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3D Tissue-Engineered Tumor Model for Ewing's Sarcoma That Incorporates Bone-like ECM and Mineralization.

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Summary

Tissue-engineered bone tumor niches enhance Ewing sarcoma progression and drug resistance. These 3D models reveal microenvironmental impacts on cancer cell signaling and therapeutic outcomes.

Keywords:
Ewing’s sarcomabioengineered tumor microenvironmentbone tumor nichecancer therapy resistanceinsulin-like growth factor-1

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Area of Science:

  • Biomaterials Science
  • Cancer Biology
  • Tissue Engineering

Background:

  • The tumor microenvironment significantly influences cancer progression through biochemical and mechanical cues.
  • Ewing sarcoma (ES) pathogenesis is critically affected by its surrounding microenvironment.
  • Understanding these interactions is vital for developing effective cancer therapies.

Purpose of the Study:

  • To engineer a 3D bone tumor niche to investigate microenvironmental effects on Ewing sarcoma.
  • To analyze the impact of the 3D niche on ES cell proliferation and signaling pathways.
  • To assess the development of drug resistance in ES cells within the engineered 3D environment.

Main Methods:

  • Fabrication of acellular 3D bone tumor niches using electrospun poly(ε-caprolactone) (PCL) scaffolds.
  • Incorporation of bone-like architecture, extracellular matrix (ECM), and mineralization into PCL scaffolds.
  • Decellularization of PCL scaffolds with cultured osteogenic human mesenchymal stem cells to create PCL-ECM constructs.
  • Evaluation of ES cell proliferation, IGF-1R/mTOR signaling, and drug response in 3D vs. monolayer cultures.

Main Results:

  • PCL-ECM constructs mimicked in vivo-like tumor architecture and enhanced ES cell proliferation.
  • 3D environments led to downregulation of the canonical insulin-like growth factor 1 receptor (IGF-1R) and mechanistic target of rapamycin (mTOR) signaling.
  • 3D culture conditions reduced IGF-1R nuclear localization and transcriptional activity.
  • ES cells in 3D environments exhibited resistance to mTOR inhibition and chemotherapy.

Conclusions:

  • Engineered PCL-ECM constructs serve as a versatile platform for studying Ewing sarcoma.
  • The 3D tumor microenvironment plays a crucial role in ES cell behavior, including signaling pathway modulation and drug resistance.
  • These findings highlight the importance of considering the tumor microenvironment in cancer research and therapeutic development.