TABLE 1.
Table summarizing molecular and cellular changes in edematous brain tissue around glioblastoma, brain metastasis, lymphoma, and abscess.
| Molecular/Cellular target | Most relevant molecular results | References | |
| Glioblastoma | Tight junctions | • Claudin-1 downregulation leads to altered TJ and increased endothelial permeability • Claudin-5 and occludin downregulated in hyperplastic tumor vessels |
Liebner et al., 2000 |
| • Downregulation of claudin-1 and claudin-5 positively correlates with increasing glioma grade | Karnati et al., 2014 | ||
| • Decreased expression of BMP4 associated with downregulation of E-cadherin and claudin • Downregulation of BMP4 promotes tumor invasion |
Zhao et al., 2019 | ||
| • Expression of MMP-9 positively correlates with increasing glioma grade • Overexpression of MMP-9 promotes glioblastoma cell proliferation |
Xue et al., 2017 | ||
| • TGF-β downregulates expression of claudin-1 and promotes endothelial permeability • anti-TGF-β antibody reverts the downregulation of claudin-1 • TGF-β induced permeability reduced by MMP inhibition |
Ishihara et al., 2008 | ||
| • Dexamethasone promotes the expression of claudin-5 and occludin. • Dexamethasone suppresses the expression of MMP-9 |
Na et al., 2017 | ||
| • Occludin expression correlates to peritumoral brain edema volume | Park et al., 2006 | ||
| • Serum occludin levels associated with peritumoral brain edema severity | Shi et al., 2020 | ||
| VEGF | • VEGF-A downregulates claudin-5 and occludin expression • Recombinant claudin-5 inhibits VEGF-induced paracellular hyperpermeability |
Argaw et al., 2009 | |
| • VEGF expression is induced under hypoxic conditions • VEGF is produced in proximity to necrotic glioblastoma |
Shweiki et al., 1992 | ||
| • VEGF expression is lower in the peritumoral brain zone compared to the tumor core • Bevacizumab (anti-VEGF antibody) decreases microvessels density and normalizes vascular structures in the peritumoral brain zone |
Tamura et al., 2018 | ||
| • HIF-1α upregulates VEGF expression | Lin et al., 2004 | ||
| • X-ray radiation promotes VEGF mRNA expression in glioblastoma cell cultures | Steiner et al., 2004 | ||
| • pSTAT3-VEGF signaling pathway associated with peritumoral brain edema volume | Wang et al., 2014 | ||
| • GBM-secreted VEGF downregulates claudin-5 in a dose-dependent manner and increases endothelial permeability | Wen et al., 2017 | ||
| • HIF-1α mediated STAT3 phosphorylation promotes glioma stem cell self-renewal under hypoxic conditions | Almiron Bonnin et al., 2018 | ||
| • VEGF stimulates glioblastoma stem cell proliferation via VEGFR-2 | Xu et al., 2013 | ||
| • VEGFR-1 promotes glioblastoma cell migration and ECM invasion. • anti-VEGFR-1 antibody inhibits ECM invasion |
Atzori et al., 2017 | ||
| • VEGF promotes inter-endothelial gaps, fragmentation of the endothelium, and degenerative changes in the vascular basement membrane | Dobrogowska et al., 1998 | ||
| • VEGF mRNA expression positively correlates with increased capillary permeability | Machein et al., 1999 | ||
| • VEGF promotes vascular hyperpermeability by the formation of vesiculo-vacuolar organelles • antisense VEGF reduces tumor edema |
Lin et al., 2008 | ||
| • STAT3 pathway is constitutively activated in GBM | Brantley et al., 2008 | ||
| • GBM overexpresses pSTAT3 • Overexpression of pSTAT3 is a negative prognostic factor |
Lin et al., 2014 | ||
| AQP4 | • AQP4-OAP expression promotes morphological alterations of glioma cells • Expression of AQP-4 tetramers decreases cellular invasiveness, cellular migration, and • MMP-9 activity in glioma cells |
Simone et al., 2019 | |
| • Peritumoral brain edema in gliomas is associated with a dysfunction of the glymphatic system | Toh and Siow, 2021 | ||
| • Glioma cells overexpress AQP4 on their surface | Warth et al., 2004 | ||
| • AQP4 expression increased in GBM • Argin and dystroglycan regulates AQP4 localization • Upregulation of MMP-3 and MMP-9 follows disruption of argin and dystroglycan complexes in GBM |
Noell et al., 2012 | ||
| • AQP4 redistribution on glioma cells surface highest in grade I and grade IV glioma • AQP4 overexpression is higher in the tumor core than in the peritumoral infiltration zone • AQP4 expression positively correlates with increasing peritumoral brain edema |
Warth et al., 2007 | ||
| • AQP4 k/o mice displayed disrupted TJs and aberrant astrocytic endfeet • AQP4 loss associated with hyperpermeable BBB |
