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<p>Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. However, the response to nCRT is variable and not always associated with improved survival. Colorectal cancer (CRC) is characterized by a complex tumor microenvironment (TME), a key component of which is cancer-associated fibroblasts (CAF). While their functions and interactions with tumor cells are under active investigation, the role of distinct CAF subpopulations and their plasticity remains largely undefined. A comprehensive characterization of CAFs during cancer progression could therefore contribute to the development of novel anticancer diagnostic and therapeutic strategies. In this study, we used immunohistochemistry to demonstrate that nCRT induces a significant reorganization of the TME in rectal adenocarcinoma. This reorganization was characterized by a redistribution of myofibroblasts (alpha-smooth muscle actin, αSMA<sup>+</sup>) and tumor-associated fibroblasts (fibroblast activation protein, FAP<sup>+</sup>; and fibroblast-specific protein&#xa0;1, FSP1<sup>+</sup>), leading to pronounced fibrosis in both central and peripheral tumor regions. A decrease in E-cadherin expression, coupled with increased vimentin and transforming growth factor beta (TGFβ) levels in a subset of patients, indicated activation of epithelial-mesenchymal transition and the emergence of vasculogenic mimicry as an alternative mechanism of tumor vascularization. Ultrastructural analysis revealed structural changes in the cytoplasm of fibroblasts suggestive of active membrane remodeling and fibroblast–myofibroblast transition, particularly at the tumor periphery. Collectively, these findings suggest that nCRT may be accompanied by a reorganization of the tumor stroma, leading to fibroblast activation, epithelial-mesenchymal transition, and vasculogenic mimicry, all of which could potentially contribute to tumor progression.</p>

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Phenotypic and ultrastructural heterogeneity of fibroblasts and vasculogenic mimicry in rectal adenocarcinoma following neoadjuvant chemoradiotherapy

  • 期刊论文

  • 发表日期：

    2025年12月9日

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  • Nataliya Bgatova,
  • Nikita Skudin,
  • Anastasia Shatruk,
  • Iuliia Taskaeva,
  • Natalya Obanina,
  • Maksim Ryaguzov,
  • Aleksey Lomakin,
  • Mikhail Karpov,
  • Sergey Fursov

摘要

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. However, the response to nCRT is variable and not always associated with improved survival. Colorectal cancer (CRC) is characterized by a complex tumor microenvironment (TME), a key component of which is cancer-associated fibroblasts (CAF). While their functions and interactions with tumor cells are under active investigation, the role of distinct CAF subpopulations and their plasticity remains largely undefined. A comprehensive characterization of CAFs during cancer progression could therefore contribute to the development of novel anticancer diagnostic and therapeutic strategies. In this study, we used immunohistochemistry to demonstrate that nCRT induces a significant reorganization of the TME in rectal adenocarcinoma. This reorganization was characterized by a redistribution of myofibroblasts (alpha-smooth muscle actin, αSMA+) and tumor-associated fibroblasts (fibroblast activation protein, FAP+; and fibroblast-specific protein 1, FSP1+), leading to pronounced fibrosis in both central and peripheral tumor regions. A decrease in E-cadherin expression, coupled with increased vimentin and transforming growth factor beta (TGFβ) levels in a subset of patients, indicated activation of epithelial-mesenchymal transition and the emergence of vasculogenic mimicry as an alternative mechanism of tumor vascularization. Ultrastructural analysis revealed structural changes in the cytoplasm of fibroblasts suggestive of active membrane remodeling and fibroblast–myofibroblast transition, particularly at the tumor periphery. Collectively, these findings suggest that nCRT may be accompanied by a reorganization of the tumor stroma, leading to fibroblast activation, epithelial-mesenchymal transition, and vasculogenic mimicry, all of which could potentially contribute to tumor progression.