/jgo.2018.12.06","article-title":"Increased circulating levels of vascular endothelial growth factor C can predict outcome in resectable gastric cancer patients","volume":"10","author":"Petrillo","year":"2019","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_36","first-page":"5741","article-title":"The correlation and clinical implication of VEGF-C expression in microvascular density and lymph node metastasis of gastric carcinoma","volume":"8","author":"Dai","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/jgh.12733","article-title":"Lymphangiogenesis in early and advanced gastric cancer: Is there any difference?","volume":"29","author":"Donizy","year":"2014","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Scartozzi, M., Loretelli, C., Galizia, E., Mandolesi, A., Pistelli, M., Bittoni, A., Giampieri, R., Faloppi, L., Bianconi, M., and Del Prete, M. (2012). Role of vascular endothelial growth factor (VEGF) and VEGF-R genotyping in guiding the metastatic process in pT4a resected gastric cancer patients. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038192"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Russi, S., Marano, L., Laurino, S., Calice, G., Scala, D., Marino, G., Sgambato, A., Mazzone, P., Carbone, L., and Napolitano, G. (2022). Gene Regulatory Network Characterization of Gastric Cancer\u2019s Histological Subtypes: Distinctive Biological and Clinically Relevant Master Regulators. Cancers, 14.","DOI":"10.3390\/cancers14194961"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/9\/1406\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:19:54Z","timestamp":1760030394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/9\/1406"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["cancers17091406"],"URL":"https:\/\/doi.org\/10.3390\/cancers17091406","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]}}}