Derbal Youcef
Ted Rogers School of Information Technology Management, Ryerson University, Toronto, Canada.
Theor Biol Med Model. 2017 Oct 3;14(1):18. doi: 10.1186/s12976-017-0066-5.
The genetic diversity of cancer and the dynamic interactions between heterogeneous tumor cells, the stroma and immune cells present daunting challenges to the development of effective cancer therapies. Although cancer biology is more understood than ever, this has not translated into therapies that overcome drug resistance, cancer recurrence and metastasis. The future development of effective therapies will require more understanding of the dynamics of homeostatic dysregulation that drives cancer growth and progression.
Cancer dynamics are explored using a model involving genes mediating the regulatory interactions between the signaling and metabolic pathways. The exploration is informed by a proposed genetic dysregulation measure of cellular processes. The analysis of the interaction dynamics between cancer cells, cancer associated fibroblasts, and tumor associate macrophages suggests that the mutual dependence of these cells promotes cancer growth and proliferation. In particular, MTOR and AMPK are hypothesized to be concurrently activated in cancer cells by amino acids recycled from the stroma. This leads to a proliferative growth supported by an upregulated glycolysis and a tricarboxylic acid cycle driven by glutamine sourced from the stroma. In other words, while genetic aberrations ignite carcinogenesis and lead to the dysregulation of key cellular processes, it is postulated that the dysregulation of metabolism locks cancer cells in a state of mutual dependence with the tumor microenvironment and deepens the tumor's inflammation and immunosuppressive state which perpetuates as a result the growth and proliferation dynamics of cancer.
Cancer therapies should aim for a progressive disruption of the dynamics of interactions between cancer cells and the tumor microenvironment by targeting metabolic dysregulation and inflammation to partially restore tissue homeostasis and turn on the immune cancer kill switch. One potentially effective cancer therapeutic strategy is to induce the reduction of lactate and steer the tumor microenvironment to a state of reduced inflammation so as to enable an effective intervention of the immune system. The translation of this therapeutic approach into treatment regimens would however require more understanding of the adaptive complexity of cancer resulting from the interactions of cancer cells with the tumor microenvironment and the immune system.
癌症的遗传多样性以及异质性肿瘤细胞、基质和免疫细胞之间的动态相互作用，给有效癌症治疗的发展带来了巨大挑战。尽管对癌症生物学的理解比以往任何时候都更深入，但这尚未转化为克服耐药性、癌症复发和转移的疗法。有效疗法的未来发展将需要更多地了解驱动癌症生长和进展的稳态失调动态。
使用一个涉及介导信号通路和代谢通路之间调节相互作用的基因的模型来探索癌症动态。该探索基于一种提出的细胞过程遗传失调测量方法。对癌细胞、癌症相关成纤维细胞和肿瘤相关巨噬细胞之间相互作用动态的分析表明，这些细胞的相互依赖促进了癌症的生长和增殖。特别是，假设雷帕霉素靶蛋白（MTOR）和腺苷酸活化蛋白激酶（AMPK）在癌细胞中被从基质中循环利用的氨基酸同时激活。这导致由糖酵解上调和由基质来源的谷氨酰胺驱动的三羧酸循环支持的增殖性生长。换句话说，虽然基因畸变引发致癌作用并导致关键细胞过程的失调，但据推测，代谢失调使癌细胞与肿瘤微环境处于相互依赖状态，并加深肿瘤的炎症和免疫抑制状态，从而使癌症的生长和增殖动态持续存在。
癌症治疗应旨在通过靶向代谢失调和炎症来逐步破坏癌细胞与肿瘤微环境之间的相互作用动态，以部分恢复组织稳态并开启免疫抗癌开关。一种潜在有效的癌症治疗策略是诱导乳酸减少并使肿瘤微环境转向炎症减轻的状态，以便能够有效干预免疫系统。然而，将这种治疗方法转化为治疗方案将需要更多地了解癌细胞与肿瘤微环境和免疫系统相互作用所导致的癌症适应性复杂性。
