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Despite of this, most current treatments including those day 20. However, disease-associated remodeling of the
[25]
against primary brain tumors still focus primarily on CNS ECM has been observed after injury, [25-28] suggesting
targeting growth and survival of the tumor cells. This lack that growing primary neoplasms in the brain may also
of adequate anti-dissemination therapies is due in part to alter the surrounding ECM. Relatively little change in
the complexity of the cell migration process itself and the the expression levels of a small set of proteins in normal
redundancy of the signaling that controls its mechanics. brain tissue and in brain tissue surrounding invasive
glioblastoma was observed in a recent study, except for
[29]
Additionally, tumor cells exploit mechanisms that normally Tenascin-R and CD168, which were both up-regulated.
direct physiological movements. However, the addiction Matrix stiffness regulates proliferation and motility of
of tumor cells to druggable pathways and our increasing Glioblastoma multiforme (GBM) cells and the increase
[30]
understanding of cell mechanics and its control offer of ECM stiffness through fiber crosslinking by the product
room for therapeutic interventions targeting tumor cell of the LOX gene causes their enhanced integrin-dependent
dissemination specifically. invasion. The specific impact of matrix stiffness on
[31]
cell migration was investigated in glioma and found to
The soil: the microenvironment in the brain decrease motility in agarose-stiffened collagen gels [19]
To address the impact of the tumor microenvironment and to increase motility in matrigel. This somewhat
[32]
on tumor growth and progression in vitro, we need (a) conflicting result may be explained by the receptors sensing
to better understand the intricate interaction between a the matrix environment and their underlying signaling,
growing neoplasm and its cellular, biophysical and chemical which markedly influence the migratory outcome. Hence,
environment and (b) to continuously implement this the impact of matrix stiffness on the migratory behavior
increasing knowledge for advancing our model systems should always be investigated in the context of the cognate
to mimic the micro environmental parameters better. The receptors. Whether matrix stiffness could exert a selective
following paragraph will briefly discuss some relevant aspects pressure on brain tumor cells contributing to the altered
of the still poorly understood interaction between the cells of genetic landscapes is still poorly understood. One potential
primary brain tumors and their cellular host environment. sensor and transducer of matrix stiffness in brain tumors
is the HA receptor CD44, which was identified in GBM to
Biophysical properties of the brain facilitate invasiveness in stiff matrices. [33]
microenvironment
Mammalian cells are sensitive to biophysical and chemical Chemical properties of the brain
signals emanating from the surrounding matrix environment, microenvironment
the extracellular matrix (ECM), which can influence their Analogous to solid tumors outside the CNS, where parallels
behavior. [18-20] Depending on the tissue, composition and between the inflammatory response in wounds and the host
stiffness of the ECM differs markedly. [21] The stiffness or tissue response to growing neoplasms has been noted,
[34]
rigidity of a material such as a meshwork of collagen I fibers, remarkable similarities in brain tissue response after injury
describes its resistance to deformation. It depends on the and in the vicinity of brain tumors exist. [35] Tissue response
elastic modulus (or compliance) of its constituting material is driven initially by a local repertoire of innate and adaptive
e.g. fibrillar polymers of the protein collagen, which describes immune cells that is subsequently supported by infiltrating
the ability to resist a distorting influence and to return to its cells of the adaptive immune system. In the brain, an
original size and shape when the influence is removed. Thus, immune privileged site of the human body, tissue response is
the stiffness of the ECM depends on its components and their driven by microglia/macrophages and astrocytes. Microglia
elastic modulus. As the parenchyma of the brain is mostly are involved in first-line innate immunity in response to
devoid of fibers with a high elastic modulus such as collagen brain injury, when they convert to an active proliferating,
or fibronectin fibrils, its stiffness is very low compared to migrating and phagocytic phenotype. Microglia and
[36]
the ECMs in other tissues of the human body. [22] Conversely, macrophages accumulate in and around glioma to which
the leptomeniges in the subarachnoid space, to where they are suspected to be attracted by glioma-secreted chemo
metastatic medulloblastoma tumors preferentially spread, [22] attractants such as monocyte chemotactic protein-3 (MCP-
are connected by a network of collagen-rich trabeculae, [23,24] 3), colony-stimulating factor 1 (CSF-1), granulocyte-
which likely is much stiffer than the parenchyma. colony stimulatory factor (G-CSF), and hepatocyte growth
factor/scatter factor. [37] Besides direct stimulatory functions
The basic constituents of the brain ECM are through secretion of growth factors or proteolytic enzymes,
glycosaminoglycans with their most prominent member glioma infiltrating macrophages were also found to
hyaluronan (Hyaluronic acid, HA), link proteins, lecticans contribute to tumor vascularization and net tumor growth. [38]
and tenascins. HA acts as a backbone for the assembly of Surprisingly, however, malignancy or primary cranial
[25]
a relatively loose and flexible meshwork. The distribution origin did not seem to determine immune cell infiltration
and composition of these ECM components in the as no significant difference in immune cell distribution
developing rodent brain is changing during embryonal and was observed between different primary or secondary
postnatal phases and reaches a mature stage at postnatal brain malignancies (Glioma, PNET/Medulloblastoma,

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 18, 2016 ¦ 151