Previous mathematical models of glioma progression have primarily focused on the growth or migration of cancerous cells from a tumor core [37—41].

Conversely, computational models of insulin signaling exist [42, 43], but have only been applied to other applications, including articular cartilage [44], ovarian cancer [45] , and human skeletal muscle [46], and exclude molecules of interest for brain cancer cells [44, 47].

Fig 1A highlights intracellular insulin signaling pathways present in brain cancer cells .

However, since the HIFloc effects are ubiquitous in all cells, alterations in HIFloc and production of IGFBP2 would be difficult to target in cancerous cells only.

Brain cancer cells use the same pathways to develop into a cancerous phenotype [20].

Tumor growth involves a dynamic interplay between cancer cells and host cells, which collectively form a tumor microenvironmental network that either suppresses or promotes tumor growth under different conditions.

Over the course of tumor growth, cancer cells interact with normal cells via processes that are difficult to understand by experiment alone.

Growth and persistence of a tumor is influenced not only by the intrinsic proliferative capacity of the cancer cells , but also by the complex ecosystem of cells, signaling molecules and vascula-ture surrounding the tumor, which collectively comprise the tumor microenvironment (TME) [1,2] An important feature of the TME is the important role played by non-tumor cells, including both immune cells and stromal cells, in promoting tumor proliferation by contributing to immune evasion, induction of angiogenesis, and other hallmarks of cancer [3,4].

For example, hypoxic pockets in tumors can promote the survival of cancer cells during chemotherapy [26] , and local gradients of key chemokines regulate chemotaxis of tumor cells and other cells in the TME to drive processes including tissue reorganization and invasion [27].

We incorporated mechanisms for macrophage chemotaxis, macrophage functional polarization to M1 or M2 states, macrophage-mediated tumor killing, and tumor necrosis-mediated activation of macrophages via release of soluble factors, along with mechanisms for oxygen uptake by cells, oxygen delivery via vasculature, angiogenesis mediated by release of pro-angiogenic factors, and hypoxia-mediated cancer cell death.

We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line.

We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line.

The activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) in the MCF7 breast cancer cell line exemplifies the impact of such transient or sustained signalling on cell fate [3, 4].

We focused on four particular time series datasets: human aortic smooth muscle cells (AoSMC) treated with FGF2 and with IL-lfi (9 time points from 0 to 360 min; 3 replicates per treatment; IL-lfi will be referred to as Ile hereafter), as well as human MCF7 breast cancer cells treated with EGF and HRG (16 time points from 0 to 480 min; 3 replicates per treatment).