AI Article Synopsis

  • The study focuses on understanding the mechanisms behind the cholangiocellular phenotype (CCA) in hepatocellular carcinoma (HCC), particularly the roles of specific cell types in tumor progression.
  • Utilizing single-cell RNA sequencing, researchers identified a unique subset of senescent endothelial cells (CD34CLDN5 ECs) that promote tumor growth by secreting IGF2, which attracts mesenchymal stem cells (MSCs) to the tumor microenvironment.
  • The interaction between these senescent ECs and MSCs was shown to enhance cancer malignancy, revealing potential targets for therapeutic intervention in HCC.

Article Abstract

Introduction: The heterogeneity of hepatocellular carcinoma (HCC) is linked to tumor malignancy and poor prognosis. Nevertheless, the precise mechanisms underlying the development of the cholangiocellular phenotype (CCA) within HCC remain unclear. Emerging studies support that the cross-talk among the host cells within tumor microenvironment (TME) sustains the cancer cell plasticity.

Objectives: This study sought to identify the specific cell types involved in the formation of CCA and to elucidate their functional roles in the progression of HCC.

Methods: Single-cell RNA sequencing was employed to identify the specific cell types involved in the formation of CCA. Both in vitro and vivo analyses were used to identify the tumor-associated senescent ECs and investigate the function in TME. The diethylnitrosamine-induced model was utilized to investigate the interaction between senescent ECs and MSCs, aiming to elucidate their synergistic contributions to the progression of CCA.

Results: Using single-cell RNA sequencing, we identified a distinct senescent-associated subset of endothelial cells (ECs), namely CD34CLDN5 ECs, which mainly enriched in tumor tissue. Further, the senescent ECs were observed to secrete IGF2, which recruited mesenchymal stem cells (MSCs) into the TME through IGF2R/MAPK signaling. In primary liver cancer model, MSCs exhibited a strong tumor-promoting effect, increasing the CCA and tumor malignancy after HCC formation. Interestingly, knockdown of IGF2R expression in MSCs inhibited the increase of CCA caused by MSCs in HCC. Meanwhile, it was revealed that MSCs released multiple inflammatory and trophic-related cytokines to enhance the cancer stem cell-like characteristics in HCC cells. Finally, we demonstrated that CEBPβ up-regulated IGF2 expression in tumor senescent ECs by combining with Igf2-promtor-sequence.

Conclusions: Together, our findings illustrated that tumor associated senescent ECs in HCC recruited the MSCs into TME, enhancing cancer stem cell (CSC)-like features of HCC cells and contributing to the CCA formation.

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http://dx.doi.org/10.1016/j.jare.2024.12.008DOI Listing

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