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庄子《南华经》有一则寓言，一位名叫“丁”的庖（厨师）为魏国文惠王杀牛：手之所触，肩之所倚，足之所履，膝之所踦，砉然向然，奏刀騞然，莫不中音，合于《桑林》之舞，乃中《经首》之会。文惠王叹为观止，问他的技术为何如此高超？庖丁放下刀答道：我喜欢摸索事物的道，而非技术；我刚开始分解牛体时，眼中看见是一整头牛；数年之后，眼中看到的就不是一整头牛，而是无数肌肉、骨骼、关节、筋腱，如此才能游刃有余，以无间入有间。同样，在科学家眼中，三阴性乳腺癌并非一种癌症，而是无数分子靶点和信号通路构成的无数种癌症。 庖丁眼中的牛 科学家眼中的三阴性乳腺癌 三阴性乳腺癌占所有人类乳腺导管腺癌的10%～20%，与其他类型的乳腺癌相比，发生远处转移的倾向较高，故预后较差。根据不同的分子，三阴性乳腺癌还可被进一步细分为具有不同转移能力的亚型。因此，针对转移能力较高的三阴性乳腺癌，亟需可被治疗干预的分子靶点。 2020年2月24日，国际抗癌联盟《国际癌症杂志》在线发表澳大利亚墨尔本大学、彼得·麦卡伦癌症中心、维多利亚综合癌症中心、奥莉维亚·纽顿-约翰癌症研究所、拉筹伯大学、莫纳什大学的研究报告，将人类三阴性乳腺癌细胞MDA-MB-231进一步细分，建立了4种具有不同自发转移能力的同基因肿瘤模型：
通过核糖核酸RNA测序对原发肿瘤进行基因表达谱分析，将成纤维细胞生长因子FGF家族之中的FGF13进一步细分为6种蛋白质异构体，其中3种FGF13i2、FGF13i3、FGF13i4高表达于HM三阴性乳腺癌。 根据临床意义分析，FGF13信使RNA高表达与低表达相比，管腔A型或基底型三阴性乳腺癌患者的无复发生存显著较差，无论其他临床因素如何，而原发肿瘤相对于附近正常乳腺表达水平相似。 通过基因技术持续抑制FGF13表达，可以限制HM三阴性乳腺癌细胞的体外克隆形成能力，减少其自发转移至肝和肺，但是不限制激素受体阳性乳腺癌细胞MCF-7或MDA-MB-361的体外克隆形成能力和自发转移。 虽然抑制FGF13可以增加体外HM细胞的转移和浸润、几乎完全阻止体内HM原位异种移植肿瘤自发转移至肺和肝，而对原发肿瘤生长的影响微乎其微。 因此，该研究结果表明，FGF13有望成为阻断某些三阴性乳腺癌转移的治疗靶点，故有必要进一步细分该靶点不同蛋白质异构体对不同亚型乳腺癌转移过程的作用。 Int J Cancer. 2020 Feb 24. [Epub ahead of print] FGF13 promotes metastasis of triple-negative breast cancer. Johnstone CN, Pattison AD, Harrison PF, Powell DR, Lock P, Ernst M, Anderson RL, Beilharz TH. Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; La Trobe University, Bundoora, Victoria, Australia; Monash University, Clayton, Victoria, Australia. What's new? Triple-negative breast cancer (TNBC) has a high degree of molecular diversity, with multiple subtypes and varying metastatic behavior. To better understand TNBC heterogeneity, the authors of this study performed RNA expression analysis on four isogenic MDA-MB-231 human TNBC tumour models characterized by distinct metastatic capacities. The three metastatic variants upregulation of the fibroblast growth factor FGF13. Elevated FGF13 expression was associated with poor survival in patients with basal-like breast cancer. In mice, FGF13 knockdown in highly metastatic MDA-MB-231 cells reduced spontaneous metastasis to liver and lung without affecting primary xenograft growth, suggesting that FGF13 is a promising antimetastatic target. Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes, due to the high propensity to develop distant metastases. Hence, new molecular targets for therapeutic intervention are needed for TNBC. We recently conducted a rigorous phenotypic and genomic characterization of four isogenic populations of MDA-MB-231 human triple-negative breast cancer cells that possess a range of intrinsic spontaneous metastatic capacities in vivo, ranging from non-metastatic (MDA-MB-231_ATCC) to highly metastatic to lung, liver, spleen and spine (MDA-MB-231_HM). Gene expression profiling of primary tumours by RNA-Seq identified the fibroblast growth factor homologous factor, FGF13, as highly upregulated in aggressively metastatic MDA-MB-231_HM tumours. Clinically, higher FGF13 mRNA expression was associated with significantly worse relapse free survival in both luminal A and basal-like human breast cancers but was not associated with other clinical variables and was not upregulated in primary tumours relative to normal mammary gland. Stable FGF13 depletion restricted in vitro colony forming ability in MDA-MB-231_HM TNBC cells but not in oestrogen receptor (ER) positive MCF-7 or MDA-MB-361 cells. However, despite augmenting MDA-MB-231_HM cell migration and invasion in vitro, FGF13 suppression almost completely blocked the spontaneous metastasis of MDA-MB-231_HM orthotopic xenografts to both lung and liver while having negligible impact on primary tumour growth. Together, these data indicate that FGF13 may represent a therapeutic target for blocking metastatic outgrowth of certain TNBCs. Further evaluation of the roles of individual FGF13 protein isoforms in progression of the different subtypes of breast cancer is warranted. KEYWORDS: triple-negative breast cancer; metastasis; mouse model; xenograft; FGF13 PMID: 31957002 DOI: 10.1002/ijc.32874
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