Knutsdottir Hildur, Condeelis John S, Palsson Eirikur
Mathematics Department/Institute of Applied Mathematics, University of British Columbia, Vancouver, BC V6 T 1Z2, Canada.
Integr Biol (Camb). 2016 Jan;8(1):104-19. doi: 10.1039/c5ib00201j. Epub 2015 Dec 21.
High density of macrophages in mammary tumors has been associated with a higher risk of metastasis and thus increased mortality in women. The EGF/CSF-1 paracrine signaling increases the number of invasive tumor cells by both recruiting tumor cells further away and manipulating the macrophages' innate ability to open up a passage into blood vessels thus promoting intravasation and finally metastasis. A 3-D individual-cell-based model is introduced, to better understand the tumor cell-macrophage interactions, and to explore how changing parameters of the paracrine signaling system affects the number of invasive tumor cells. The simulation data and videos of the cell movements correlated well with findings from both in vitro and in vivo experimental results. The model demonstrated how paracrine signaling is necessary to achieve co-migration of tumor cells and macrophages towards a specific signaling source. We showed how the paracrine signaling enhances the number of both invasive tumor cells and macrophages. The simulations revealed that for the in vitro experiments the imposed no-flux boundary condition might be affecting the results, and that changing the setup might lead to different experimental findings. In our simulations, the 3 : 1 tumor cell/macrophage ratio, observed in vivo, was robust for many parameters but sensitive to EGF signal strength and fraction of macrophages in the tumor. The model can be used to identify new agents for targeted therapy and we suggest that a successful strategy to prevent or limit invasion of tumor cells would be to block the tumor cell-macrophage paracrine signaling. This can be achieved by either blocking the EGF or CSF-1 receptors or supressing the EGF or CSF-1 signal.
乳腺肿瘤中巨噬细胞的高密度与转移风险增加相关，进而导致女性死亡率上升。表皮生长因子/集落刺激因子-1（EGF/CSF-1）旁分泌信号通过招募远处的肿瘤细胞以及操纵巨噬细胞打开进入血管通道的固有能力，增加了侵袭性肿瘤细胞的数量，从而促进肿瘤细胞进入血管并最终发生转移。本文引入了一个基于三维单细胞的模型，以更好地理解肿瘤细胞与巨噬细胞之间的相互作用，并探索旁分泌信号系统参数的变化如何影响侵袭性肿瘤细胞的数量。细胞运动的模拟数据和视频与体外和体内实验结果的发现高度相关。该模型展示了旁分泌信号对于肿瘤细胞和巨噬细胞向特定信号源共同迁移的必要性。我们展示了旁分泌信号如何增加侵袭性肿瘤细胞和巨噬细胞的数量。模拟结果显示，对于体外实验，施加的无通量边界条件可能会影响结果，改变实验设置可能会导致不同的实验发现。在我们的模拟中，体内观察到的3:1肿瘤细胞/巨噬细胞比例对许多参数具有稳健性，但对EGF信号强度和肿瘤中巨噬细胞的比例敏感。该模型可用于识别靶向治疗的新药物，我们认为预防或限制肿瘤细胞侵袭的成功策略是阻断肿瘤细胞与巨噬细胞的旁分泌信号。这可以通过阻断EGF或CSF-1受体或抑制EGF或CSF-1信号来实现。
