{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:22:23Z","timestamp":1785410543089,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005378","name":"Hacettepe University","doi-asserted-by":"publisher","award":["19300"],"award-info":[{"award-number":["19300"]}],"id":[{"id":"10.13039\/501100005378","id-type":"DOI","asserted-by":"publisher"}]},{"award":["19300"],"award-info":[{"award-number":["19300"]}],"id":[{"id":"https:\/\/ror.org\/04kwvgz42","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study evaluated the prognostic significance of vasohibin-1 (VASH1) expression, cluster of differentiation 34 (CD34)-defined microvessel density (MVD), and vascular endothelial growth factor (VEGF) expression, as well as the differences in these parameters between primary and metastatic colorectal cancer (CRC) lesions. Tissue microarrays were used to quantify VASH1 and VEGF expression and CD34-defined MVD. Receiver operating characteristic (ROC) analysis identified optimal cut-off values for overall survival (OS). Correlations among markers were analyzed with Spearman\u2019s test, paired tissue comparisons by the Wilcoxon signed-rank test, and survival outcomes by Kaplan\u2013Meier and Cox regression analyses. The study included 144 CRC patients (median age: 60 years; 59% male). ROC analysis determined optimal thresholds of 6 for VASH1 (area under the curve [AUC]: 0.79, 95% confidence interval [CI]: 0.72\u20130.87), 37 for CD34-defined MVD (AUC: 0.76, 95% CI: 0.68\u20130.84), and 6 for VEGF (AUC: 0.67, 95% CI: 0.58\u20130.76). Patients with high VASH1 expression, high CD34-defined MVD, and high VEGF expression had significantly shorter OS compared with their corresponding low-marker groups (VASH1, p &lt; 0.001; CD34-defined MVD, p &lt; 0.001; VEGF, p = 0.007). Among the 45 patients with paired primary and metastatic samples, metastatic lesions showed significantly lower VASH1 and VEGF expression and lower CD34-defined MVD than matched primary tumors, with median values decreasing from 6.0 to 4.0 for VASH1 (p = 0.002), from 4 to 3 for VEGF (p &lt; 0.001), and from 32 to 27 for CD34-defined MVD (p &lt; 0.001). In multivariate analysis, high VASH1 expression (hazard ratio [HR]: 2.05, 95% CI: 1.01\u20134.20, p = 0.048) and high CD34-defined MVD (HR: 2.12, 95% CI: 1.15\u20133.89, p = 0.015) remained independent predictors of poor OS. High VASH1 expression and high CD34-defined MVD were independent adverse prognostic factors for OS in CRC. Lower angiogenesis-related marker levels in metastatic lesions suggest heterogeneity in tumor angiogenesis. External validation is required before clinical application.<\/jats:p>","DOI":"10.3390\/ijms27146319","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:08:34Z","timestamp":1784189314000},"page":"6319","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic Significance and Primary\u2013Metastatic Differences in VASH1 Expression, CD34-Defined Microvessel Density, and VEGF Expression in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3540-0701","authenticated-orcid":false,"given":"Oktay Halit","family":"Aktepe","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dokuz Eylul University, Izmir 35330, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9046-1772","authenticated-orcid":false,"given":"Rezan Berkay","family":"Izgor","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir 35330, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozlem","family":"Aydin Isak","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Ankara Etlik City Hospital, Ankara 06170, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olcay","family":"Kurtulan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara 06230, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tugce","family":"Ulasli","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dokuz Eylul University, Izmir 35330, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suayib","family":"Yalcin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara 06230, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, T., Guo, Y., Qiu, B., Dai, X., Wang, Y., and Cao, X. (2025). Global, Regional, and National Trends in Colorectal Cancer Burden from 1990 to 2021 and Projections to 2040. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1466159"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s13046-023-02729-7","article-title":"Liver Metastasis from Colorectal Cancer: Pathogenetic Development, Immune Landscape of the Tumour Microenvironment and Therapeutic Approaches","volume":"42","author":"Wang","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12943-025-02465-w","article-title":"Circulating Tumor Cells: Mechanisms and Clinical Significance in Colorectal Cancer Metastasis","volume":"24","author":"Ren","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1038\/sj.bjc.6603176","article-title":"Microvessel Density and VEGF Expression Are Prognostic Factors in Colorectal Cancer. Meta-Analysis of the Literature","volume":"94","author":"Uzzan","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.4240\/wjgs.v15.i9.2052","article-title":"Quantitative Evaluation of Colorectal Tumour Vasculature Using Contrast-Enhanced Ultrasound: Correlation with Angiogenesis and Prognostic Significance","volume":"15","author":"Li","year":"2023","journal-title":"World J. Gastrointest. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Zhou, H., Shi, J., Guan, A., Zhu, Y., Hou, Z., and Li, R. (2021). Decreased M6A Modification of CD34\/CD276(B7-H3) Leads to Immune Escape in Colon Cancer. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.715674"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e38997","DOI":"10.1097\/MD.0000000000038997","article-title":"The Prognostic Significance of CD117-Positive Mast Cells and Microvessel Density in Colorectal Cancer","volume":"103","author":"Dere","year":"2024","journal-title":"Medicine"},{"key":"ref_8","first-page":"e49186","article-title":"Utility of CD34 in Assessing Microvessel Density and Its Correlation with Clinicopathological Parameters in Colorectal Carcinoma Patients","volume":"15","author":"Pandey","year":"2023","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1172\/JCI200421152","article-title":"Vasohibin as an Endothelium-Derived Negative Feedback Regulator of Angiogenesis","volume":"114","author":"Watanabe","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1136\/jclinpath-2013-201444","article-title":"Vasohibin-1 Is a New Predictor of Disease-Free Survival in Operated Patients with Renal Cell Carcinoma","volume":"66","author":"Kanomata","year":"2013","journal-title":"J. Clin. