普遍認(rèn)為,，只有基底樣細(xì)胞具有干細(xì)胞特性，可以形成侵入性腫瘤,。但是,，PNAS上一篇新研究提出了另一觀點(diǎn)，它指出,，導(dǎo)管樣細(xì)胞是一種癌細(xì)胞亞群,，無可檢測(cè)的干細(xì)胞特性，具致瘤性,、高侵襲性,，能產(chǎn)生更巨大的腫瘤。這對(duì)于乳腺癌診斷與治療可能具有重要意義,，將來的個(gè)性化癌癥醫(yī)學(xué)也如此,。
當(dāng)前流行的觀點(diǎn)是：如果癌癥干細(xì)胞被殺死，乳腺癌就是一種可治療的疾病,。但是,，亞型致瘤細(xì)胞的存在則告訴我們，腫瘤需要徹底根除,，不只是基底樣細(xì)胞,。
許多乳腺癌開始于乳導(dǎo)管和小葉，它們由基底樣細(xì)胞包圍的導(dǎo)管樣細(xì)胞組成,，這兩種細(xì)胞是最常見的兩種人類乳腺癌細(xì)胞,，因它們與正常乳腺2個(gè)主要譜系相似性而命名為導(dǎo)管樣和基底樣。在過去的幾年里,，廣泛認(rèn)為基底樣細(xì)胞無干細(xì)胞的未分化特性,，是侵入性腫瘤的起源。然而,，大多數(shù)乳腺癌表現(xiàn)出管腔細(xì)胞分化,，于是研究人員研究了基底樣細(xì)胞譜系內(nèi)導(dǎo)管樣分化的細(xì)胞是否可能成為致瘤細(xì)胞，或者這些導(dǎo)管樣細(xì)胞必須獲得基底樣特質(zhì)才變成惡性細(xì)胞,。
研究發(fā)現(xiàn),，導(dǎo)管樣細(xì)胞沒有特異的基底細(xì)胞樣特性,，在實(shí)驗(yàn)測(cè)試小鼠上完全能引發(fā)腫瘤，導(dǎo)管樣細(xì)胞產(chǎn)生的腫瘤實(shí)際上遠(yuǎn)遠(yuǎn)大于基底樣細(xì)胞產(chǎn)生的,。另外,，在侵入性測(cè)試中，這些純導(dǎo)管樣細(xì)胞表型的侵襲性強(qiáng)于基底樣細(xì)胞,。這表明,，基底樣細(xì)胞象當(dāng)前界定的那樣，不是乳腺腫瘤侵襲性的必要條件,，單一腫瘤內(nèi)存在多種具致瘤潛能的細(xì)胞,。這對(duì)當(dāng)前致瘤性層次喪失或分化喪失的假設(shè)提出了質(zhì)疑。
研究中用乳粘蛋白（MM,，milk mucin）作為分離導(dǎo)管樣癌細(xì)胞的標(biāo)志,，其中乳粘蛋白是一種聚糖，這種糖分子廣泛存在于細(xì)胞表面和細(xì)胞信號(hào)通路核心,，用M18抗體檢測(cè),。CD271蛋白為基底樣細(xì)胞的標(biāo)志，用ME20.4抗體檢測(cè),。
此外,，導(dǎo)管樣乳腺癌細(xì)胞形成強(qiáng)侵入性腫瘤的能力決定于糖蛋白基因GCNT1的表達(dá)，這個(gè)基因是用M18抗體檢測(cè)MM聚糖所必需的,；如果侵襲性導(dǎo)管樣癌細(xì)胞表達(dá)MM抗原決定簇,，抑制GCNT1活性就能阻止它們的侵襲行為,。因而,，可推測(cè)這一發(fā)現(xiàn)可能具有潛在的臨床重要性，對(duì)將來的個(gè)性化醫(yī)學(xué)也可能有重要意義,。（生物谷bioon.com）
doi:10.1073/pnas.1203203109
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PMID:
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.
