Montazeri Vahid, Varshosaz Parisa, Fakhrjou Ashraf, Pirouzpanah Saeed
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Cancer Rep (Hoboken). 2025 May;8(5):e70101. doi: 10.1002/cnr2.70101.
Biomarkers of angiogenesis and lymphangiogenesis have been explored in cancer prognostic models; however, their potential role in assessing local tumor invasiveness remains poorly understood.
This study aimed to evaluate the correlations of angiogenic biomarkers, specifically the angiopoietin (ANG)-Tie system and vascular endothelial growth factor-C (VEGF-C), with lymphangiogenesis and the related histopathological characteristics in Iranian women with breast cancer.
In this consecutive case series (n = 149) from the Breast Cancer Risk and Lifestyle (BCRL) study, plasma levels of pro-angiogenic factors, including VEGF-C, ANGs, and Tie-2, were assessed using ELISA. Clinicopathological data were collected, excluding stage IV cases to focus on patients with localized disease. Axillary lymph node metastasis (ANLM), and vascular invasion (VI) were common in the study population, occurring in 61.5% and 77.6% of cases, respectively (p < 0.01). Estrogen receptor-positive (ER) tumors were observed in 89.1% of ANLM participants, while human epidermal growth factor receptor-2-positive (HER-2) tumors were identified in 22.8% of patients with ALNM. Plasma levels of ANG-1 (r = 0.19) and VEGF-C (r = 0.29) were positively correlated with the ALNM ratio (p < 0.05). Multivariate analysis in patients with grade II tumors revealed significant inverse correlations between VEGF-C and angiogenic biomarkers, including ANG-2 (β = -0.25), the ANG-2/Tie-2 ratio (β = -0.28), and the (ANG-1 + ANG-2)/Tie-2 ratio (β = -0.29) (p < 0.05). Receiver operating characteristic (ROC) curve analysis indicated that ANG-2 could effectively assess ALNM status, with an optimal cutoff of 3.39 pg/mL, identifying ALNM in 66.0% of patients with low VEGF-C levels (95% CI: 0.54-0.78), increasing to 68.0% when combined with ANG-1 as the ANGs/Tie-2 ratio (95% CI: 0.56-0.80). In ER tumors, high plasma ANG-2 levels were observed (p < 0.05). Significantly higher levels of the (ANG-1 + ANG-2)/VEGF-C ratio were noted in patients with VI+ (p < 0.05). Findings descriptively highlighted ER status as a common characteristic in VI and ALNM tumors. In HER-2 patients, both ANG-1 and the (ANG-1 + ANG-2)/Tie-2 ratio showed inverse correlations with VEGF-C, while in ER breast cancer patients, ANG-2 was inversely correlated with VEGF-C.
These findings provide new insights into the inverse correlation between plasma levels of ANGs and VEGF-C, particularly in cases with positive ALNM, underscoring the role of hormone receptor-dependent characteristics. The integration of the triple angiogenic biomarkers ANG-2/Tie-2/VEGF-C within the tumor microenvironment, combined with the regulatory influence of hormonal receptors, merits further investigation as a potential biomarker panel for identifying lymphatic anomalies and VI positivity in breast cancer patients.
血管生成和淋巴管生成的生物标志物已在癌症预后模型中得到探索；然而，它们在评估局部肿瘤侵袭性方面的潜在作用仍知之甚少。
本研究旨在评估血管生成生物标志物，特别是血管生成素（ANG）-Tie系统和血管内皮生长因子-C（VEGF-C）与伊朗乳腺癌女性患者淋巴管生成及相关组织病理学特征之间的相关性。
在乳腺癌风险与生活方式（BCRL）研究的这个连续病例系列（n = 149）中，使用酶联免疫吸附测定法评估了包括VEGF-C、ANGs和Tie-2在内的促血管生成因子的血浆水平。收集了临床病理数据，排除IV期病例以聚焦于局限性疾病患者。腋窝淋巴结转移（ANLM）和血管侵犯（VI）在研究人群中很常见，分别发生在61.5%和77.6%的病例中（p < 0.01）。在89.1%的ANLM参与者中观察到雌激素受体阳性（ER）肿瘤，而在22.8%的腋窝淋巴结转移患者中发现人表皮生长因子受体2阳性（HER-2）肿瘤。ANG-1（r = 0.19）和VEGF-C（r = 0.29）的血浆水平与腋窝淋巴结转移率呈正相关（p < 0.05）。对II级肿瘤患者的多变量分析显示，VEGF-C与血管生成生物标志物之间存在显著的负相关，包括ANG-2（β = -0.25）、ANG-2/Tie-2比值（β = -0.28）和（ANG-1 + ANG-2）/Tie-2比值（β = -0.29）（p < 0.05）。受试者工作特征（ROC）曲线分析表明，ANG-2可以有效评估腋窝淋巴结转移状态，最佳截断值为3.39 pg/mL，在低VEGF-C水平的患者中识别出66.0%的腋窝淋巴结转移（95%置信区间：0.5-0.78），当与ANG-1作为ANGs/Tie-2比值联合使用时增加到68.0%（95%置信区间：0.56-0.80）。在ER肿瘤中，观察到较高的血浆ANG-2水平（p < 0.05）。在VI+患者中，（ANG-1 + ANG-2）/VEGF-C比值显著更高（p < 0.05）。研究结果描述性地突出了ER状态是VI和ANLM肿瘤的一个共同特征。在HER-2患者中，ANG-1和（ANG-1 + ANG-2）/Tie-2比值均与VEGF-C呈负相关，而在ER乳腺癌患者中，ANG-2与VEGF-C呈负相关。
这些发现为ANGs和VEGF-C血浆水平之间的负相关提供了新的见解，特别是在腋窝淋巴结转移阳性的病例中，强调了激素受体依赖性特征的作用。肿瘤微环境中血管生成生物标志物三联体ANG-2/Tie-2/VEGF-C的整合，结合激素受体的调节影响，作为识别乳腺癌患者淋巴管异常和VI阳性的潜在生物标志物组合值得进一步研究。
