Tumor cells and stromal cells actively “talk” to each other via an array of soluble signaling molecules, leading to co-evolution of the tumor and its microenvironment 
. This also implies that the tumor microenvironment itself is a critical aspect of disease mechanism and that the microenvironmental components, including cells and soluble mediators, may represent a new set of targets for anti-tumor therapy 
. However, due to the inherent heterogeneity of the tumor microenvironment and the complexity of the cell-cell communication network, it remains poorly understood at the systems level how these cells and their communication network collectively shape a heterogeneous tumor microenvironment and modulate tumorigenesis and metastasis. Conventional approaches that examine one or two selected pathways are incapable of fully assessing complex signaling networks and recapitulate the dynamics of the tumor microenvironment, and often result in contradictory conclusions. Thus, a systems approach that examines various cell types and the associated intercellular signaling networks in the tumor microenvironment is highly desired.
In this work we choose to study the dynamics of glioblastoma multiforme (GBM) development. GBM is one of the most malignant brain tumors, with conventional therapies against “common” oncogenic targets usually ineffective due in part to the high degree of tumor heterogeneity. Astrocytes, microglia, and infiltrating immune cells actively interact with glioma and glioma stem cells via complex intercellular signaling networks mediated by an array of soluble signaling molecules, e.g., cytokines, growth factors, and neuropoientins 
. All these collectively shape a tumor microenvironment that could be distinct from one patient to another. Despite substantial research efforts and significant advances in cancer therapeutics, human GBM remains the most aggressive and lethal brain tumor in humans. In addition to inter-tumoral and inter-patient heterogeneity, GBM also exhibits significant intra-tumoral heterogeneity down to the single-cell level 
. First, glioma cells originate from a variety of dynamically evolving progenitor cells 
. It has been demonstrated that GBM cells demarcated by the neural stem cell marker CD133 exhibit much enhanced competencies for self-renewal and tumor initiation 
. Recent studies have also shown instances in which CD133-negative cells were able to generate the same outcomes 
. Second, glioma cells constantly interact with a variety of stromal cells. There is evidence that glioma cells acquire the ability to recruit and subvert their untransformed neighbor microglia into active collaborators to facilitate tumorigenesis. Direct correlation has been reported between the grade of glioma and the level of resident tumor microglia 
, suggesting the mutual paracrine stimulation between microglial cells and glioma cells 
. Microglial cells recruited by glioma can promote tumor growth 
, dictated by paracrine loops responsible for glioma initiation and progression (e.g., IL-6, IL-10, TGF-β, prostaglandins, G-CSF, and GM-CSF, and growth factors such as EGF, VEGF, HGF, and SCF). The crosstalk between activated astroglial and glioma cells has also been documented, although the mechanism of their interactions has not been full revealed. For example, astroglial cells produce IL-1β 
that promotes cell proliferation 
and tumor angiogenesis 
. Upon stimulation by the autocrine IL-1β these cells further secrete TNF-α and IL-6 
. The former was found to increase VEGF 
, EGF receptor 
, and MMP-9 
expression in glioma cells, suggesting that astroglia-produced cytokines may influence all the three most critical aspects of glioma cell survival: angiogenesis (VEGF), proliferation (EGFR), and migration (MMP-9).
models of tumor microenvironment integrate information about the biological context in which cancers develop, and thus represent a multi-scale consideration of oncogenesis as it occurs within somatic tissues 
. Multiple factors involved in the development of an intrinsically complex tumor microenvironment have been studied including extracellular biomolecules, a spatially intricate and dynamic vasculature, and the immune system. Thus far, these models can be broadly divided into ‘continuum’ models, and discrete or ‘agent-based’ models as summarized in a review by Price and coauthors 
. The latter describe the dynamics of individual interacting units, such as cancer cells, in small confined space; the former can be applied to a large tissue scale where agent-based modeling is computationally prohibitive. However, none of these methods have been integrated with a large cell-cell communication network in a complex tumor microenvironment. Herein we integrate all the intercellular signaling pathways known to date for human glioblastoma and generate a dynamic cell-cell communication network associated with the glioma microenvironment. Then we apply evolutionary population dynamics and the Hill functions to interrogate this intercellular signaling network and execute an in silico
tumor microenvironment development. The observed results reveal a profound influence of the microenvironmental cues on tumor initiation and growth, and suggest new venues for glioblastoma treatment by targeting cells or soluble mediators in the tumor microenvironment.