Hematopoetik Kök Hücrelerin Kemik Metastazındaki Rolü: Hayvan Modellerinde Tümör Gelişimi Üzerindeki Etkisi

Öz

Meme kanseri tedavi edilebilir olmasına rağmen metastatik formu, kadınlarda kanser kaynaklı ölümlerin ikinci en sık nedenidir. Meme kanseri sıklıkla kemik metastazı yapar; ancak bu sürecin biyolojik mekanizmaları tam olarak açıklığa kavuşmamıştır. Literatürde, hematopoetik kök hücrelerin (HKH) metastatik nişte önemli bir rol oynayabileceği ve kanser hücreleri ile benzer mikro çevresel sinyallere yanıt verebileceği öne sürülmektedir. Bu durum, HKH’lerin ve kanser hücrelerinin kemik iliğinde ortak bir niş paylaşabileceğini ve rekabet halinde olabileceklerini düşündürmektedir. Bu hipotez doğrultusunda, HKH’lerin ortamdan uzaklaştırılması durumunda meme kanseri hücrelerinin endosteal nişe daha fazla yerleştiği gözlemlenmiştir. Ancak, bu sürecin tümör gelişimi üzerindeki etkileri ve klinik yansımaları henüz netlik kazanmamıştır. Bu çalışmada, HKH mobilizasyonunun tümör gelişimine etkilerini incelemek amacıyla bağışıklığı baskılanmış ksenograft ve eş genetik (syngeneik) tümör modelleri kullanılmıştır. İlk olarak, BALB/c Nude farelerine 5 gün boyunca AMD3100 (CXCR4 antagonisti) uygulandıktan sonra MDA-MB-231 hücreleri intrakardiyak yol ile enjekte edilerek metastatik bir model oluşturulmuş ve tümör gelişimi in-vivo görüntüleme (IVIS) yöntemiyle takip edilmiştir. Daha sonra, BALB/c ve C57BL/6j farelerinde AMD3100 ve G-CSF kullanılarak HKH mobilizasyonu syngeneik model seçimi amacıyla gerçekleştirilmiş; yapılan koloni analizleri sonucunda en verimli mobilizasyonun BALB/c–G-CSF kombinasyonu ile gerçekleştiği belirlenmiştir. Bu bulgu sonucunda ksenograft çalışmasına benzer bir syngeneik model 4T1 fare meme kanserinin G-CSF uygulamasından sonra intrakardiyak enjeksiyonuyla oluşturulmuş ve tümör gelişimi IVIS yöntemiyle takip edilmiştir. Deney sonuçları, her iki modelde de HKH mobilizasyonunun tümör oluşumunu hızlandırdığını, ancak ilerleyen hastalık süreci ve diğer organ metastazları üzerinde belirgin bir etkisi olmadığını göstermiştir. Bulgular, HKH’lerin kemik metastazındaki kritik rolünü vurgulamakta ve bu hücrelerin metastatik sürecin yönetiminde potansiyel terapötik hedefler olabileceğini göstermektedir.

Anahtar Kelimeler

• Hematopoetik Kök Hücreler
• Meme Kanseri
• Hayvan Modeli
• Mobilizasyon
• Kemik Metastazı

The Role of Hematopoietic Stem Cells in Bone Metastasis: Effects on Tumor Progression in Animal Models

Öz

Despite being a treatable disease, metastatic breast cancer remains the second leading cause of cancer-related mortality among women. It frequently spreads to the bone, yet the precise biological mechanisms underlying this process are not fully understood. Literature suggests that hematopoietic stem cells (HSCs) play a key role in the metastatic niche, responding to microenvironmental cues similar to cancer cells. This interaction implies potential competition between HSCs and cancer cells for the bone marrow niche. Accordingly, HSC depletion has been shown to enhance the colonization of breast cancer cells in the endosteal niche, though its impact on tumor progression and clinical outcomes remains uncertain. This study explored the effects of HSC mobilization on tumor progression using both immunocompromised (xenograft) and immunocompetent (syngeneic) mouse models. BALB/c Nude mice received AMD3100 (CXCR4 antagonist) for five days, followed by intracardiac injection of MDA-MB-231 cells to establish a metastatic model, with tumor progression tracked with in vivo imaging (IVIS). Additionally, HSC mobilization was induced in BALB/c and C57BL/6j mice using AMD3100 and G-CSF, identifying BALB/c–G-CSF as the most effective combination. A syngeneic model was then developed using intracardiac injection of 4T1 mouse breast cancer cells, mimicking the xenograft approach. Results revealed that HSC mobilization accelerated tumor formation in both models but did not significantly affect disease progression or metastasis to other organs. These findings underscore the critical role of HSCs in bone metastasis and suggest their potential as therapeutic targets in metastatic breast cancer.

Anahtar Kelimeler

• Hematopoetic Stem Cells
• Breast Cancer
• Animal Model
• Mobilisation
• Bone Metastasis

Kaynakça

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