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4145","DOI":"10.1158\/1078-0432.CCR-12-0073","article-title":"The Prognostic Significance of Vasohibin-1 Expression in Patients with Upper Urinary Tract Urothelial Carcinoma","volume":"18","author":"Miyazaki","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"567","DOI":"10.4103\/jcrt.jcrt_281_21","article-title":"Significance of Vasohibin 1 in Cancer Patients","volume":"18","author":"Liu","year":"2022","journal-title":"J. Cancer Res. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7880","DOI":"10.18632\/oncotarget.3493","article-title":"Vasohibin-1 Suppresses Colon Cancer","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/s41392-025-02249-0","article-title":"Vascular Endothelial Growth Factor Signaling in Health and Disease: From Molecular Mechanisms to Therapeutic Perspectives","volume":"10","author":"Lee","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, X., Bove, A.M., Simone, G., and Ma, B. (2020). Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.599281"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"272","DOI":"10.5306\/wjco.v2.i6.272","article-title":"Role of Endoglin and VEGF Family Expression in Colorectal Cancer Prognosis and Anti-Angiogenic Therapies","volume":"2","author":"Martins","year":"2011","journal-title":"World J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"430","DOI":"10.2353\/ajpath.2009.080788","article-title":"Vasohibin-1 Expression in Endothelium of Tumor Blood Vessels Regulates Angiogenesis","volume":"175","author":"Hosaka","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.2353\/ajpath.2010.090829","article-title":"Endogenous Angiogenesis Inhibitor Vasohibin1 Exhibits Broad-Spectrum Antilymphangiogenic Activity and Suppresses Lymph Node Metastasis","volume":"176","author":"Heishi","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.21873\/anticanres.11437","article-title":"Vasohibin-1 as a Novel Prognostic Factor for Head and Neck Squamous Cell Carcinoma","volume":"37","author":"Torii","year":"2017","journal-title":"Anticancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/labinvest.2017.26","article-title":"Increased Vasohibin-1 Expression Is Associated with Metastasis and Poor Prognosis of Renal Cell Carcinoma Patients","volume":"97","author":"Mikami","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_21","first-page":"5265","article-title":"Expression of Vasohibin-1 and -2 Predicts Poor Prognosis among Patients with Squamous Cell Carcinoma of the Esophagus","volume":"16","author":"Ninomiya","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_22","first-page":"5321","article-title":"Vasohibin-1 Increases the Malignant Potential of Colorectal Cancer and Is a Biomarker of Poor Prognosis","volume":"34","author":"Kitajima","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1007\/s12032-013-0816-0","article-title":"A Novel Molecular Marker of Prognosis in Colorectal Cancer: Vasohibin-1","volume":"31","author":"Yan","year":"2014","journal-title":"Med. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Nguyen, L., Fifis, T., Malcontenti-Wilson, C., Chan, L.S., Costa, P.N.L., Nikfarjam, M., Muralidharan, V., and Christophi, C. (2012). Spatial Morphological and Molecular Differences within Solid Tumors May Contribute to the Failure of Vascular Disruptive Agent Treatments. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-522"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41392-023-01460-1","article-title":"Angiogenic Signaling Pathways and Anti-Angiogenic Therapy for Cancer","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"A321","DOI":"10.1186\/1749-8090-10-S1-A321","article-title":"Validation of the Endothelial Staining Markers CD31 and CD34 in Immunohistochemistry of the Long Saphenous Vein","volume":"10","author":"Krishnamoorthy","year":"2015","journal-title":"J. Cardiothorac. Surg."},{"key":"ref_27","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_28","first-page":"3558","article-title":"Angiogenesis in Primary Colorectal Cancer and Matched Metastatic Tissues: Biological and Clinical Implications for Anti-angiogenic Therapies","volume":"19","author":"Yin","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1056\/NEJMoa032691","article-title":"Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer","volume":"350","author":"Hurwitz","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"571","DOI":"10.4132\/KoreanJPathol.2010.44.6.571","article-title":"Differences in Expression of VEGF-A, VEGFR-1, VEGFR-2 and Microvessel Density in Colorectal Cancer with Liver Metastasis","volume":"44","author":"Jeong","year":"2010","journal-title":"Korean J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1002\/ijc.29904","article-title":"Microvessel Density and Endothelial Cell Proliferation Levels in Colorectal Liver Metastases from Patients given Neo-adjuvant Cytotoxic Chemotherapy and Bevacizumab","volume":"138","author":"Eefsen","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4505","DOI":"10.21873\/anticanres.15261","article-title":"Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response","volume":"41","author":"Okamoto","year":"2021","journal-title":"Anticancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23960","DOI":"10.18632\/oncotarget.25251","article-title":"Identification of Different Mutational Profiles in Cancers Arising in Specific Colon Segments by next Generation Sequencing","volume":"9","author":"Oliveira","year":"2018","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"(2012). The Cancer Genome Atlas (TCGA) Research Network. Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. Nature, 487, 330\u2013337.","DOI":"10.1038\/nature11252"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The Consensus Molecular Subtypes of Colorectal Cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/S1658-3876(09)50007-6","article-title":"Validation of Tissue Microarray Biomarker Expression of Breast Carcinomas in Saudi Women","volume":"2","author":"Alkushi","year":"2009","journal-title":"Hematol. Oncol. Stem Cell Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1002\/ijc.21581","article-title":"Tissue Microarrays for Comparing Molecular Features with Proliferation Activity in Breast Cancer","volume":"118","author":"Ruiz","year":"2006","journal-title":"Int. J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6319\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T08:09:22Z","timestamp":1784189362000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146319"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146319","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]}}}