Increased Tissue Stiffness in Tumors from Mice with Neurofibromatosis-1 Optic Glioma

Abstract

Children with neurofibromatosis type 1 (NF1) cancer predisposition syndrome are prone to the development of low-grade brain tumors (gliomas) within the optic pathway (optic gliomas). One of the key obstacles to developing successful therapeutic strategies for these tumors is the striking lack of information about the mechanical properties that characterize these tumors relative to non-neoplastic optic nerve tissue. To study the physical changes that may occur when an optic nerve glioma is present, we employed atomic force microscopy to measure the stiffness of healthy versus tumor-bearing optic nerve tissue. We found that the average elastic moduli of non-neoplastic and tumor-bearing optic nerves were ∼3 and ∼6 kPa, respectively. Based on previous studies implicating changes in extracellular matrix remodeling in other, related optic nerve pathological states, we found decreased expression of one major metalloproteinase protein (MMP-2) and unchanged expression of lysyl oxidase and a second metalloproteinase, MMP-9, in murine optic gliomas relative to normal non-neoplastic optic nerve. Collectively, these observations suggest a productive interplay between physical properties of mouse optic nerve gliomas and the extracellular matrix.

Soft Substrates Containing Hyaluronan Mimic the Effects of Increased Stiffness on Morphology, Motility, and Proliferation of Glioma Cells

“…Some studies show increased stiffness in glial cell-derived tumors. 13–15 In other studies either the shear modulus of glioma tissue was softer than that of normal tissue from the contralateral side 16 or increased stiffening was not observed for the large majority of samples when studied in vivo by ultrasound elastography 17,18 or ex vivo with microindentation 19,20 unless the tissue was compressed. An important finding not generally considered in studies of tumor stiffness is that even when tumor elastic moduli are indistinguishable from those of normal tissue, there is a large difference in viscosity, with gliomas showing less viscous response than adjacent nonmalignant tissue.…”

Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine

“…However, few reports have demonstrated the expression of MMPs in neurofibromatosis 1. Walter et al showed that increased stiffness of optic nerve tumor may be related to the downregulation of MMP2 in neurofibromatosis 1 29 . In addition, Muir reported that the expression of MMP1 and MMP-9 was increased in cultured cutaneous neurofibroma containing an abundance of Schwann cells 30 .…”

Zebrafish Xenograft: An Evolutionary Experiment in Tumour Biology

“…Cells are sensitive to physical force, and mechanical load on the ECM can expose cryptic ligands [ 24 ]. A stiffer matrix can in and of itself stimulate a cell to undergo an epithelial to mesenchymal transition and begin to migrate [ 25 , 26 ], and there is evidence that the correlation between stiffness and tumour progression also applies in the natural tumour microenvironment [ 27 , 28 ]. Traditional in vitro assays for migration that use a matrix extract or artificial matrix is as a substrate through which cells may or may not migrate may under- or overestimate the invasive potential of some cells that would invade under conditions that might be found in the tumour itself.…”