Investigating the contribution of hyaluronan to the breast tumour microenvironment using multiparametric MRI and MR elastography
Résumé
Hyaluronan (HA) is a key component of the dense extracellular matrix in breast cancer, and its accumulation is associated with poor prognosis and metastasis. Pegvorhyaluronidase alfa (PEGPH20) enzymatically degrades HA and can enhance drug delivery and treatment response in preclinical tumour models. Clinical development of stromal‐targeted therapies would be accelerated by imaging biomarkers that inform on therapeutic efficacy in vivo . Here, PEGPH20 response was assessed by multiparametric magnetic resonance imaging (MRI) in three orthotopic breast tumour models. Treatment of 4T1/HAS3 tumours, the model with the highest HA accumulation, reduced T 1 and T 2 relaxation times and the apparent diffusion coefficient (ADC), and increased the magnetisation transfer ratio, consistent with lower tissue water content and collapse of the extracellular space. The transverse relaxation rate R 2 * increased, consistent with greater erythrocyte accessibility following vascular decompression. Treatment of MDA‐MB‐231 LM2‐4 tumours reduced ADC and dramatically increased tumour viscoelasticity measured by MR elastography. Correlation matrix analyses of data from all models identified ADC as having the strongest correlation with HA accumulation, suggesting that ADC is the most sensitive imaging biomarker of tumour response to PEGPH20.
Mots clés
diaminobenzidine
DWI
diffusionweighted imaging
ECM
extracellular matrix
FBS
foetal bovine serum
FFPE
formalin-fixed paraffin-embedded
FOV
field of view
GAG
glycosaminoglycan
G d
elastic modulus
G l
viscous modulus
H&E
haematoxylin and eosin
HA
hyaluronan
HAS3
hyaluronan synthase 3
IFP
interstitial fluid pressure
IHC
immunohistochemistry
IS-MRI
intrinsic susceptibility magnetic resonance imaging
MGE
multiple gradient echo
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
MTR
magnetisation transfer ratio
PEGPH20
pegvorhyaluronidase alfa
PTFE
polytetrafluoroethylene
R 2 *
breast cancer extracellular matrix hyaluronan multiparametric MRI PEGPH20 ADC
apparent diffusion coefficient CV WS
within-subject test-retest coefficient of variation DAB
diaminobenzidine DWI
diffusionweighted imaging ECM
extracellular matrix FBS
foetal bovine serum FFPE
formalin-fixed paraffin-embedded FOV
field of view GAG
glycosaminoglycan G d
elastic modulus G l
viscous modulus H&E
haematoxylin and eosin HA
hyaluronan HAS3
hyaluronan synthase 3 IFP
interstitial fluid pressure IHC
immunohistochemistry IS-MRI
intrinsic susceptibility magnetic resonance imaging MGE
multiple gradient echo MRE
magnetic resonance elastography MRI
magnetic resonance imaging MTR
magnetisation transfer ratio PEGPH20
pegvorhyaluronidase alfa PTFE
polytetrafluoroethylene R 2 *
transverse relaxation rate
breast cancer
multiparametric MRI
PEGPH20 ADC
apparent diffusion coefficient
CV WS
within-subject test-retest coefficient of variation
DAB
Domaines
Sciences du Vivant [q-bio]
Fichier principal
Molecular Oncology - 2023 - Reeves - Investigating the contribution of hyaluronan to the breast tumour microenvironment.pdf (9.57 Mo)
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