Related Experiment Video
Updated: May 9, 2025
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Interference with systemic negative feedback as a potential mechanism for nonmonotonic dose-responses of
Mayur S Mitra1, Wendy Halpern2, Michelle Lepherd1
1Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, United States.
Abstract:
Environmental endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed; however, whether and how systemic negative feedback-a global structure of all homeostatic endocrine systems-may render NMDRs is poorly understood. We hypothesized that an EDC may produce nonmonotonic effects by competing with the endogenous hormone for receptors simultaneously (i) at the central site to interfere with the feedback regulation and (ii) at the peripheral site to disrupt the hormone's endocrine action. We constructed a dynamical model of a generic hypothalamic-pituitary-endocrine axis with negative feedback to evaluate the hypothesis and biological conditions that favor NMDR. Our modeling found that when an EDC interferes sufficiently with the central feedback action, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to the endogenous hormone, for the peripheral and central receptors. Novel quantitative relationships between these biological parameter variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. In conclusion, the ubiquitous negative feedback regulation in endocrine systems may act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on the key receptor kinetic and signaling properties of EDCs and endogenous hormones, certain individuals may be more susceptible to these complex endocrine effects.
Insights
Selective inhibition of transforming growth factor-β (TGFβ) isoforms, unlike broad inhibition, shows promise for safer therapies. Targeting individual TGFβ isoforms (TGFβ1, TGFβ2, or TGFβ3) avoids toxicities seen with pan-TGFβ inhibition.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- The transforming growth factor-β (TGFβ) cytokine family is crucial in diseases like cancer and fibrosis.
- Previous attempts to inhibit TGFβ broadly have led to significant toxicities, limiting therapeutic development.
Purpose of the Study:
- To evaluate toxicities associated with selective inhibition of individual or dual TGFβ isoforms.
- To assess the safety of isoform-specific TGFβ inhibition in preclinical models.
Main Methods:
- Utilized monoclonal antibodies (mAbs) targeting specific TGFβ isoforms (TGFβ1, TGFβ2, TGFβ3).
- Administered isoform-specific mAbs to mice and cynomolgus monkeys to assess toxicity profiles.
- Investigated effects of individual (TGFβ1, TGFβ2, TGFβ3) and dual (TGFβ1,2 or TGFβ2,3) inhibition.
Main Results:
- Dual inhibition of TGFβ2,3 caused adverse cardiovascular toxicities.
- Selective inhibition of TGFβ1, TGFβ2, or TGFβ3 was generally well-tolerated without significant adverse effects.
- The anti-TGFβ3 mAb RO7303509 showed good tolerability in toxicology studies, with minor findings.
Conclusions:
- Isoform-specific inhibition of TGFβ is generally safe in preclinical toxicology studies.
- Targeting individual TGFβ isoforms offers a potentially safer therapeutic strategy compared to broad inhibition.
- Further exploration of isoform-specific TGFβ inhibition for therapeutic intervention is warranted.
