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Production of soluble autocrine inhibitory factors by human glioma cell lines
W T Couldwell1, V W Yong, P Dore-Duffy
1Neuroimmunology Unit, Montreal Neurological Hospital and Institute, Canada.
Abstract:
Gliomas in vitro exhibit density-limited growth upon the attainment of confluency, an effect usually attributed to cell-cell contact inhibition. Since gliomas have been demonstrated to secrete an array of soluble factors which can enhance tumor growth, we undertook this study to ascertain whether production of soluble factors by the tumor may also inhibit growth in an autocrine manner, and whether production of such factors is associated with the growth phase of the glioma. We observed that cell-conditioned medium (supernatants) from non-confluent glioma cultures induced growth, while confluent culture supernatants produced pronounced growth suppression. These latter supernatants enhanced proliferation of non-transformed astrocytes. Supernatants derived from all stages of confluency produced inhibition of lymphocyte proliferation. To characterize these factors, dialyzed supernatant was tested and found to continue to produce lymphocyte suppression but no glioma growth limitation. Growth of tumors in indomethacin or in acetylsalicylic acid to abolish prostanoid synthesis abrogated the inhibitory influence on glioma growth but only partially reversed the lymphocyte suppressive capacity. These studies suggest that gliomas do produce a growth phase dependent autocrine inhibitory factor(s), and that the production of these small molecular weight factors is at least partially under control of the cyclooxygenase pathway.
Insights
Glioma cells produce factors that inhibit their own growth in a density-dependent manner. These autocrine factors, potentially linked to the cyclooxygenase pathway, also suppress lymphocyte proliferation.
Area of Science:
- Neuro-oncology
- Cell Biology
- Tumor Microenvironment
Background:
- Gliomas exhibit density-limited growth, typically attributed to contact inhibition.
- Gliomas secrete soluble factors that can influence tumor progression.
Purpose of the Study:
- To investigate if gliomas produce autocrine inhibitory factors.
- To determine if factor production is linked to glioma growth phase.
Main Methods:
- Cultured glioma cells and analyzed cell-conditioned medium (supernatants).
- Assessed the effect of supernatants on glioma cell proliferation and lymphocyte proliferation.
- Utilized dialyzed supernatants and inhibitors of prostanoid synthesis (indomethacin, acetylsalicylic acid).
Main Results:
- Supernatants from non-confluent cultures promoted glioma growth, while confluent cultures suppressed it.
- Confluent culture supernatants enhanced non-transformed astrocyte proliferation.
- All supernatants inhibited lymphocyte proliferation.
- Dialysis removed glioma growth inhibition but retained lymphocyte suppression.
- Prostanoid synthesis inhibition abrogated glioma growth inhibition and partially reversed lymphocyte suppression.
Conclusions:
- Gliomas produce growth phase-dependent autocrine inhibitory factors.
- Production of these small molecular weight factors is partly controlled by the cyclooxygenase pathway.