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adenocarcinoma, melanoma meningioma). A more incorporating environmental parameters into experimental
[39]
recent study correlating inflammatory gene expression protocols to explore their contribution to the proteomic
with the molecular subgroup of medulloblastoma, revealed landscape and the functional outcomes of primary brain tumors.
significantly increased immune cell infiltration of tumor
associated macrophages and other immune cells in the SHH CURRENT IN VITRO MODEL SYSTEMS TO
subgroup, suggesting a potential therapeutic relevance of ADDRESS FUNCTIONS OF METASTATIC
[40]
immune cell targeting specifically for this subgroup. PRIMARY BRAIN TUMORS
Microglia are outnumbered by astrocytes, which account Preclinical evaluation of novel anti-metastatic therapy
for nearly half of all cells resident in the brain. Astrocytes strategies in animal models will remain an essential step
respond to brain injury and tumor growth in a process towards the development of novel therapeutics. However,
named reactive gliosis. On the one hand, reactive gliosis cell culture models are instrumental for deciphering
and the associated secretion of growth factors and cytokines essential morphological and functional aspects of the
help repairing injury in the CNS. On the other hand, biology that drives neoplastic lesions into disseminated
[41]
the astrocytic response in the tumor microenvironment diseases. They also provide essential insights for designing
also contributes to disease progression. Of note in this appropriate animal models and help elucidating the causes
context is the capability of U87MG glioblastoma cells that may underlie controversial outcomes of in vivo studies.
to induce astrocyte activation through the secretion of Although a general trend towards 3D model systems
Receptor Activator of NF-kB ligand (RANKL), which can be noted, a majority of experiments in tumor-related
in turn facilitates glioblastoma invasiveness in vivo by research are still conducted in 2D settings. For a general, in
releasing FGF4, FGF6, TGF-β and Hepatocyte growth depth description and comparison of 2D versus 3D culture
factor. Consistently, co-cultured astrocytes display systems, the reader is referred to Zimmermann et al. [48] who
[42]
increased expression levels of a number of growth factors emphasized the need of higher throughput approaches to
and cytokines and enhance invasiveness of glioblastoma understand cell dissemination capabilities on one hand and
stem-like cells. Another decisive input could stem the role of the microenvironment on the other hand.
[43]
from astrocytes activated by the neoplastic lesion and the
consequent up-regulation of matricellular proteins such The “ideal” in vitro cell culture model should mimic one or
as secreted protein acidic and rich in cys-teins (SPARC) several of the following characteristics of the in vivo tumor:
in astrocytoma and medulloblastoma or connective proliferative capabilities and morphology of the tumor cells,
[44]
[45]
tissue growth factor in glioma, which jointly with cellular and phenotypic heterogeneity, a dynamic tumor
[46]
additional matricellular proteins remodel neuronal tissue microenvironment and the drug response profile. A series of
during development or after brain injury. Significantly, excellent reviews have recently described in depth the use
[28]
the concept of reciprocal stimulation of tumor cells and of 3D tissue culture model systems in pathophysiology
[49]
astrocytes was recently also identified in metastatic and high-throughput drug candidate toxicity analysis,
[50]
melanoma, which elicits an inflammatory cytokine response to identify tumor-specific signaling pathways and
in astrocytes that facilitates brain metastasis. biomarkers, and to determine growth determinants for
[47]
[51]
drug target discovery. These reviews delineate what
[52]
Combined, these studies emphasize the importance of parameters contribute to a disease representing, efficient

Figure 2: Tumor cell growth, survival and dissemination are governed by extrinsic and intrinsic parameters. Tumor cells are under the spheres of influence
of intrinsic and extrinsic parameters. Colored ovals represent various degrees and manifestation patterns of such parameters, which dramatically increase in
number and complexity in the organotypic environment

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