Zhou et al., 2008 | ||
| • AQP4 overexpressed in high-grade glioma • AQP4 overexpression positively correlates with increasing BBB opening |
Saadoun et al., 2002b | ||
| • AQP4 overexpression appears to be a reaction to VEGF-induced edema in glioma • AQP4 expression is not directly driven by VEGF |
Yang et al., 2012 | ||
| • AQP4 expression is higher in peritumoral tissue compared to tumor tissue • AQP4 overexpression positively correlates with edema index and degree of peritumoral edema • AQP4 redistributed in glioma • AQP4 correlates with VEGF and HIF-1α expression |
Mou et al., 2010 | ||
| • AQP4 expression upregulated upon VEGF administration | Rite et al., 2008 | ||
| • Downregulation of AQP4 in endothelial argin k/o mice | Rauch et al., 2011 | ||
| Immune changes | • IL-1β production in microglia and bone marrow-derived macrophages blocked by dexamethasone • Dexamethasone reduces cytokine production in bone marrow-derived macrophages • Dexamethasone reduces TAM infiltration • Inhibition of the IL-1 signaling pathway decreases edema formation and reduces BBB permeability |
Herting et al., 2019 | |
| • Immune micro-environment in GBM predetermined by genetic driver mutations TAMs demonstrate heterogenous M0-, M1- and M2-like phenotypes | Chen et al., 2020 | ||
| • Microglia/macrophages infiltrate tumor tissue and regulate tumor invasion • TAMs do not produce pro-inflammatory cytokines • Reduction of immune cell pool attenuates tumor growth |
Gabrusiewicz et al., 2011 | ||
| • Sulfasalazin treatment modulates tumor micro-environment | Sehm et al., 2016 | ||
| • IL-6 upregulates VEGF expression • IL-6 augments VEGF promoter activity in GBM |
Loeffler et al., 2005 | ||
| • IL-1 receptor antagonist reduces glioma-related edema | Shevtsov et al., 2015 | ||
| Brain metastasis | Tight junctions | • VEGF/VEGFR-2 pathway is implied in developing peritumoral brain edema. • Apatinib (tyrosine kinase inhibitor targeting VEGFR-2) decreases peritumoral edema volume |
Song et al., 2018 |
| • Overexpression of SUR1 contributes to TJ disruption with subsequent peritumoral brain edema in melanoma metastases • SUR1 inhibitor as effective as dexamethasone in antiedematous therapy • Overexpression of SUR1 downregulates ZO-1 |
Thompson et al., 2013 | ||
| • Occludin downregulation leads to endothelial TJ disruption and increased BBB permeability | Papadopoulos et al., 2001 | ||
| VEGF | • VEGF promotes downstream Ras-ERK pro-angiogenic activity viaαvβ5 | Hood et al., 2003 | |
| • Low levels of αvβ6 correlates with increased metastatic infiltration | Berghoff et al., 2013 | ||
| • Density of tumor-infiltrating lymphocytes associated with the extent of peritumoral edema • VEGF expressed by both melanoma cells and tumor-infiltrating lymphocytes |
Trembath et al., 2020 | ||
| • cGMP induces hyperpermeability of the BBB | Chi et al., 1999 | ||
| • VEGF induces hyperpermeability of venules and capillaries • anti-VEGF monoclonal antibodies reverted hyperpermeable state |
Roberts and Palade, 1995 | ||
| • VEGF induces permeability and dilatation of cerebral arterioles via release of NO/cGMP | Mayhan, 1999 | ||
| AQP4 | • Anti-PD-1 therapy in melanoma decreases peritumoral edema volume | Tran et al., 2019 | |
| • AQP4 overexpressed in peritumoral brain edema | Zhao et al., 2015 | ||
| • Glymphatic dysfunction contributes to the development of peritumoral brain edema | Toh et al., 2021 | ||
| Immune changes | • Inflammatory cells infiltrate peritumoral brain edema | Utsuki et al., 2007 | |
| • Glial cells promote metastatic growth via secretion of multiple factors | Fitzgerald et al., 2008 | ||
| • Density of tumor-infiltrating lymphocytes positively correlates with peritumoral brain edema volume | Berghoff et al., 2016 | ||
| Others | • nNOS expression increased in high-grade tumors and melanoma metastasis • eNOS may promote brain edema |
Broholm et al., 2003 | |
| • AQP4 upregulated in astrocytes in edematous zones • Expression of α-syntrophin positively correlates with AQP4 upregulation |
Saadoun et al., 2003 | ||
| • SUR1 upregulation linked to the development of cerebral edema in stroke • Inhibition of SUR1 reduces brain edema |
Simard et al., 2006 | ||
| • SUR1 inhibitor reduces BBB disruption and caspase-3 activity in SAH | Simard et al., 2009 | ||
| • Astrocytic endothelin-1 overexpression leads to increased cerebral water content and increased expression of AQP4 • Vasopressin V2 receptor antagonist reduces cerebral edema and downregulates AQP4 expression |
