細胞外基質是決定細胞行為的局部環(huán)境（即微環(huán)境）主要組成部分。癌細胞轉移生長期間，通過羥基化膠原蛋白，重塑轉移微環(huán)境的細胞外基質，以促進自己轉移生長。不過，只有特定的營養(yǎng)素才能幫助癌細胞羥基化膠原蛋白，因為營養(yǎng)素決定了癌細胞的哪些酶促反應被激活。

　　2019年2月27日，全球自然科學三大旗艦期刊之一、英國《自然》正刊在線發(fā)表比利時弗拉芒生物科技研究所、荷蘭語天主教魯汶大學、魯汶癌癥生物學中心、魯汶癌癥研究所的研究報告，發(fā)現(xiàn)癌細胞需要丙酮酸才能形成轉移微環(huán)境。

　　丙酮酸是所有生物細胞糖代謝及體內多種物質相互轉化的重要中間體。該研究發(fā)現(xiàn)癌細胞需要丙酮酸驅動肺轉移微環(huán)境細胞外基質的膠原蛋白羥基化。該具體機制為，攝入丙酮酸可以誘發(fā)α-酮戊二酸的產(chǎn)生，該代謝產(chǎn)物反過來通過增加酶膠原蛋白脯氨酰-4-羥化酶（P4HA）活性以激活膠原蛋白羥基化。抑制丙酮酸代謝，足以削弱膠原蛋白羥基化，繼而削弱癌細胞肺轉移灶的生長。

　　因此，該研究結果表明，膠原蛋白羥基化與癌細胞轉移微環(huán)境營養(yǎng)環(huán)境相關，有望成為癌細胞轉移的營養(yǎng)治療靶點。

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