Epitelyal-Mezenkimal Geçiş
Özet
Epitelyal-mezenkimal geçiş (EMT), polarize epitel hücrelerinin gen ekspresyonu değişiklikleri, hücre polaritesi ve bağlantılarının kaybı ile motilite ve invaziv özellikler kazanarak mezenkimal fenotipe dönüştüğü kritik bir hücresel süreçtir. Embriyonik morfogenez (Tip I), doku fibrozisi ve yara iyileşmesi (Tip II) ile tümör progresyonu ve kanser metastazı (Tip III) olmak üzere üç ana tipte sınıflandırılan EMT sırasında E-kaderin gibi epitel belirteçleri azalırken, N-kaderin ve vimentin gibi mezenkimal faktörler artar. TGF-β, NFkB, Wnt ve Notch gibi sinyal yolakları tarafından aktive edilen Snail, Slug, Twist ve ZEB gibi transkriptör faktörler bu süreci yöneterek E-kaderini doğrudan baskılar. Epigenetik mekanizmalar ve miRNA'lar tarafından da düzenlenen EMT, kanser hücrelerine birincil tümörden ayrılarak dolaşıma katılma, uzak organlara metastaz yapma, antikanser ilaçlara karşı direnç geliştirme ve kanser kök hücresi özellikleri kazanma gibi agresif nitelikler kazandırır. Kanser kaynaklı ölümlerin %90'ından sorumlu olan metastaz kaskadının bu ilk ve ölümcül adımının moleküler mekanizmalarını tam olarak aydınlatmak, erken evrede tümör yayılımını önleyecek veya ileri evrelerdeki metastatik hücreleri yok edecek yeni terapötik tedavi stratejilerinin geliştirilmesi ve hastaların yaşam sürelerinin artırılması açısından kritik bir öneme sahiptir.
Epithelial-mesenchymal transition (EMT) is a critical cellular process in which polarized epithelial cells acquire a mesenchymal phenotype through changes in gene expression, loss of cell polarity and junctions, and the acquisition of motility and invasive properties. Classified into three main types as embryonic morphogenesis (Type I), tissue fibrosis and wound healing (Type II), and tumor progression and cancer metastasis (Type III), EMT is characterized by a decrease in epithelial markers such as E-cadherin and an increase in mesenchymal factors like N-cadherin and vimentin. Transcription factors including Snail, Slug, Twist, and ZEB, which are activated by signaling pathways such as TGF-β, NFkB, Wnt, and Notch, govern this process and directly repress E-cadherin. Also regulated by epigenetic mechanisms and miRNAs, EMT endows cancer cells with aggressive features, including detaching from the primary tumor to enter circulation, metastasizing to distant organs, developing resistance to anticancer drugs, and acquiring cancer stem cell properties. Fully elucidating the molecular mechanisms of this first and lethal step of the metastatic cascade, which is responsible for 90% of cancer-related deaths, is of critical importance for developing novel therapeutic treatment strategies to prevent tumor dissemination at early stages or eradicate existing metastatic cells at advanced stages, thereby increasing patient survival.
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