6MO - Radiochemotherapy-induced changes in brain extracellular matrix are associated with tumour development in mouse recurrent glioblastoma model

Background

Despite intensive treatment, most of patients with glioblastoma (GBM) develop a relapse in 6 months after the first surgery, but the mechanisms of the disease recurrence are not well understood. Insufficient efficiency of the used adjuvant radiochemotherapy might be related to its side-effects on the normal surrounding brain tissue, resulting in the formation of a microenvironmental niche for recurrent tumour growth. Here, we studied the functional effects of therapy on the normal brain extracellular matrix (ECM) and tumour growth in mouse GBM relapse models.

Methods

To model GBM relapse, mouse brain was multiple irradiated (7 Gy/day for 3 days) or the animals were treated with chemotherapeutic drug temozolomide (TMZ) (150 mg/m2) and/or dexamethasone (DXM) (1 mg/kg) for 6 weeks followed by inoculation of GBM U87 cells into the brain in vivo. Orthotropic tumour growth rate was analysed by MRI. Brain ECM composition, and structure was analysed by RT-PCR and IHC. Adhesion, proliferation and invasion of U87 cells on the treated and non-treated organotypic hippocampal slices were studied using co-culture system ex vivo.

Results

Both X-ray irradiation and TMZ/DXM significantly affected the expression of key brain ECM glycosylated components proteoglycans. The changed ECM composition was associated with the increased tumour growth and invasive capacity of GBM cells in the mice received TMZ and/or DXM (2,5-fold) compared with the control animals in vivo. Organotypic slices from the irradiated mouse brain or from mice treated with the drugs were more susceptible to the increased adhesion (by DXM), proliferation (by TMZ) or invasion (by irradiation) of U87 cells during co-culture ex vivo. Combined treatment with TMZ/DXM increased adhesion, proliferation and invasion of U87 cells into the organotypic slices, whereas non-treated brain tissue did not possess these effects.

Conclusions

Anti-glioblastoma radiochemotherapy significantly affects normal brain ECM structure creating a favourable niche for GBM cells proliferation and invasion and potentially contributing to GBM relapse development.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Federal Research Center of Fundamental and Transnational Medicine.

Funding

Russian Foundation for Basic Research (grant #18-29-01036/19). Tsidulko A.Y. and Suhovskih A.V. were supported by a scholarship of the President of the Russian Federation for young scientists (SP-5435.2018.4 and SP-1816.2019.4).

Disclosure

All authors have declared no conflicts of interest.