Международный эндокринологический журнал Том 20, №7, 2024

Метастази є провідною причиною смерті від злоякісних пухлин. Метастатичний процес передбачає вихід ракових клітин з первинної пухлини в кровоносну або іншу транспортну систему, колонізацію та проліферацію у віддаленому органі. Ключовим процесом метастатичного каскаду є епітеліально-мезенхімальний перехід (ЕМТ), який полягає в тому, що епітеліальні клітини перетворюються на мезенхімальні, здатні до міграції. При цьому відбувається заміна епітеліальних маркерів (E-кадгерин) на мезенхімальні (N-кадгерин, віментин, фібронектин). У злоякісних пухлинах ЕМТ ініціюється різними сигнальними шляхами через регуляцію факторів транскрипції (EMT-TF) і мікроРНК. Зниження експресії E-кадгерину індукується трансформуючим фактором росту β, епідермальним фактором росту, фактором росту фібробластів та інтерлейкіном-6. Фактори росту активують внутрішньоклітинні сигнальні шляхи, які, у свою чергу, індукують кілька репресорів транскрипції гена Е-кадгерину, таких як Snail, Slug, ZEB1 (zinc finger E-box binding homeobox 1), ZEB2, Twist, TBX-2 і SIX. ZEB1 — основний EMT-TF сімейства ZEB, він пов’язаний з клітинною пластичністю, дисемінацією та перемиканням зі сплячого на проліферативний фенотип у віддалених метастатичних сайтах, а також є визначальним фактором гіршого клінічного прогнозу для більшості видів раку людини. ZEB1 знаходиться в авангарді транскрипційних факторів, які беруть участь у контролі EMT, і сприяє переміщенню й дифузії пухлинних клітин, стовбуровості клітин, резистентності до лікування, метастазуванню й уникненню імунної реакції. Оскільки ZEB1 є ключовим регулятором ЕМТ, метастазування асоціюється з утворенням ракових стовбурових клітин і резистентністю до терапії для багатьох видів раку, у тому числі папілярної карциноми щитоподібної залози, він може бути найважливішим маркером інвазивності пухлин. Доопераційне дослідження його рівня в клітинах і плазмі крові при карциномах щитоподібної залози може допомогти у визначенні об’єму хірургічного втручання і подальшої терапії радіойодом.

Metastases are the leading cause of death from malignant tumors. The metastatic process involves the exit of cancer cells from the primary tumor into the blood or other transport system, colonization and proliferation in a distant organ. The key process of the metastatic cascade is the epithelial-mesenchymal transition (EMT), which consists in the transformation of epithelial cells into mesenchymal, capable for migration. At the same time, epithelial markers (E-cadherin) are replaced by mesenchymal ones (N-cadherin, vimentin, fibronectin). In malignant tumors, EMT is initiated by different signaling pathways through the regulation of transcription factors (EMT-TFs) and miRNAs. Downregulation of E-cadherin expression is induced by transforming growth factor β, epidermal growth factor, fibroblast growth factor, and interleukin-6. Growth factors activate intracellular signaling pathways, which in turn induce several repressors of E-cadherin gene transcription, such as Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), ZEB2, Twist, TBX-2, and SIX. ZEB1 is the main EMT-TF of the ZEB family and is associated with cellular plasticity, dissemination, and the switch from a dormant to proliferative phenotype at distant metastatic sites and is a determinant of poorer clinical prognosis in most human cancers. ZEB1 is at the forefront of transcription factors involved in the EMT control and promotes tumor cell migration and diffusion, cell stemness, resistance to treatment, metastasizing and evasion of the immune response. Since ZEB1 is a key regulator of EMT, metastasizing is associated with cancer stem cell formation and resistance to therapy in many cancers, including papillary thyroid carcinoma. It may be an important marker of tumor invasiveness. Preoperative examination of its level in blood cells and plasma in thyroid carcinomas can help in determining the extent of surgical intervention and subsequent radioiodine therapy.

папілярна карцинома щитоподібної залози; епітеліально-мезенхімальний перехід; ZEB1

papillary thyroid carcinoma; epithelial-mesenchymal transition; ZEB1

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