Prognostic Significance of Tumor Budding in Bladder Cancer: A Call for Molecular Insights: Letter to the Editor ; Mesane Kanserinde Tümör Tomurcuklanmasının Prognostik Önemi: Moleküler Perspektifte Bir Çağrı: Editöre Mektup

Dear Editor, We wish to share our insights on the critical prognostic significance of tumor budding (TB) in bladder cancer (BC) and underscore the urgent necessity for further molecular-level investigations in this domain, prompted by recent studies. Tumor buds, also referred to as “sprouts,” are defined as isolated single tumor cells and/or small clusters comprising fewer than five tumor cells, which originate from the invasive tumor margin and infiltrate the stroma. These entities were first characterized by Imai in the 1950s (1). The TB scoring system, established by the “International Tumour Budding Consensus Conference” (ITBCC) in 2016, has been validated as an independent predictor of lymph node metastasis in pT1 colorectal cancer cases and poor survival outcomes in stage 2 colon cancer cases, and it is now routinely reported by pathologists (2). Tumor buds are intimately associated with epithelial-mesenchymal transition (EMT) and engage in interactions with the tumor microenvironment (TME), tumor stroma, and immune system cells (3). This dynamic interaction at the molecular level in budding tumor cells establishes a distinctive signature characterized by: upregulation of MMP-7 and MMP-9 expressions, which play a role in extracellular matrix degradation; anoikis resistance through the enhanced expression of TrkB; frequent upregulation of stem cell markers such as LGR5, ALDH1, and CD44; immune evasion facilitated by the loss of MHC class I expression; increased TGFβ expression and regulation of TGFβ signaling; regulation of WNT signaling; a decrease in miRNA-200 expression, accompanied by the epigenetic upregulation of EMT-associated transcription factors, including ZEB, TWIST, and SNAIL; reduced expression of E-cadherin, particularly at the cell membrane, and β-catenin; an increase in mesenchymal markers like Vimentin, alongside a reduction in Cytokeratin expression; low levels of Ki-67 and Caspase-3 expression; and a relatively spindle-shaped morphology with podia formation (3). While it is generally ...