Pankreatik Duktal Adenokarsinomada Ekstrasellüler Matriks Degradasyonu Hedefli Tedavi Yaklaşımları

Abstract

Pankreatik duktal adenokarsinoma (PDAC) mortalitesi ve morbiditesi en fazla olan kanser türleri arasında yer almaktadır. PDAC’nin kötü prognozunun nedenleri arasında hücre döngüsünü sağlayan moleküler mekanizmaların bozulması, hücrelerin apoptozise ve kemoterapiye direnç geliştirmesi, hücrelerin tümör mikroçevresiyle etkileşimi sonucu yapısının bozulması, hipoksi oluşumu ve stromal yapının değişimi gösterilebilir. Ekstrasellüler matriksteki proteinlerin yapım ve yıkım hızındaki değişikliklerden dolayı oluşan yoğun fibrotik stroma sırasıyla invazyon, migrasyon, ve metastaz sürecini hızlandırır. İlk olarak kanser hücreleri tarafından sitokin, peptid, mRNA ve protein inhibitörleri içeren eksozomlar salgılanarak fibroblastların ve kollajenlerin doğal yapısının bozulması sonucu kanser ilişkili fibroblastlar ve düzensiz kollajen örgüsü oluşur. Daha sonra hyaluronan sentaz enzimlerinin aktivitesinin aşırı artmasına bağlı olarak sentezlenen hyaluronan birikimi de stromanın yoğunlaşmasında etkilidir. Bununla birlikte endotelyal hücrelerin, pankreatik yıldızsı hücrelerin ve kanser ilişkili fibroblastların salgıladıkları interlökin ve kemokinlere yanıt olarak proteolitik enzimlerin ekpresyonunun artması sonucu kanser hücrelerinin migrasyonu kolaylaşır. Matriks morfolojisinin bozulmasıyla gelişen immunsupresif tümör mikroçevrenin oluşumu PDAC tedavisinde kullanılan immunoterapi ve kemoterapi yöntemlerinin başarı oranını azaltmaktadır. Ekstrasellüler matriks yıkımını arttıran gemsitabin ve paklitaksel gibi kemoterapötik ajanların etkinliğinin arttırılmasına dayalı tedavi stratejileri geliştirilmelidir. Bu kapsamda stromada biriken hyaluronanın parçalanması veya sentezinin inhibisyonu, matriks metalloproteinaz inhibitörleri kullanılarak migrasyonunun engellenmesi, Hedgehod reseptörlerine antagonist monoklonal antikor ve küçük peptidlerin kullanımı ile fibrotik stromanın oluşumunu engellenmesi, tümör mikroçevresine makrofajin filtrasyonunu arttırmak için CD40 agonistleri kullanımı gibi terapötik yaklaşımların geliştirilmesi için faz çalışmaları önem kazanarak devam etmektedir. Bu derlemede, pankreatik tümör mikroçevresinin anlaşılması, ekstrasellüler matriks degradasyonunu etkileyen moleküler mekanizmaların açıklanması amaçlanmış olup, çalışmamızın böylelikle ekstrasellüler matriks hedefli yeni terapötik stratejilerin geliştirilmesi ile ilgili araştırmalara ışık tutacağına inanmaktayız.

Keywords

• PDAC,Ekstrasellüler Matriks,ECM,Metastaz,Terapötik Yaklaşım

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