Yeung et al., 2009 | ||
| • Endothelin B receptor-mediates eNOS activation increases MMP-9 activity with subsequent downregulation of TJ • Endothelin B receptor antagonist decreases vasogenic brain edema in status epilepticus |
Kim et al., 2015 | ||
| • TNF-α induces ET-1/eNOS activity with subsequent BBB hyperpermeability and vasogenic edema in status epilepticus | Kim et al., 2013 | ||
| • Smaller peritumoral brain edema characterized by lower HIF-1α expression and lower microvascular density | Spanberger et al., 2013 | ||
| Brain lymphoma | VEGF | • VEGF expression associated with high microvascular density and alterations of BBB • VEGF expression leads to occludin and ZO-1 downregulation • VEGF expression associated with longer survival |
Takeuchi et al., 2007 |
| • VEGF overexpression in Non-Hodgkin lymphoma outside the CNS is associated with a worse prognosis | Yang et al., 2015 | ||
| Endothelium |
• Overexpression of pStat3 in PCNSL • Tumor cells may form tumor-associated endothelial microvessels |
Ruggieri et al., 2017 | |
| • Endothelial cells lack direct contact with astrocytic end-feet • Pericytes show irregular and discontinued basal membranes |
Molnár et al., 1999 | ||
| Others | • Higher vascular permeability in PCNSL compared to glioblastoma as detected by MRI |
Kickingereder et al., 2014
|
|
| • B-lymphoma cells infiltrate fiber tracks and in subarachnoid space • Reactive gliosis present in tumor tissue |
Soussain et al., 2007 | ||
| Brain abscess | VEGF | • VEGF upregulated in infiltrating inflammatory cells and perilesional astrocytes • VEGF contributes to the development of perilesional edema |
Vaquero et al., 2001 |
| AQP4 | • AQP4 has a protective role in the formation of peri-abscess edema in mouse abscess model • AQP4 promotes fluid reabsorption from the brain tissue around the abscess |
Bloch et al., 2005 | |
| • AQP4 downregulated in mouse brain abscess model • Nuclear factor erythroid-2 related factor depletion correlates with AQP4 downregulation in mouse brain abscess model |
Ampawong and Luplertlop, 2019 | ||
| Immune changes | • TNF upregulation detrimental to brain edema • IL-10 k/o mouse brain abscess model leads to severe brain edema |
Stenzel et al., 2005a | |
| • Brain edema significantly increased in TNF k/o mouse brain abscess model • TNF regulates immune response and controls edema formation in brain abscess |
Stenzel et al., 2005b | ||
| • PAMs-TLR-2 interaction promotes pro-inflammatory astrocytic activation | Esen et al., 2004 | ||
| • TLR2 promotes pro-inflammatory microglial activation | Kielian et al., 2005a | ||
| • TLR2 regulates pro-inflammatory mediators’ expression | Kielian et al., 2005b | ||
| • MyD88 promotes a protective inflammatory response in mouse brain abscess mode • MyD88 k/o exaggerates cerebral edema |
Kielian et al., 2007 | ||
| • Increased levels of potassium, zinc, iron, and copper ions found in brain abscess • Inhibition of GABA and glutamate receptor promotes ROS formation |
Dahlberg et al., 2015a | ||
| • Th1 and Th17 lymphocytes regulate immune cell infiltration and release of inflammatory mediators | Holley and Kielian, 2012 | ||
| • Expression of inflammatory mediators positively correlates with increased BBB disruption • BBB disruption also positively correlates with increased neutrophil and macrophage/microglia infiltration |
Baldwin and Kielian, 2004 | ||
| • Neuroinflammation promotes immune cell-mediated secretion of MMPs • MMPs degrade TJ and basement membrane |
Rempe et al., 2016 | ||
| • Inflammatory response during cerebritis implied in BBB disruption and edema formation | Lo et al., 1994 | ||
| • CXC chemokines and MIP-2 that are expressed by resident glial cells implied in the recruitment of neutrophils | Kielian et al., 2001 | ||
| Others | • Elevated ammonia levels in brain abscess • Ammonia associated with neurotoxicity and brain edema |
Dahlberg et al., 2016 | |
| • Formation of ROS crucial in BBB disruption | Pun et al., 2009 | ||
| • GFAP k/o mice associated with poorly demarcated inflammatory lesions and severe brain edema • Astrocytic GFAP promotes restriction of pathogenic spread in brain abscess |
Stenzel et al., 2004 | ||
| • Brain infection leads to increased levels of extracellular glutamate, GABA, and zinc | Hassel et al., 2014 | ||
| • Elevated extracellular levels of glutamate promote vascular hyperpermeability and BBB disruption through activation of NMDA receptors | Vazana et al., 2016 |