Vascular permeability in the RG2 glioma model can be mediated by macropinocytosis and be independent of the opening of the tight junction.
This study evaluates the extravasation pathways of circulating macromolecules in a rat glioma model (RG2) which was observed by both magnetic resonance imaging using ultrasmall superparamagnetic iron oxide and electron microscopy. Although magnetic resonance imaging signal enhancement was observed as soon as 10 min after injection (9.4% 2 h after injection), electron microscopy showed that endothelial cells were still tightly sealed. However, circulating immunoglobulin G and ultrasmall superparamagnetic iron oxide were found in large membrane compartments of endothelial cells, in the basal lamina (7.4 ± 1.2 gold particles/µm2in the tumor versus 0.38 ± 0.17 in healthy tissue, p = 1.4.10-5) and between tumoral cells. Altogether, this strongly suggests an active transport mediated by macropinocytosis. To challenge this transport mechanism, additional rats were treated with amiloride, an inhibitor of macropinocytosis, leading to a reduction of membrane protrusions (66%) and of macropinosomes. Amiloride however also opened tumoral tight junctions allowing a larger extravasation of ultrasmall superparamagnetic iron oxide (magnetic resonance imaging signal enhancement of 35.7% 2 h after injection). Altogether, these results suggest that ultrasmall superparamagnetic iron oxide and immunoglobulin G in the RG2 glioma model follow an active extravasation pathway mediated by a macropinocytosis process. Amiloride also appears as a potential strategy to facilitate the extravasation of chemotherapeutic drugs in glioma.
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Karin
K
Pernet-Gallay
3 CEA, Institut Nanosciences et Cryogénie, Grenoble, France.|4 Univ. Grenoble Alpes, Institut Nanosciences et Cryogénie, Grenoble, France.
Pierre-Henri
PH
Jouneau
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Anne
A
Bertrand
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Julie
J
Delaroche
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Régine
R
Farion
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Chantal
C
Rémy
1 INSERM, U 1216, Grenoble, France.|2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
Emmanuel L
EL
Barbier
D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000473:pathology / Q000502:physiology*; D001932:Brain Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology*; D045744:Cell Line, Tumor; D052203:Ferrosoferric Oxide; D005910:Glioma / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D009368:Neoplasm Transplantation; D010873:Pinocytosis / Q000502:physiology*; D011916:Rats, Inbred F344; D019108:Tight Junctions / Q000502:physiology*
D058185:Magnetite Nanoparticles; D052203:Ferrosoferric Oxide
Neurooncology; blood–brain barrier; imaging; magnetic resonance imaging; microscopy