Stem-like tumor cells involved in heterogeneous vasculogenesis in breast cancer

Area of Science:

• Oncology
• Cancer Biology
• Angiogenesis Research

Background:

• Sorafenib, an antiangiogenic tyrosine kinase inhibitor, failed in breast cancer trials due to limited efficacy.
• Tumor cell-derived vasculatures, like vasculogenic mimicry and mosaic vessels, contribute to resistance against antiangiogenic therapies.
• The mechanisms of tumor cell-driven vasculogenesis remain poorly understood.

Purpose of the Study:

• To investigate the role of breast cancer stem-like cells (BCSCs) in tumor vascularization and their contribution to sorafenib resistance.
• To elucidate the molecular mechanisms underlying BCSCs-mediated vasculogenesis.
• To explore the therapeutic potential of pigment epithelium-derived factor (PEDF) in inhibiting tumor angiogenesis.

Main Methods:

• Identification and isolation of ALDH1+ breast cancer stem-like cells (BCSCs) from triple-negative breast cancer tissues.
• Assessment of tube formation and angiogenesis capabilities of BCSCs in vitro.
• Analysis of the effect of sorafenib on endothelial cell- and BCSCs-derived vascularization.
• Investigation of the role of α-SMA and HIF-1α in BCSCs-mediated vascular formation.
• Evaluation of PEDF's impact on angiogenesis and HIF-1α expression in breast cancer models.

Main Results:

• ALDH1+ BCSCs were identified as key players in vasculogenic mimicry and mosaic vessel formation in triple-negative breast cancer.
• Only ALDH1+ BCSCs exhibited significant tube formation and angiogenesis potential.
• Sorafenib inhibited endothelial cell vascularization but not BCSCs-derived angiogenesis.
• α-SMA was identified as a crucial molecule for BCSCs vascular formation, with HIF-1α enhancing its expression.
• PEDF suppressed both endothelial and tumor cell-derived angiogenesis by downregulating HIF-1α.

Conclusions:

• BCSCs contribute to tumor vascularization through vasculogenic mimicry, explaining the limited efficacy of sorafenib in breast cancer.
• The HIF-1α/α-SMA pathway is critical for BCSCs-mediated angiogenesis.
• PEDF demonstrates potential as a therapeutic agent by inhibiting both endothelial and tumor cell-driven angiogenesis in breast cancer.