The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cancer Biol Ther. 2010 Sep 15;10(6):537-42. doi: 10.4161/cbt.10.6.13370. Epub 2010 Sep 19.
We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other stromal cells. Oxidative stress in the tumor stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer cells, thereby promoting the anabolic growth of cancer cells (via an energy imbalance). We also show that ketones and lactate help "fuel" tumor growth and cancer cell metastasis and can act as chemo-attractants for cancer cells. We have termed this new paradigm for accelerating tumor-stroma co-evolution, "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism". Heterotypic signaling in cancer-associated fibroblasts activates the transcription factors HIF1alpha and NFκB, potentiating the onset of hypoxic and inflammatory response(s), which further upregulates the autophagic program in the stromal compartment. Via stromal autophagy, this hypoxic/inflammatory response may provide a new escape mechanism for cancer cells during anti-angiogenic therapy, further exacerbating tumor recurrence and metastasis.
我们最近提出了一个新的模型来理解肿瘤如何进化。为了实现成功的“肿瘤-基质共同进化”，癌细胞在相邻的成纤维细胞中诱导氧化应激，可能还有其他基质细胞。肿瘤基质中的氧化应激模拟了缺氧的影响，在有氧条件下，导致活性氧（ROS）的过度产生。基质中 ROS 的过度产生会促使相邻癌细胞启动抗氧化防御，保护它们免受凋亡。此外，基质中 ROS 的过度产生具有“旁观者效应”，导致相邻癌细胞的 DNA 损伤和非整倍体，这都是基因组不稳定性的标志。最后，ROS 驱动的氧化应激会诱导肿瘤微环境中的自噬和线粒体自噬，导致基质中回收营养物质（包括富含能量的代谢物，如酮体和 L-乳酸）的过度产生。这些回收的营养物质或化学构建块有助于促进癌细胞中线粒体的生物发生，从而促进癌细胞的合成代谢生长（通过能量失衡）。我们还表明，酮体和乳酸有助于“为”肿瘤生长和癌细胞转移提供燃料，并可作为癌细胞的趋化剂。我们将这种加速肿瘤-基质共同进化的新范例称为“癌细胞代谢的自噬性肿瘤基质模型”。癌相关成纤维细胞中的异型信号激活转录因子 HIF1alpha 和 NFκB，增强缺氧和炎症反应的发生，进一步上调基质部分的自噬程序。通过基质自噬，这种缺氧/炎症反应可能为癌细胞在抗血管生成治疗期间提供新的逃逸机制，进一步加剧肿瘤复发和转移。
