比利时发现癌细胞转移的营养靶点

　　细胞外基质是决定细胞行为的局部环境（即微环境）主要组成部分。癌细胞转移生长期间，通过羟基化胶原蛋白，重塑转移微环境的细胞外基质，以促进自己转移生长。不过，只有特定的营养素才能帮助癌细胞羟基化胶原蛋白，因为营养素决定了癌细胞的哪些酶促反应被激活。

　　2019年2月27日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表比利时弗拉芒生物科技研究所、荷兰语天主教鲁汶大学、鲁汶癌症生物学中心、鲁汶癌症研究所的研究报告，发现癌细胞需要丙酮酸才能形成转移微环境。

　　丙酮酸是所有生物细胞糖代谢及体内多种物质相互转化的重要中间体。该研究发现癌细胞需要丙酮酸驱动肺转移微环境细胞外基质的胶原蛋白羟基化。该具体机制为，摄入丙酮酸可以诱发α-酮戊二酸的产生，该代谢产物反过来通过增加酶胶原蛋白脯氨酰-4-羟化酶（P4HA）活性以激活胶原蛋白羟基化。抑制丙酮酸代谢，足以削弱胶原蛋白羟基化，继而削弱癌细胞肺转移灶的生长。

　　因此，该研究结果表明，胶原蛋白羟基化与癌细胞转移微环境营养环境相关，有望成为癌细胞转移的营养治疗靶点。

Nature. 2019 Feb 27. [Epub ahead of print]

Breast cancer cells rely on environmental pyruvate to shape the metastatic niche.

Elia I, Rossi M, Stegen S, Broekaert D, Doglioni G, van Gorsel M, Boon R, Escalona-Noguero C, Torrekens S, Verfaillie C, Verbeken E, Carmeliet G, Fendt SM.

VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium; KU Leuven and Leuven Cancer Institute, Leuven, Belgium; KU Leuven, Leuven, Belgium.

The extracellular matrix is a major component of the local environment (that is, the niche) that determines cell behaviour. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells. Here we show that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodelling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodelling and the nutrient environment in the metastatic niche.

PMID: 30814728

DOI: 10.1038/s41586-019-0977-x