The language of glioblastoma: A tale of cytokines and sex hormones communication

Abstract

Glioblastoma (GB) is the most aggressive and frequent tumor in the central nervous system and, in humans, represents the worst prognosis for cancer. GB develops a very complex microenvironment, recruiting and interacting with a variety of cells and soluble factors, including immune cells, cytokines, and sex hormones, that contribute to GB survival and progression. Recent evidence has shown a crosstalk between cytokine and sex hormone signaling in GB. This communication could provide GB resistance to treatments and malignancy. Then, how GB orchestrates this communication is a matter of interest. For instance, a critical interaction between tumor necrosis factor-beta (TGF-β) and estrogen receptor signaling has been reported in regulating epithelial-mesenchymal transition, an essential step in GB progression. Furthermore, an inhibition of TGF-β signaling by androgen receptor has been reported to promote GB tumorigenesis in men. Conversely, it has been described that cytokines regulate steroid hormone production in different organs, and this mechanism could be involved in GB development and progression. All these data suggest an intercommunication between the immune and endocrine systems in the tumor microenvironment. Thus, in this review, we focus on explaining the knowledge about this critical intercommunication system and its implication in GB progression.

Keywords: cytokines; glioblastoma; immunoendocrine communication; sex hormones; tumor microenvironment.

Figure 1.

Main Cytokines in GB-Tumor Microenvironment (TM). GB can secrete various cytokines, which help GB immune evasion and tumor progression. Including IL-6, IL-1β, TNF-α, and TGF-β. All induce an autocrine effect in GB cells but activate different responses. (A) IL-6 and IL-1β induce monocyte-neutrophil recruitment. (B) IL-6, TNF-α, and TGF-β induce GB cell migration, proliferation, and invasion. (C) In response to TNF-α or IL-1β produces a proangiogenic effect in TM. D) In the TM, TGF-β Induces Treg recruitment and differentiation, which results in immune suppression.

Figure 2.

Sex hormones in GB-TME. Sex hormones can regulate different processes in GB cells. (A) Testosterone (T) can increase GB cell migration, proliferation, and invasion through its receptor AR. (B) Estradiol (E2) effects differ depending on which receptor (ER) is activated; ERα induces GB cell migration, proliferation, and invasion (arrow); in sharp contrast, ERβ induces GB cell apoptosis (arrow) and decreases proliferation (inhibitor). (C) Progesterone (P4) has a dual effect depending on the concentration; high levels (inhibitor) of P4 decrease GB cell proliferation, migration, and invasion. On the other hand, low levels (arrow) of P4 increase these processes in GB cells.

Figure 3.

Crosstalk between cytokines and sex hormones in GB-TM. Cytokines and sex hormones affect GB progression. (A) Inflammation in the tumor microenvironment induces immune cell recruitment and influences GB development and progression. (B) In a paracrine response to an inflammatory environment, GB cells can secrete more cytokines, which could influence sex hormone production, as described in other conditions. (C) In turn, sex hormones can influence GB cell proliferation, migration, and invasion. (D) Additionally, testosterone (T) regulates neutrophil recruitment to the site of inflammation. (E) T, Estradiol (E2), and progesterone (P4) can influence immune cell development and responses.