Related Experiment Videos
Nerve growth factor suppresses the transforming phenotype of human prolactinomas
1Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Italy.
Abstract:
The most effective therapy of human prolactinomas is represented by dopamine D-2 receptor agonists; there is, however, a population of nonresponder patients who require surgical intervention. In the present study, we report that prolactinomas totally resistant to pharmacological therapy have a high potential of both growing in soft agar and forming tumors in nude mice and lack D-2 receptors for dopamine. These tumors express the receptors for nerve growth factor (NGF) and are sensitive to its differentiating activity. After exposure to NGF for 4 days, prolactinoma cells decreased their proliferation rate, lost their capability to form colonies in soft agar, lost their tumorigenic activity in nude mice, and reexpressed the lactotroph-specific D-2 receptor protein inhibiting prolactin release. These effects were permanent after NGF withdrawal and were reproducible in vivo in nude mice transplanted with the tumors. NGF in fact remarkably and lastingly depressed tumor growth and induced expression of D-2 receptors when injected intravenously once a day for 5 days into prolactinoma-bearing nude mice. These data suggest that NGF may induce a long-lasting switch of gene expression in human prolactinomas, modifying their transforming phenotype and reverting them to more differentiated, less malignant, dopamine-sensitive lactotroph-like cells. The possibility thus arises that short-term treatment with NGF may restore the refractory patients to conventional pharmacological therapy with D-2 agonists.
Insights
Dopamine agonists are effective for prolactinomas, but some patients don't respond. Nerve growth factor (NGF) treatment can re-sensitize resistant prolactinoma cells to dopamine therapy by restoring D-2 receptors.
Area of Science:
- Endocrinology
- Oncology
- Molecular Biology
Background:
- Dopamine D-2 receptor agonists are the primary treatment for human prolactinomas.
- A subset of patients exhibit resistance to pharmacological therapy, necessitating surgical intervention.
- Resistant prolactinomas often exhibit aggressive characteristics, including high growth potential and lack of D-2 receptors.
Purpose of the Study:
- To investigate the therapeutic potential of nerve growth factor (NGF) in dopamine-resistant prolactinomas.
- To determine if NGF can restore sensitivity to dopamine therapy in refractory prolactinoma cells.
Main Methods:
- In vitro culture of prolactinoma cells in soft agar.
- Tumorigenicity assays in nude mice.
- Exposure of prolactinoma cells and tumors to NGF.
- Assessment of D-2 receptor expression and cell proliferation.
- In vivo treatment of prolactinoma-bearing nude mice with NGF.
Main Results:
- Prolactinomas resistant to dopamine therapy lack D-2 receptors but express NGF receptors.
- NGF treatment decreased prolactinoma cell proliferation and tumorigenicity in vitro and in vivo.
- NGF induced re-expression of D-2 receptors in prolactinoma cells, restoring dopamine sensitivity.
- These therapeutic effects of NGF were long-lasting and reproducible in vivo.
Conclusions:
- NGF can induce a sustained phenotypic switch in human prolactinomas, promoting differentiation and dopamine sensitivity.
- Short-term NGF treatment may offer a strategy to restore patients resistant to conventional dopamine agonist therapy.
- NGF represents a potential novel therapeutic agent for aggressive, treatment-refractory prolactinomas.