Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Obu, Japan.
Cancer Sci. 2019 Jan;110(1):269-278. doi: 10.1111/cas.13873. Epub 2018 Dec 3.
Cancer-associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor-cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse-Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.
癌相关成纤维细胞（CAF）是肿瘤微环境的关键组成部分，在肿瘤转移和化疗耐药中发挥功能作用。我们之前曾报道过，从淋巴瘤样本中分离出的 CAF 增加了无氧糖酵解并减少了细胞内活性氧的产生，从而促进了肿瘤细胞的存活。在此，我们分析了 CAF 支持肿瘤细胞存活的机制。由于肿瘤细胞与 CAF 的直接接触对于存活支持并不是必需的，因此我们确定了 CAF 显著分泌了一种名为丙酮酸的体液因子。此外，丙酮酸的存在促进了淋巴瘤细胞的存活，而单羧酸转运蛋白的抑制则消除了这种促进作用。与 CAF 共培养的淋巴瘤细胞的代谢组学分析表明，柠檬酸循环的中间产物显著增加，表明肿瘤细胞通过有氧代谢产生能量。这些发现表明，淋巴瘤细胞的能量产生不仅受到无氧糖酵解的调节，还受到有氧代谢的调节，即反向沃伯格效应，涉及 CAF 从丙酮酸的分泌，从而增加了柠檬酸循环在淋巴瘤细胞中的利用。
