New extracellular factors in glioblastoma multiforme development: neurotensin, growth differentiation factor-15, sphingosine-1-phosphate and cytomegalovirus infection

Abstract

Recent years have seen considerable progress in understanding the biochemistry of cancer. For example, more significance is now assigned to the tumor microenvironment, especially with regard to intercellular signaling in the tumor niche which depends on many factors secreted by tumor cells. In addition, great progress has been made in understanding the influence of factors such as neurotensin, growth differentiation factor-15 (GDF-15), sphingosine-1-phosphate (S1P), and infection with cytomegalovirus (CMV) on the 'hallmarks of cancer' in glioblastoma multiforme. Therefore, in the present work we describe the influence of these factors on the proliferation and apoptosis of neoplastic cells, cancer stem cells, angiogenesis, migration and invasion, and cancer immune evasion in a glioblastoma multiforme tumor. In particular, we discuss the effect of neurotensin, GDF-15, S1P (including the drug FTY720), and infection with CMV on tumor-associated macrophages (TAM), microglial cells, neutrophil and regulatory T cells (T_reg), on the tumor microenvironment. In order to better understand the role of the aforementioned factors in tumoral processes, we outline the latest models of intratumoral heterogeneity in glioblastoma multiforme. Based on the most recent reports, we discuss the problems of multi-drug therapy in treating glioblastoma multiforme.

Keywords: cytomegalovirus; glioblastoma multiforme; growth differentiation factor-15; neurotensin; sphingosine-1-phosphate.

Figure 1. Secretory factors in normal tissue and in the tumor microenvironment

Secretory factors responsible for the ‘hallmarks of cancer’ occur in low concentrations in non-cancerous tissue. However, the development of a tumor increases the concentration of these factors. This process is non-specific and so the combinations and levels of secretory factors vary among tumors and even within a single tumor.

Figure 2. The influence of secretory factors on the ‘hallmarks of cancer’

Cancer cells secrete various secretory factors into the tumor microenvironment. The total pool of these secretory factors affects the hallmarks of cancer, in particular via autocrine stimulation of tumor cell proliferation, angiogenesis, migration and invasion, and tumor immune escape.

Figure 3. The carcinogenic effect of CMV on different cells

CMV affects cells in the tumor niche, particularly macrophages and astrocytes which affects the tumor immune escape. CMV also affects cancer cells. It stimulates migration and invasion GSC, stimulates divisions and disturbs apoptosis. CMV in the tumor cell is responsible for the tumor immune escape via the production of vIL-10.

Figure 4. The cytoplasmic effect of CMV infection

CMV virions enter cells via the PDGFR-α or EGFR receptors. The viral proteins transmit the signal that causes changes characteristic for cancer. In particular, the US28 viral receptor is involved in angiogenesis, migration and invasion. vIL-10 is involved in tumor immune escape.

Figure 5. Signal transduction in the tumor cell from the NTSR₁ receptor

In general, the activation of NTSR₁ leads to activation of ERK1/2 MAPK and PI3K-PKB cascades. The signal transmission involves EGFR, activated via c-Src. EGFR can also be activated by MMP1 and MMP9. These metalloproteins release the EGF-like ligands, thus activating these receptors. As a result, the ERK1/2 MAPK cascade and the PI3K-PKB pathway are activated. Nevertheless, the ERK1/2 MAPK cascade can be directly activated by the NTSR₁-PLCβ-PKC pathway, without the involvement of other receptors. Similarly, the PI3K-PKB pathway can be activated by signal transduction to IGF-1R.

Figure 6. The effect of NT on GSC markers

Activation of NTSR₁ results in signal transmission to IGF-1R or EGFR and increased IL-8/CXCL8 expression. Then, the activation of CXCR1, an IL-8/CXCL8 receptor, activates STAT3 and increases the expression of stem cell markers: nestin and Sox2.

Figure 7. Activation of Notch1 pathway by S1P

The activation of S1PR₃ activates the Notch1 pathway. This activation is independent of the Notch1 ligand and is dependent on the ADAM17 protein, which results in GSC self-renewal.