Power Karen, Leandri Rebecca, Federico Giorgia, De Vico Gionata, Leonardi Leonardo
Department of Biology, University of Naples Federico II, Naples, Italy.
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.
Front Vet Sci. 2025 Mar 24;12:1546872. doi: 10.3389/fvets.2025.1546872. eCollection 2025.
Canine osteosarcomas (COS) are the most common bone tumors in dogs, characterized by high metastatic rates, poor prognosis, and poor responsiveness to routine therapies, which highlights the need for new treatment targets. In this context, the metabolism of neoplastic cells represents an increasingly studied element, as cancer cells depend on particular metabolic pathways that are also elements of vulnerability. Among these, tumor cells (TCs) show higher iron requirements to sustain proliferation (so-called iron addiction), which are achieved by increasing iron uptake and/or by activating ferritinophagy, a process mediated by the Nuclear receptor Co-Activator 4 (NCOA4) leading to iron mobilization from ferritin (Ft) deposits. Previous studies have shown that COS cells overexpress Transferrin Receptor 1 (TfR1) to increase iron uptake. In this study we evaluated the immunohistochemical expression of ferritinophagy-related proteins, namely Ferritin Heavy chain (FTH1) and NCOA4, and proliferating cell nuclear antigen (PCNA) in canine normal bone and canine osteoblastic osteosarcoma (COOS) samples. Normal samples revealed negative/weak immunoreactivity for FTH1, NCOA4 and PCNA in <10% of osteocytes. In COOS samples the majority of neoplastic cells showed immunoreactivity to FTH1, NCOA4 and PCNA. Our data suggest that the activation of ferritinophagy by COOS cells responds to the need for feed their "iron addiction." These data, though preliminary, further suggest that targeting iron metabolism represents a new potential strategy worthy of further study to be transferred into clinical practice.
犬骨肉瘤（COS）是犬类中最常见的骨肿瘤，其特征为高转移率、预后差以及对常规治疗反应不佳，这凸显了对新治疗靶点的需求。在此背景下，肿瘤细胞的代谢成为一个研究日益深入的因素，因为癌细胞依赖特定的代谢途径，而这些途径也是其脆弱性的组成部分。其中，肿瘤细胞（TCs）显示出更高的铁需求以维持增殖（即所谓的铁成瘾），这通过增加铁摄取和/或激活铁自噬来实现，铁自噬是一个由核受体共激活因子4（NCOA4）介导的过程，导致铁从铁蛋白（Ft）沉积物中释放出来。先前的研究表明，COS细胞过度表达转铁蛋白受体1（TfR1）以增加铁摄取。在本研究中，我们评估了铁自噬相关蛋白，即铁蛋白重链（FTH1）和NCOA4，以及增殖细胞核抗原（PCNA）在犬正常骨和犬成骨性骨肉瘤（COOS）样本中的免疫组化表达。正常样本中，<10%的骨细胞对FTH1、NCOA4和PCNA显示阴性/弱阳性免疫反应。在COOS样本中，大多数肿瘤细胞对FTH1、NCOA4和PCNA显示免疫反应。我们的数据表明，COOS细胞激活铁自噬是为了满足其“铁成瘾”的需求。这些数据虽然初步，但进一步表明，靶向铁代谢是一种值得进一步研究以转化为临床实践的新潜在策略。
