Related Experiment Video
Updated: Oct 21, 2025
Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics
Published on: November 30, 2012
Tumor-induced disruption of the blood-brain barrier promotes host death
Jung Kim1, Hsiu-Chun Chuang1, Natalie K Wolf1
1Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA.
Abstract:
Cancer patients often die from symptoms that manifest at a distance from any tumor. Mechanisms underlying these systemic physiological perturbations, called paraneoplastic syndromes, may benefit from investigation in non-mammalian systems. Using a non-metastatic Drosophila adult model, we find that malignant-tumor-produced cytokines drive widespread host activation of JAK-STAT signaling and cause premature lethality. STAT activity is particularly high in cells of the blood-brain barrier (BBB), where it induces aberrant BBB permeability. Remarkably, inhibiting STAT in the BBB not only rescues barrier function but also extends the lifespan of tumor-bearing hosts. We identify BBB damage in other pathological conditions that cause elevated inflammatory signaling, including obesity and infection, where BBB permeability also regulates host survival. IL-6-dependent BBB dysfunction is further seen in a mouse tumor model, and it again promotes host morbidity. Therefore, BBB alterations constitute a conserved lethal tumor-host interaction that also underlies other physiological morbidities.
Insights
Cancer-induced systemic effects are driven by cytokines activating JAK-STAT signaling, damaging the blood-brain barrier (BBB) and causing premature death. Inhibiting STAT in the BBB prolongs survival in tumor-bearing hosts.
Area of Science:
- Biomedical research
- Cancer biology
- Physiology
Background:
- Paraneoplastic syndromes are systemic symptoms distant from tumors, contributing to cancer mortality.
- Understanding these syndromes can benefit from non-mammalian model systems.
- Mechanisms of paraneoplastic syndromes are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of paraneoplastic syndromes using a Drosophila model.
- To identify the role of the blood-brain barrier (BBB) in tumor-induced morbidity.
- To explore conserved mechanisms of tumor-host interactions.
Main Methods:
- Utilized a non-metastatic Drosophila adult model with tumors.
- Analyzed cytokine-driven JAK-STAT signaling activation in tumor-bearing hosts.
- Assessed blood-brain barrier (BBB) permeability and STAT activity.
- Inhibited STAT signaling specifically in the BBB.
- Examined BBB dysfunction in mouse models of cancer, obesity, and infection.
Main Results:
- Malignant-tumor-produced cytokines activate widespread JAK-STAT signaling, leading to premature lethality.
- STAT activation is notably high in blood-brain barrier (BBB) cells, causing aberrant permeability.
- Inhibiting STAT in the BBB rescues barrier function and extends host lifespan.
- BBB damage and increased permeability are observed in other inflammatory conditions like obesity and infection.
- IL-6-dependent BBB dysfunction promotes morbidity in a mouse tumor model.
Conclusions:
- BBB alterations are a conserved, lethal tumor-host interaction.
- BBB permeability is a critical factor in paraneoplastic syndrome lethality.
- BBB dysfunction contributes to morbidity in various pathological conditions beyond cancer.
- Targeting BBB STAT signaling may offer therapeutic potential for cancer and other diseases.
