Tocilizumab’ın Akciğer ve Karaciğer Metastatik Lezyonları Üzerindeki İyileştirici Etkileri

Year 2025, Volume: 10 Issue: 2, 486 - 495, 31.08.2025

Ceren Kizilates , Özlem Özmen , Pınar Aslan Koşar , Simge Garlı , Şerife Taşan , Dilek Aşcı Çelik

https://doi.org/10.24880/meditvetj.1707215

Abstract

Üçlü negatif meme kanseri (ÜNMK), sınırlı tedavi seçenekleri ve yüksek metastatik potansiyeli ile karakterize agresif bir alt tiptir. Bu çalışma, IL-6 reseptör antagonisti olan Tocilizumab’ın tek başına ve Cisplatin ile kombinasyon halinde uygulanmasının anti-metastatik etkilerini 4T1 hücreleri ile oluşturulan murin ÜNMK modelinde araştırmıştır. Dişi BALB/c farelerine ortotopik olarak 4T1 hücreleri enjekte edilmiş ve hayvanlar beş gruba ayrılmıştır: negatif kontrol, tümör kontrol, Tocilizumab, Cisplatin ve kombinasyon tedavisi. Tedaviler dört hafta boyunca intraperitoneal olarak uygulanmıştır. Ötanazi sonrası akciğer ve karaciğer dokuları makroskopik, histolojik ve immünohistokimyasal yöntemlerle değerlendirilmiş; metastatik yük ile IL-6, NF-κB, TNF-α ve Caspase-3 ekspresyon düzeyleri incelenmiştir. Histopatolojik analizler, metastatik odak sayısı ve büyüklüğünde anlamlı bir azalma olduğunu göstermiş; bu etkinin en belirgin şekilde kombinasyon grubunda ortaya çıktığı gözlemlenmiştir. İmmünohistokimyasal bulgular, özellikle kombinasyon grubunda belirgin olmak üzere Caspase-3 ekspresyonunun arttığını ve bunun artmış apoptozisi işaret ettiğini ortaya koymuştur. Tocilizumab uygulanan gruplarda IL-6 ekspresyonunun artmış olması, reseptör blokaj mekanizmasıyla uyumlu bulunmuştur. NF-κB ve TNF-α düzeylerinde ise tedaviye bağlı olarak değişken bir modülasyon gözlenmiş; bu durum, tümör mikroçevresinde dinamik değişimlerin yaşandığını düşündürmektedir. Genel olarak elde edilen bulgular, ÜNMK'da IL-6 aracılı sinyal yolaklarının hedeflenmesinin terapötik potansiyeline işaret etmektedir. Tocilizumab ve Cisplatin’in kombinasyonunun yalnızca metastazı baskılamakla kalmayıp, aynı zamanda inflamatuvar ve apoptotik yolakları da etkilediği gösterilmiştir. Bu sonuçlar, metastatik ÜNMK tedavisinde immünomodülatör ajanların standart kemoterapi ile birlikte kullanımının klinik sonuçları iyileştirebileceğine dair preklinik düzeyde kanıt sunmaktadır.

Keywords

4T1 , Meme Kanseri , Deneysel Model , Metastaz , Patoloji , Tocilizumab

Project Number

TDK-2025-9596

Ameliorative Effects of Tocilizumab on Lung and Liver Metastatic Lesions

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options and high metastatic potential. This study investigated the anti-metastatic effects of Tocilizumab, an IL-6 receptor antagonist, alone and in combination with Cisplatin in a 4T1 murine TNBC model. Female BALB/c mice were orthotopically implanted with 4T1 cells and assigned to five groups: negative control, tumor control, Tocilizumab, Cisplatin, and combination therapy. Treatments were administered intraperitoneally over four weeks. After euthanasia, lung and liver tissues were evaluated macroscopically, histologically, and immunohistochemically to assess metastatic burden and expression levels of IL-6, NF-κB, TNF-α, and Caspase-3. Histopathological analysis revealed a significant reduction in the number and size of metastatic lesions, with the greatest suppression observed in the combination group. Immunohistochemical results showed increased Caspase-3 expression, particularly in the combination group, indicating enhanced apoptosis. IL-6 expression was elevated in Tocilizumab-treated groups, consistent with receptor blockade mechanisms. NF-κB and TNF-α levels showed variable, treatment-dependent modulation, suggesting dynamic changes in the tumor microenvironment. Overall, the findings highlight the therapeutic potential of targeting IL-6-mediated signaling in TNBC. The synergistic effect of Tocilizumab combined with Cisplatin not only suppressed metastasis but also influenced key inflammatory and apoptotic pathways. These results provide preclinical evidence supporting the integration of immunomodulatory agents with standard chemotherapy to improve outcomes in metastatic TNBC.

Keywords

4T1 , Breast cancer , Experimental Model , Metastasis , Pathology , Tocilizumab

Ethical Statement

The experimental procedures of this study were approved by the Local Animal Ethics Committee of Burdur Mehmet Akif Ersoy University (MAKÜ-HADYEK) under decision number 1250, dated January 17, 2024.

Supporting Institution

This work was supported by Süleyman Demirel University Scientific Research Projects Coordination Unit under project number TDK-2025-9596.

Project Number

TDK-2025-9596

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