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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Regulation of intercellular biomolecule transfer-driven tumor angiogenesis and responses to anticancer therapies
Zhen Lu1, Angelica Ortiz1, Ioannis I Verginadis2
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Abstract:
Intercellular biomolecule transfer (ICBT) between malignant and benign cells is a major driver of tumor growth, resistance to anticancer therapies, and therapy-triggered metastatic disease. Here we characterized cholesterol 25-hydroxylase (CH25H) as a key genetic suppressor of ICBT between malignant and endothelial cells (ECs) and of ICBT-driven angiopoietin-2-dependent activation of ECs, stimulation of intratumoral angiogenesis, and tumor growth. Human CH25H was downregulated in the ECs from patients with colorectal cancer and the low levels of stromal CH25H were associated with a poor disease outcome. Knockout of endothelial CH25H stimulated angiogenesis and tumor growth in mice. Pharmacologic inhibition of ICBT by reserpine compensated for CH25H loss, elicited angiostatic effects (alone or combined with sunitinib), augmented the therapeutic effect of radio-/chemotherapy, and prevented metastatic disease induced by these regimens. We propose inhibiting ICBT to improve the overall efficacy of anticancer therapies and limit their prometastatic side effects.
Insights
Cholesterol 25-hydroxylase (CH25H) suppresses intercellular biomolecule transfer (ICBT), crucial for tumor growth and metastasis. Inhibiting ICBT enhances cancer therapy efficacy and prevents metastasis.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Intercellular biomolecule transfer (ICBT) fuels tumor progression, therapy resistance, and metastasis.
- Endothelial cells (ECs) play a critical role in ICBT-driven tumor growth and angiogenesis.
Purpose of the Study:
- To identify key regulators of ICBT between malignant and endothelial cells.
- To investigate the role of cholesterol 25-hydroxylase (CH25H) in suppressing ICBT and its impact on tumor biology.
Main Methods:
- Characterization of CH25H function in ICBT using cellular and in vivo models.
- Analysis of CH25H expression in colorectal cancer patient samples.
- Pharmacological inhibition of ICBT using reserpine and combination therapies.
Main Results:
- CH25H was identified as a critical suppressor of ICBT between malignant cells and ECs.
- Downregulation of CH25H in human colorectal cancer ECs correlated with poor outcomes.
- Endothelial CH25H knockout promoted angiogenesis and tumor growth.
- Reserpine-mediated ICBT inhibition demonstrated angiostatic effects and enhanced radio-/chemotherapy efficacy, preventing metastasis.
Conclusions:
- CH25H is a key suppressor of ICBT, impacting tumor angiogenesis and growth.
- Targeting ICBT offers a promising strategy to improve anticancer therapy outcomes and mitigate prometastatic side effects.
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