PNAS：乳腺癌新发现

普遍认为，只有基底样细胞具有干细胞特性，可以形成侵入性肿瘤。但是，PNAS上一篇新研究提出了另一观点，它指出，导管样细胞是一种癌细胞亚群，无可检测的干细胞特性，具致瘤性、高侵袭性，能产生更巨大的肿瘤。这对于乳腺癌诊断与治疗可能具有重要意义，将来的个性化癌症医学也如此。

当前流行的观点是：如果癌症干细胞被杀死，乳腺癌就是一种可治疗的疾病。但是，亚型致瘤细胞的存在则告诉我们，肿瘤需要彻底根除，不只是基底样细胞。

许多乳腺癌开始于乳导管和小叶，它们由基底样细胞包围的导管样细胞组成，这两种细胞是最常见的两种人类乳腺癌细胞，因它们与正常乳腺2个主要谱系相似性而命名为导管样和基底样。在过去的几年里，广泛认为基底样细胞无干细胞的未分化特性，是侵入性肿瘤的起源。然而，大多数乳腺癌表现出管腔细胞分化，于是研究人员研究了基底样细胞谱系内导管样分化的细胞是否可能成为致瘤细胞，或者这些导管样细胞必须获得基底样特质才变成恶性细胞。

研究发现，导管样细胞没有特异的基底细胞样特性，在实验测试小鼠上完全能引发肿瘤，导管样细胞产生的肿瘤实际上远远大于基底样细胞产生的。另外，在侵入性测试中，这些纯导管样细胞表型的侵袭性强于基底样细胞。这表明，基底样细胞象当前界定的那样，不是乳腺肿瘤侵袭性的必要条件，单一肿瘤内存在多种具致瘤潜能的细胞。这对当前致瘤性层次丧失或分化丧失的假设提出了质疑。

研究中用乳粘蛋白（MM，milk mucin）作为分离导管样癌细胞的标志，其中乳粘蛋白是一种聚糖，这种糖分子广泛存在于细胞表面和细胞信号通路核心，用M18抗体检测。CD271蛋白为基底样细胞的标志，用ME20.4抗体检测。

此外，导管样乳腺癌细胞形成强侵入性肿瘤的能力决定于糖蛋白基因GCNT1的表达，这个基因是用M18抗体检测MM聚糖所必需的；如果侵袭性导管样癌细胞表达MM抗原决定簇，抑制GCNT1活性就能阻止它们的侵袭行为。因而，可推测这一发现可能具有潜在的临床重要性，对将来的个性化医学也可能有重要意义。

doi:10.1073/pnas.1203203109
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Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

Jiyoung Kim, René Villadsen, Therese Sørlie, Louise Fogh,Signe Z. Grønlund, Agla J. Fridriksdottir, Irene Kuhn, Fritz Rank,Vera Timmermans Wielenga, Hiroko Solvang, Paul A. W. Edwards,Anne-Lise Børresen-Dale,  Lone Rønnov-Jessen, Mina J. Bissell, and Ole William Petersen

The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually exclusive lineage markers to isolate subsets of luminal-like and basal-like cells from human breast tumors. We enriched for populations with or without prominent basal-like traits from individual tumors or single cell cloning from cell lines and recovered cells with a luminal-like phenotype. Tumor cells with basal-like traits mimicked phenotypic and functional behavior associated with stem cells assessed by gene expression, mammosphere formation and lineage markers. Luminal-like cells without basal-like traits, surprisingly, were fully capable of initiating invasive tumors in NOD SCID gamma (NSG) mice. In fact, these phenotypically pure luminal-like cells generated larger and more invasive tumors than their basal-like counterparts. The tumorigenicity and invasive potential of the luminal-like cancer cells relied strongly on the expression of the gene GCNT1, which encodes a key glycosyltransferase controlling O-glycan branching. These findings demonstrate that basal-like cells, as defined currently, are not a requirement for breast tumor aggressiveness, and that within a single tumor there are multiple "stem-like" cells with tumorigenic potential casting some doubt on the hypothesis of hierarchical or differentiative loss of tumorigenicity.