Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2011;6(6):e20701. doi: 10.1371/journal.pone.0020701. Epub 2011 Jun 8.
Cancer stem cells (CSCs) or tumor initiating cells (TICs) make up only a small fraction of total tumor cell population, but recent evidence suggests that they are responsible for tumor initiation and the maintenance of tumor growth. Whether CSCs/TICs originate from normal stem cells or result from the dedifferentiation of terminally differentiated cells remains unknown. Here we provide evidence that sustained expression of the proinflammatory protein tissue transglutaminase (TG2) confers stem cell like properties in non-transformed and transformed mammary epithelial cells. Sustained expression of TG2 was associated with increase in CD44(high)/CD24(low/-) subpopulation, increased ability of cells to form mammospheres, and acquisition of self-renewal ability. Mammospheres derived from TG2-transfected mammary epithelial cells (MCF10A) differentiated into complex secondary structures when grown in Matrigel cultures. Cells in these secondary structures differentiated into Muc1-positive (luminal marker) and integrin α6-positive (basal marker) cells in response to prolactin treatment. Highly aggressive MDA-231 and drug-resistant MCF-7/RT breast cancer cells, which express high basal levels of TG2, shared many traits with TG2-transfected MCF10A stem cells but unlike MCF10A-derived stem cells they failed to form the secondary structures and to differentiate into Muc1-positive luminal cells when grown in Matrigel culture. Downregulation of TG2 attenuated stem cell properties in both non-transformed and transformed mammary epithelial cells. Taken together, these results suggested a new function for TG2 and revealed a novel mechanism responsible for promoting the stem cell characteristics in adult mammary epithelial cells.
癌症干细胞（CSCs）或肿瘤起始细胞（TICs）仅占肿瘤细胞总数的一小部分，但最近的证据表明，它们负责肿瘤的起始和肿瘤的生长维持。CSCs/TICs 是来自正常干细胞还是来自终末分化细胞的去分化仍不清楚。在这里，我们提供的证据表明，持续表达促炎蛋白组织转谷氨酰胺酶（TG2）赋予非转化和转化的乳腺上皮细胞类似干细胞的特性。TG2 的持续表达与 CD44（高）/CD24（低/-）亚群的增加、细胞形成乳腺球体的能力增加以及获得自我更新能力有关。从转染 TG2 的乳腺上皮细胞（MCF10A）衍生的乳腺球体在 Matrigel 培养物中分化为复杂的二级结构。这些二级结构中的细胞在催乳素处理下分化为 Muc1 阳性（管腔标记）和整合素α6 阳性（基底标记）细胞。高度侵袭性的 MDA-231 和耐药 MCF-7/RT 乳腺癌细胞表达高水平的 TG2 basal，与转染 TG2 的 MCF10A 干细胞有许多共同特征，但与 MCF10A 衍生的干细胞不同，它们不能在 Matrigel 培养物中形成二级结构并分化为 Muc1 阳性的管腔细胞。TG2 的下调减弱了非转化和转化的乳腺上皮细胞中的干细胞特性。总之，这些结果表明了 TG2 的新功能，并揭示了促进成年乳腺上皮细胞中干细胞特征的新机制。
