Konstorum Anna, Lowengrub John S
Center for Quantitative Medicine, UConn Health, Farmington, CT, USA.
Department of Mathematics, University of California, Irvine, CA, USA; Center for Complex Biological Systems, University of California, Irvine, CA, USA; Department of Biomedical Engineering, University of California, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, USA.
J Theor Biol. 2018 Feb 14;439:86-99. doi: 10.1016/j.jtbi.2017.11.025. Epub 2017 Dec 5.
The tumor microenvironment is an integral component in promoting tumor development. Cancer-associated fibroblasts (CAFs), which reside in the tumor stroma, produce Hepatocyte Growth Factor (HGF), an important trigger for invasive and metastatic tumor behavior. HGF contributes to a pro-tumorigenic environment by activating its cognate receptor, c-Met, on tumor cells. Tumor cells, in turn, secrete growth factors that upregulate HGF production in CAFs, thereby establishing a dynamic tumor-host signaling program. Using a spatiotemporal multispecies model of tumor growth, we investigate how the development and spread of a tumor is impacted by the initiation of a dynamic interaction between tumor-derived growth factors and CAF-derived HGF. We show that establishment of such an interaction results in increased tumor growth and morphological instability, the latter due in part to increased cell species heterogeneity at the tumor-host boundary. Invasive behavior is further increased if the tumor lowers responsiveness to paracrine pro-differentiation signals, which is a hallmark of neoplastic development. By modeling anti-HGF and anti-c-Met therapy, we show how disruption of the HGF/c-Met axis can reduce tumor invasiveness and growth, thereby providing theoretical evidence that targeting tumor-microenvironment interactions is a promising avenue for therapeutic development.
肿瘤微环境是促进肿瘤发展的一个不可或缺的组成部分。位于肿瘤基质中的癌症相关成纤维细胞（CAFs）会产生肝细胞生长因子（HGF），这是肿瘤侵袭和转移行为的一个重要触发因素。HGF通过激活肿瘤细胞上的同源受体c-Met，营造了一个促肿瘤发生的环境。反过来，肿瘤细胞会分泌生长因子，上调CAFs中HGF的产生，从而建立一个动态的肿瘤-宿主信号程序。利用肿瘤生长的时空多物种模型，我们研究了肿瘤衍生生长因子和CAF衍生的HGF之间动态相互作用的启动如何影响肿瘤的发展和扩散。我们发现，这种相互作用的建立会导致肿瘤生长增加和形态不稳定，后者部分归因于肿瘤-宿主边界处细胞种类异质性的增加。如果肿瘤降低对旁分泌促分化信号的反应性，侵袭行为会进一步增强，这是肿瘤发展的一个标志。通过模拟抗HGF和抗c-Met疗法，我们展示了HGF/c-Met轴的破坏如何降低肿瘤的侵袭性和生长，从而提供了理论证据，表明靶向肿瘤-微环境相互作用是治疗发展的一个有前景的途径。
