中国学者发现脂肪细胞促进乳腺癌细胞生长的机理
脂肪细胞是乳腺组织最丰富的间质。然而，与癌症相关成纤维细胞相比，既往研究对乳腺癌细胞与脂肪细胞之间的相互作用关注较少。
2017年3月10日，英国《自然·通讯》在线发表中国台湾大学医学院、台湾中央研究院基因组学研究中心、台湾大学附设医院、台北医学大学、台北市立万芳医院、台中市澄清综合医院、台中市中国医药大学的研究报告，发现脂肪细胞通过β-羟基丁酸促进单羧酸转运蛋白2表达和乳腺肿瘤恶性生长。
该研究将乳腺癌细胞与从乳腺分离出来的脂肪细胞共同培养，发现在培养过程中，脂肪细胞促进了肿瘤细胞的生长，并促进其分泌单羧酸转运蛋白2（MCT2），该蛋白质的主要作用是运输脂肪细胞分泌的β-羟基丁酸，促进肿瘤细胞若干基因的表达，进而促进肿瘤细胞生长。
该研究的基本原理如上，其设计极为严谨复杂，首先设计了一个共培养系统，即乳腺癌细胞和从乳腺癌手术切除肿瘤组织分离出来的乳腺来源脂肪细胞（MGDA）共同培养。随后通过微阵列分析和核糖核酸（RNA）干扰敲除筛选，发现了该系统新的运输蛋白质（MCT2）可以有效地调节MGDA与肿瘤细胞之间的相互作用。对产生MCT2的乳腺癌细胞进行MGDA共培养，或者用β-羟基丁酸刺激，均会增加组蛋白H3K9乙酰化，诱导白介素（IL）-1β和LCN2基因的大量表达，最终导致了肿瘤形成作用大幅度增强，促进癌症发生。
此外，该研究分析了MCT2、IL-1β、LCN2、β-羟基丁酸的表达与乳腺癌患者总生存之间的相关性，结果发现MCT2和IL-1β同时过表达、MCT2和LCN2同时过表达的患者总生存率显著较低（P=0.029、0.017）。
因此，该研究通过严密的设计，最终证实乳腺脂肪细胞与乳腺癌细胞之间的相关性，对乳腺癌的发生和发展有促进作用。
2017年3月29日，英国《自然》编辑部对此发表报道：脂肪如何促进乳腺癌。
Nature. 2017 Mar 30;543(7647):593.
Cancer: How fat boosts breast cancer.
A molecule made by fat cells in human breast tissue increases the growth of certain breast-cancer cells. The finding suggests a potential reason why larger breast size seems to correlate with a higher risk of cancer.
Fat cells are thought to interact with cancer cells in the breast. To learn how, Wen-Hwa Lee at China Medical University in Taiwan and his colleagues grew human breast-cancer cells along with fat cells isolated from human breast tumours that had been surgically removed. The team found that the fat cells promoted the growth of cancer cells that made a protein called MCT2. The researchers pinpointed a small molecule, β-hydroxybutyrate, that is secreted by the fat cells and is transported into tumour cells by MCT2. This molecule upregulated several cancer genes, boosting the growth of human breast-tumour cells that express MCT2.
PMID: 28358090
DOI: 10.1038/543593b
Nat Commun. 2017 Mar 10;8:14706.
Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via β-hydroxybutyrate.
Huang CK, Chang PH, Kuo WH, Chen CL, Jeng YM, Chang KJ, Shew JY, Hu CM, Lee WH.
College of Medicine, National Taiwan University, Taipei, Taiwan; Genomics Research Center, Academia Sinica, Taipei, Taiwan; National Taiwan University Hospital, Taipei, Taiwan; Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Cheng Chin General Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan.
Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. Here we find, through systematic screening, that primary mammary gland-derived adipocytes (MGDAs) promote growth of breast cancer cells that express monocarboxylate transporter 2 (MCT2) both in vitro and in vivo. We show that β-hydroxybutyrate is secreted by MGDAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, β-hydroxybutyrate is sufficient to promote tumorigenesis of a mouse xenograft model of MCT2-expressing breast cancer cells. Mechanistically we observe that upon co-culturing with MGDAs or treatment with β-hydroxybutyrate, breast cancer cells expressing MCT2 increase the global histone H3K9 acetylation and upregulate several tumour-promoting genes. These results suggest that adipocytes promote malignancy of MCT2-expressing breast cancer via β-hydroxybutyrate potentially by inducing the epigenetic upregulation of tumour-promoting genes.
PMID: 28281525
PMCID: PMC5353665
DOI: 10.1038/ncomms14706