The tumour microenvironment, treatment resistance and recurrence in glioblastoma

Abstract

The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.

Fig. 1

Glioblastoma standard of care typical regimen. Typical treatment regime for glioblastoma (GBM) patients with surgery followed by irradiation (IR) and chemotherapy with temozolomide (TMZ). Statistics based on the 2019 study of 100,672 GBM patients in the United States from 1998 to 2011 [15]

Fig. 2

Glioblastoma subtype classification. The three main subtypes of glioblastoma, MES, CL, and PN, are classified by differing mutation frequencies [37]. CL and PN subtypes are most commonly observed to switch to the more aggressive MES upon recurrence, whilst MES tumours preferentially transition to the CL subtype, which is classed as being more aggressive than the PN subtype [33]

Fig. 3

Interactions with stromal cells in a glioblastoma tumour. Neuron-derived neuroligin-3 can increase PI3K-mTOR pathway attenuation, whilst neuronal excitement can be propagated across glioblastoma (GBM) cell networks via gap junctions [–57]. Tumour-associated astrocytes (TARA’s) can transfer mitochondria to GBM cells via gap junctions. The infiltration of glioma-associated microglia/macrophages (GAMs), and increased presence of oligodendrocytes and glioma stem cells (GSCs) with increased secretion of tenascin-C (TNC) by GSCs at the leading edge, regulates increased proliferation and invasion of GBM [, –61]

Fig. 4

Extracellular vesicles can regulate glioblastoma treatment resistance. Tumour-associated reactive astrocyte (TARA) and glioblastoma (GBM) treatment-resistant cell (GTR) derived extracellular vesicles (EVs) can induce treatment resistance in glioblastoma treatment-sensitive cells [109, 110]

Fig. 5

Glioblastoma models advantages and disadvantages. Advantages and disadvantages of three-dimensional tumour spheres, the xenograft mouse model and cerebral organoids which are increasingly becoming the basis for complex glioblastoma models