Graduate Institute of Molecular and Comparative Pathobiology, National Taiwan University, Taipei, Taiwan.
Department of Pathology, Show Chwan Memorial Hospital, Changhua, Taiwan.
BMC Vet Res. 2020 May 6;16(1):125. doi: 10.1186/s12917-020-02338-y.
The microenvironment within solid malignant tumors, including feline mammary gland carcinomas (FMGCs), is commonly hypoxic, possibly due to the lack of functional blood vessels in rapidly proliferating neoplastic tissue. Malignant cells can undergo genetic and adaptive changes that prevent them from dying due to oxygen deprivation through expressions of hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). Therefore, HIF-1α and VEGF are ideal biomarkers for cancer therapy and prognostic evaluation. The aims of this study were to evaluate the expression of HIF-1α and VEGF in feline mammary carcinomas and analyze their correlations with clinical and pathological factors, such as clinical stage, histologic grading, regional metastasis, and overall survival rate.
Paraffin-embedded tissue samples collected from 72 cats with FMGCs were retrospectively studied. Histologic pattern and histologic grading (Elston and Ellis grading system) of these FMGCs were determined. Our data indicated that grade II tubulopapillary carcinomas (43/72, 59.7%) prevailed in this study, and most FMCGs showed apparent necrosis, squamous metaplasia, and intratumoral stromal response. According to the results of immunohistochemical (IHC) stainings performed in tissue microarrays (TMAs), HIF-1α and VEGF overexpressions were respectively noted in 69.4% (50/72) and 77.8% (56/72) of FMGC cases. Chi-square test showed no correlation of HIF-1α overexpression with clinical and pathological factors. VEGF overexpression was significantly correlated with histologic pattern (p = 0.021), stromal response (p = 0.048), squamous metaplasia (p = 0.001), and lymphovascular invasion (p = 0.007). However, neither HIF-1α nor VEGF overexpression was correlated with histologic grading and metastasis. Of 38 cats with 1-year follow-up, IHC stainings of HIF-1α and VEGF were performed on whole tissue sections. The results showed that overexpression of HIF-1α was significantly correlated with the overall survival rate (p < 0.05) (log-rank test), whereas there was no significant correlation between VEGF overexpression and overall survival rate.
This study suggests that the overexpression of HIF-1α may indicate poor prognosis/overall survival rate in cats with FMGCs. Developing compounds that inhibit HIF-1α may be a potential approach to FMGC treatment.
包括猫乳腺肿瘤在内的实体恶性肿瘤的微环境通常是缺氧的，这可能是由于快速增殖的肿瘤组织中缺乏功能性血管。恶性细胞可以发生遗传和适应性变化，通过表达缺氧诱导因子 1α（HIF-1α）和血管内皮生长因子（VEGF）来防止因缺氧而死亡。因此，HIF-1α 和 VEGF 是癌症治疗和预后评估的理想生物标志物。本研究的目的是评估猫乳腺肿瘤中 HIF-1α 和 VEGF 的表达，并分析其与临床和病理因素（如临床分期、组织学分级、区域性转移和总生存率）的相关性。
本研究回顾性分析了 72 只患有猫乳腺肿瘤的猫的石蜡包埋组织样本。这些 FMGC 的组织学模式和组织学分级（Elston 和 Ellis 分级系统）得到了确定。我们的数据表明，在这项研究中，II 级管状乳头状癌（43/72，59.7%）占主导地位，大多数 FMGC 表现出明显的坏死、鳞状化生和肿瘤内间质反应。根据组织微阵列（TMA）中进行的免疫组织化学（IHC）染色的结果，分别在 69.4%（50/72）和 77.8%（56/72）的 FMGC 病例中观察到 HIF-1α 和 VEGF 的过度表达。卡方检验显示 HIF-1α 过表达与临床和病理因素无关。VEGF 过表达与组织学模式（p=0.021）、间质反应（p=0.048）、鳞状化生（p=0.001）和血管淋巴管侵犯（p=0.007）显著相关。然而，HIF-1α 和 VEGF 的过表达均与组织学分级和转移无关。在 38 只具有 1 年随访的猫中，对整个组织切片进行了 HIF-1α 和 VEGF 的 IHC 染色。结果表明，HIF-1α 的过表达与总生存率显著相关（p<0.05）（对数秩检验），而 VEGF 过表达与总生存率无显著相关性。
本研究表明，HIF-1α 的过表达可能预示着患有猫乳腺肿瘤的猫的预后/总生存率较差。开发抑制 HIF-1α 的化合物可能是 FMGC 治疗的一种潜在方法。
