_:b453861450 "4"^^ . _:b453861461 "3"^^ . . _:b453861460 "3"^^ . . _:b453861463 "3"^^ . _:b453861462 "3"^^ . _:b453861457 "4"^^ . . _:b453861456 "4"^^ . _:b453861459 "3"^^ . . _:b453861458 "4"^^ . _:b453861469 "3"^^ . _:b10028516 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,4], brain [>>5<<], colon [6], and pancreas [7,8]." . _:b453861536 . _:b453861468 "3"^^ . . _:b453861471 "3"^^ . _:b10028522 "EMT is an embryonic developmental process in which epithelial cells lose expression of many markers of differentiation, acquire fibroblast-like properties and show reduced intercellular adhesion and increased motility [>>16<<-18]. EMT has been recognized not only as a physiological mechanism for development and tissue remodeling, but also as a pathological mechanism in the progression of various diseases including inflammation, fibrosis and cancer [16,17]." . _:b453861470 "3"^^ . . . _:b453861465 "3"^^ . _:b453861525 . . _:b453861464 "3"^^ . _:b453861467 "3"^^ . . _:b453861466 "3"^^ . _:b453861477 "3"^^ . . _:b453861476 "3"^^ . _:b453861479 "3"^^ . _:b453861600 . _:b453861478 "3"^^ . _:b453861918 . _:b453861473 "3"^^ . . _:b453861472 "3"^^ . _:b453861475 "3"^^ . _:b453861838 . _:b453861474 "3"^^ . _:b453861485 "3"^^ . _:b453861484 "3"^^ . . _:b10028501 . _:b453861487 "3"^^ . _:b453861486 "3"^^ . _:b453861481 "3"^^ . _:b453861480 "3"^^ . . _:b453861483 "3"^^ . . _:b453861482 "3"^^ . _:b453861493 "3"^^ . _:b453861582 . _:b453861492 "3"^^ . _:b453861812 . _:b453861495 "3"^^ . _:b453861494 "3"^^ . _:b453861521 . _:b453861489 "3"^^ . _:b453861721 . _:b453861488 "3"^^ . _:b453861491 "3"^^ . _:b453861759 . _:b453861490 "3"^^ . _:b453861507 . _:b453861651 . . _:b453861501 "3"^^ . . _:b453861500 "3"^^ . . . _:b453861503 "3"^^ . _:b453861502 "3"^^ . _:b453861497 "3"^^ . _:b453861496 "3"^^ . _:b453861499 "3"^^ . _:b453861865 . _:b453861498 "3"^^ . _:b453861378 . . _:b453861509 "3"^^ . . _:b453861508 "3"^^ . . _:b453861511 "3"^^ . . _:b453861510 "3"^^ . _:b453861655 . . _:b453861505 "3"^^ . _:b453861504 "3"^^ . _:b453861912 . _:b453861507 "3"^^ . . . _:b453861506 "3"^^ . _:b453861517 "3"^^ . _:b453861561 . _:b453861516 "3"^^ . _:b453861519 "3"^^ . . _:b453861518 "3"^^ . . _:b453861513 "3"^^ . . . _:b453861512 "3"^^ . _:b453861515 "3"^^ . _:b453861572 . _:b453861514 "3"^^ . . _:b453861743 . _:b453861701 . _:b453861525 "3"^^ . _:b10028515 . _:b453861524 "3"^^ . . . . _:b453861527 "3"^^ . _:b453861491 . _:b453861526 "3"^^ . _:b453861521 "3"^^ . _:b453861520 "3"^^ . _:b453861523 "3"^^ . _:b10028521 . _:b453861500 . _:b453861713 . _:b453861522 "3"^^ . _:b453861686 . _:b453861533 "3"^^ . . _:b453861856 . _:b453861752 . _:b453861532 "3"^^ . . . _:b453861535 "3"^^ . . _:b453861609 . _:b453861534 "3"^^ . . _:b453861529 "3"^^ . _:b453861528 "3"^^ . _:b453861531 "3"^^ . . . _:b453861530 "3"^^ . . _:b453861541 "3"^^ . _:b453861855 . _:b453861540 "3"^^ . _:b453861418 . . _:b453861543 "3"^^ . _:b453861718 . . _:b453861542 "3"^^ . . _:b453861537 "3"^^ . _:b453861536 "3"^^ . . _:b453861539 "3"^^ . _:b453861538 "3"^^ . _:b453861746 . _:b453861549 "2"^^ . _:b453861910 . . _:b453861548 "2"^^ . . _:b453861551 "2"^^ . _:b453861517 . _:b453861550 "2"^^ . _:b453861545 "3"^^ . . . _:b453861410 . _:b453861544 "3"^^ . _:b453861547 "3"^^ . _:b453861546 "3"^^ . _:b453861518 . _:b453861557 "2"^^ . _:b453861556 "2"^^ . . _:b453861529 . . _:b453861559 "2"^^ . _:b453861456 . _:b453861558 "2"^^ . _:b453861905 . _:b453861804 . _:b453861383 . _:b453861553 "2"^^ . _:b453861552 "2"^^ . _:b453861555 "2"^^ . _:b453861729 . _:b453861554 "2"^^ . . . _:b453861565 "2"^^ . _:b10028490 "Twist has been shown to activate the Akt signaling pathway by inducing the expression of Akt [>>29<<]. To examine whether the expression of Twist activates the Akt signaling, we measured the phosphorylation of Akt in cells expressing Twist and their corresponding parental cells." . _:b453861564 "2"^^ . . _:b453861567 "2"^^ . . _:b453861566 "2"^^ . _:b453861740 . _:b453861505 . _:b453861561 "2"^^ . _:b453861606 . . . . _:b453861560 "2"^^ . _:b453861760 . _:b453861563 "2"^^ . _:b453861562 "2"^^ . . _:b453861573 "2"^^ . _:b453861677 . . _:b453861572 "2"^^ . . _:b453861511 . _:b453861575 "2"^^ . _:b453861594 . _:b453861574 "2"^^ . _:b453861569 "2"^^ . _:b453861568 "2"^^ . _:b453861571 "2"^^ . _:b453861570 "2"^^ . . _:b453861581 "2"^^ . _:b453861580 "2"^^ . . . _:b453861583 "2"^^ . _:b453861582 "2"^^ . . _:b453861648 . _:b453861577 "2"^^ . _:b453861604 . . _:b453861576 "2"^^ . . _:b453861670 . _:b453861579 "2"^^ . . _:b10028530 "E-cadherin is a cell-cell adhesion molecule that participates in homotypic, calcium-dependent interactions to form epithelial adherent junctions [>>20<<,21]. Loss of E-cadherin expression is often correlated with the tumor grade and stage [20,21], because it results in the disruption of cell-cell adhesion and an increase in nuclear \u03B2-catenin, thus leading to cell growth and survival. On" . . _:b453861578 "2"^^ . _:b10028498 . _:b10028521 "Although the CSCs hypothesis suggests that tumors can arise from stem or progenitor cells, studies from many laboratories indicate that epithelial-mesenchymal transition (EMT) can endow cells with stem-cell like characteristics [>>12<<-15]. EMT is an embryonic developmental process in which epithelial cells lose expression of many markers of differentiation, acquire fibroblast-like properties and show reduced intercellular adhesion and increased motility [16-18]." . _:b453861621 . _:b453861589 "2"^^ . . . _:b453861588 "2"^^ . _:b10028529 . _:b10028508 . _:b453861591 "2"^^ . _:b453861898 . _:b453861590 "2"^^ . _:b453861514 . _:b453861585 "2"^^ . _:b453861584 "2"^^ . _:b453861587 "2"^^ . _:b453861574 . _:b453861586 "2"^^ . _:b453861597 "2"^^ . . _:b453861823 . . _:b453861596 "2"^^ . . . _:b453861599 "2"^^ . . _:b453861598 "2"^^ . _:b453861593 "2"^^ . . _:b453861592 "2"^^ . . _:b453861541 . _:b453861595 "2"^^ . _:b453861594 "2"^^ . _:b453861605 "2"^^ . _:b453861604 "2"^^ . _:b453861439 . _:b453861607 "2"^^ . _:b10028517 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,4], brain [5], colon [>>6<<], and pancreas [7,8]." . _:b453861567 . _:b453861606 "2"^^ . _:b453861722 . . _:b453861601 "2"^^ . _:b10028524 . _:b453861397 . _:b453861600 "2"^^ . _:b453861564 . _:b453861450 . _:b10028520 . _:b453861603 "2"^^ . _:b453861602 "2"^^ . _:b453861613 "2"^^ . _:b453861612 "2"^^ . _:b453861619 . _:b453861615 "2"^^ . _:b10028522 . _:b453861614 "2"^^ . . _:b453861445 . _:b453861609 "2"^^ . _:b453861495 . _:b453861404 . _:b453861608 "2"^^ . _:b10028500 . _:b453861897 . _:b10028528 . . _:b453861611 "2"^^ . _:b453861811 . _:b453861610 "2"^^ . _:b453861621 "2"^^ . . . _:b453861789 . _:b453861620 "2"^^ . _:b453861623 "2"^^ . _:b453861695 . . _:b453861622 "2"^^ . . _:b453861617 "2"^^ . . _:b453861793 . _:b453861616 "2"^^ . _:b453861619 "2"^^ . _:b10028531 . _:b453861618 "2"^^ . _:b453861629 "2"^^ . . _:b453861407 . _:b10028533 . _:b453861628 "2"^^ . . _:b453861664 . _:b453861631 "2"^^ . _:b453861630 "2"^^ . _:b453861716 . _:b453861502 . _:b453861673 . _:b453861625 "2"^^ . . _:b453861473 . _:b453861624 "2"^^ . . _:b453861627 "2"^^ . . _:b453861385 . _:b453861626 "2"^^ . _:b453861637 "2"^^ . _:b10028525 "Weinberg and his colleagues showed that induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form tumorspheres, and in the expression of stem cell-like markers [>>13<<]. Specifically, cells with CD44+CD24low phenotype, which yielded tumor formation with as few as 100 cells (compared with that the control), were found significant increased when cells were treated with transforming growth factor-beta or" . . . _:b453861636 "2"^^ . _:b453861639 "2"^^ . . _:b453861638 "2"^^ . _:b453861633 "2"^^ . _:b453861519 . _:b453861632 "2"^^ . . _:b453861635 "2"^^ . _:b453861634 "2"^^ . _:b453861462 . _:b453861645 "2"^^ . . _:b453861501 . _:b453861644 "2"^^ . _:b453861585 . _:b10028506 "The phosphorylation of these molecules by GSK-3\u03B2 results in the consequent degradation of \u03B2-catenin and Snail by E3 ligase \u03B2-Trcp [30,>>33<<]. Consistent with these findings, we discovered that Akt was activated in Twist-overexpressing cells, which lead to the phosphorylation and suppression of GSK-3\u03B2 and resulted in the significant protein stabilization of \u03B2-catenin and Snail" . _:b453861647 "2"^^ . . _:b453861474 . _:b453861656 . _:b453861646 "2"^^ . _:b453861405 . _:b453861641 "2"^^ . _:b453861640 "2"^^ . _:b453861643 "2"^^ . _:b453861642 "2"^^ . _:b453861522 . _:b453861653 "2"^^ . _:b453861652 "2"^^ . . _:b453861887 . _:b453861444 . _:b453861655 "2"^^ . . . . _:b453861654 "2"^^ . _:b453861649 "2"^^ . _:b453861923 . _:b453861648 "2"^^ . _:b453861651 "2"^^ . . _:b453861650 "2"^^ . _:b453861661 "2"^^ . _:b10028492 "methods" . _:b453861660 "2"^^ . . _:b453861663 "2"^^ . _:b453861662 "2"^^ . _:b453861725 . _:b453861657 "2"^^ . _:b453861570 . _:b453861656 "2"^^ . _:b453861659 "2"^^ . . . _:b453861658 "2"^^ . _:b453861669 "2"^^ . _:b453861703 . _:b453861668 "2"^^ . _:b453861671 "2"^^ . _:b453861467 . _:b453861634 . _:b453861670 "2"^^ . _:b453861867 . _:b453861665 "2"^^ . _:b453861664 "2"^^ . . _:b453861667 "2"^^ . . _:b453861928 . _:b453861666 "2"^^ . _:b10028496 . _:b453861920 . _:b453861677 "2"^^ . . . _:b453861676 "2"^^ . . _:b453861679 "2"^^ . _:b10028501 . _:b453861788 . _:b10028529 "A hallmark of EMT is the loss of E-cadherin expression [>>16<<-18]. E-cadherin is a cell-cell adhesion molecule that participates in homotypic, calcium-dependent interactions to form epithelial adherent junctions [20,21]." . _:b453861678 "2"^^ . _:b453861372 . . _:b453861673 "2"^^ . _:b453861422 . _:b453861672 "2"^^ . _:b453861623 . . _:b453861873 . _:b453861675 "2"^^ . . _:b10028521 . _:b453861883 . . _:b453861674 "2"^^ . _:b10028534 "On one hand, \u03B2-catenin is an essential component of adherent junctions, where it provides the link between E-cadherin and \u03B2-catenin and modulates cell-cell adhesion and cell migration [>>22<<]. On the other hand, \u03B2-catenin also functions as a transcription cofactor with T cell factor (TCF). In unstimulated cells, the level of free cytoplasmic \u03B2-catenin is kept low through a destruction complex, which consists of axin," . _:b453861685 "2"^^ . . _:b453861420 . _:b453861684 "2"^^ . _:b453861878 . _:b453861687 "2"^^ . . _:b10028525 . _:b453861738 . _:b453861686 "2"^^ . _:b453861681 "2"^^ . . _:b453861680 "2"^^ . _:b10028526 . _:b453861683 "2"^^ . . . . _:b453861682 "2"^^ . . . _:b453861693 "2"^^ . . _:b453861692 "2"^^ . _:b453861695 "2"^^ . "PMC0" . _:b453861559 . _:b453861694 "2"^^ . _:b453861689 "2"^^ . _:b453861442 . _:b453861688 "2"^^ . _:b453861691 "2"^^ . _:b453861690 "2"^^ . . _:b453861701 "2"^^ . . . _:b453861700 "2"^^ . _:b453861399 . _:b453861573 . _:b453861526 . _:b453861703 "2"^^ . _:b453861702 "2"^^ . _:b453861892 . _:b453861697 "2"^^ . _:b453861917 . . _:b453861696 "2"^^ . _:b453861830 . _:b453861662 . _:b453861699 "2"^^ . _:b453861698 "2"^^ . . _:b453861709 "2"^^ . _:b453861374 . _:b453861724 . _:b453861708 "2"^^ . _:b453861711 "2"^^ . _:b453861579 . . _:b453861710 "2"^^ . _:b453861705 "2"^^ . _:b453861704 "2"^^ . _:b453861640 . _:b453861707 "2"^^ . _:b10028509 . _:b453861706 "2"^^ . _:b453861458 . _:b453861717 "2"^^ . _:b453861716 "2"^^ . . _:b453861719 "2"^^ . _:b453861718 "2"^^ . _:b453861443 . . _:b453861713 "2"^^ . _:b453861470 . _:b453861612 . _:b453861712 "2"^^ . . . _:b453861715 "2"^^ . _:b453861697 . _:b453861756 . _:b453861714 "2"^^ . . _:b453861725 "2"^^ . _:b453861712 . _:b453861749 . _:b453861724 "2"^^ . . _:b453861727 "2"^^ . _:b453861726 "2"^^ . . _:b453861719 . _:b453861721 "2"^^ . _:b453861720 "2"^^ . . _:b453861613 . _:b453861723 "2"^^ . _:b10028486 "The CD44high/CD24low phenotype has been used to isolate stem cells from the human normal mammary epithelium [>>2<<]. It has been shown that as few as 200 of these cells generated tumors in NOD/SCID mice whereas 20,000 cells that did not display this phenotype failed to do so." . _:b453861722 "2"^^ . _:b453861733 "2"^^ . . _:b453861732 "2"^^ . _:b453861678 . _:b453861851 . _:b453861735 "2"^^ . _:b453861844 . _:b453861734 "2"^^ . _:b453861729 "2"^^ . . _:b453861728 "2"^^ . _:b453861731 "2"^^ . _:b453861730 "2"^^ . _:b453861741 "2"^^ . . _:b453861740 "2"^^ . _:b453861797 . _:b453861597 . _:b453861743 "2"^^ . _:b453861742 "2"^^ . _:b453861528 . _:b453861737 "2"^^ . _:b453861539 . _:b453861757 . _:b453861736 "2"^^ . _:b10028507 . . _:b453861739 "2"^^ . . . . _:b453861738 "2"^^ . _:b453861749 "2"^^ . _:b453861748 "2"^^ . _:b453861782 . . _:b453861751 "2"^^ . _:b453861744 . _:b453861750 "2"^^ . . _:b453861745 "2"^^ . _:b453861833 . _:b453861744 "2"^^ . _:b453861460 . . _:b453861747 "2"^^ . . _:b453861746 "2"^^ . _:b453861757 "2"^^ . _:b453861787 . _:b10028505 "The phosphorylation of these molecules by GSK-3\u03B2 results in the consequent degradation of \u03B2-catenin and Snail by E3 ligase \u03B2-Trcp [>>30<<,33]. Consistent with these findings, we discovered that Akt was activated in Twist-overexpressing cells, which lead to the phosphorylation and suppression of GSK-3\u03B2 and resulted in the significant protein stabilization of \u03B2-catenin and" . _:b453861756 "2"^^ . _:b453861759 "2"^^ . _:b10028498 "The gain-of-function of stem cell-like properties in EMT may confer tumor cells the survivability against chemo- and endocrine therapies, in addition to a distinct advantage for invasion and metastasis [13,14,>>19<<]. However, the molecular link between EMT and the gain of CSCs properties is unclear; whether a shared signaling pathway regulates both processes remains to be determined. The Wnt/\u03B2-catenin pathway mediates a wide variety of processes," . _:b453861416 . _:b453861682 . _:b453861758 "2"^^ . _:b453861481 . _:b453861753 "2"^^ . _:b453861752 "2"^^ . _:b453861627 . _:b453861755 "2"^^ . _:b453861754 "2"^^ . . _:b453861765 "2"^^ . . _:b453861764 "2"^^ . _:b10028520 . . _:b453861767 "2"^^ . . _:b453861766 "2"^^ . _:b453861702 . _:b453861761 "2"^^ . . _:b453861760 "2"^^ . _:b453861773 . _:b453861763 "2"^^ . _:b453861762 "2"^^ . . . _:b453861773 "2"^^ . . _:b453861796 . _:b453861772 "2"^^ . _:b453861658 . . _:b453861775 "2"^^ . _:b453861396 . _:b453861774 "2"^^ . _:b10028512 . . _:b453861769 "2"^^ . . _:b453861768 "2"^^ . . _:b453861899 . _:b453861771 "2"^^ . _:b453861601 . . _:b453861770 "2"^^ . _:b453861629 . _:b453861781 "2"^^ . . _:b453861780 "2"^^ . _:b453861783 "2"^^ . _:b453861782 "2"^^ . _:b453861761 . _:b453861864 . _:b453861777 "2"^^ . _:b453861776 "2"^^ . _:b453861577 . . . _:b453861513 . _:b453861779 "2"^^ . _:b453861800 . _:b453861778 "2"^^ . _:b453861789 "2"^^ . _:b453861893 . . . _:b453861788 "2"^^ . _:b453861892 . _:b453861464 . _:b453861791 "2"^^ . _:b453861895 . . _:b453861644 . _:b453861790 "2"^^ . _:b453861894 . _:b453861785 "2"^^ . _:b453861889 . _:b453861684 . _:b453861784 "2"^^ . _:b453861888 . . _:b453861787 "2"^^ . _:b453861891 . _:b453861786 "2"^^ . _:b453861890 . . _:b453861797 "2"^^ . _:b453861432 . _:b453861901 . _:b453861796 "2"^^ . _:b453861900 . _:b453861805 . . _:b453861799 "2"^^ . _:b453861903 . . _:b453861798 "2"^^ . _:b453861902 . _:b453861793 "2"^^ . _:b453861897 . _:b453861792 "2"^^ . _:b453861441 . _:b453861896 . _:b453861795 "2"^^ . _:b453861899 . . _:b453861794 "2"^^ . _:b453861898 . . _:b453861805 "2"^^ . _:b453861909 . _:b453861804 "2"^^ . _:b453861908 . _:b453861807 "2"^^ . _:b453861911 . _:b453861806 "2"^^ . _:b453861910 . _:b453861801 "2"^^ . _:b453861905 . . . _:b453861800 "2"^^ . _:b453861904 . _:b453861688 . _:b453861803 "2"^^ . _:b453861907 . . _:b453861802 "2"^^ . _:b453861906 . . _:b453861813 "2"^^ . _:b453861917 . _:b453861459 . _:b453861812 "2"^^ . _:b453861916 . _:b453861815 "2"^^ . _:b453861429 . _:b453861919 . _:b453861814 "2"^^ . . _:b453861918 . _:b453861809 "2"^^ . _:b453861913 . _:b453861808 "2"^^ . _:b453861912 . . _:b10028514 . _:b453861811 "2"^^ . _:b453861915 . _:b453861926 . _:b453861810 "2"^^ . _:b453861914 . . . _:b453861821 "2"^^ . _:b453861925 . . _:b453861820 "2"^^ . _:b453861924 . _:b10028527 "Consistent with this finding, tumor cells resistant to chemo- and endocrine therapies activate the EMT program, which results in the expansion of CSCs with CD44+CD24low expression [13,>>14<<,19]. However, it is unclear how the activation of the EMT program contributes to the expansion of CSCs with CD44+CD24low traits." . _:b453861417 . . . _:b453861823 "2"^^ . _:b453861927 . _:b453861490 . _:b453861822 "2"^^ . . _:b453861926 . . _:b453861817 "2"^^ . . . _:b453861921 . _:b453861816 "2"^^ . . _:b453861783 . _:b453861920 . . _:b453861414 . _:b453861819 "2"^^ . _:b453861923 . . _:b453861818 "2"^^ . _:b453861922 . _:b453861829 "2"^^ . _:b453861512 . _:b453861660 . _:b453861828 "2"^^ . _:b453861831 "2"^^ . . _:b453861839 . _:b453861830 "2"^^ . _:b453861825 "2"^^ . . _:b453861598 . _:b453861824 "2"^^ . _:b453861928 . . . _:b453861652 . _:b453861827 "2"^^ . . _:b453861826 "2"^^ . _:b453861837 "2"^^ . _:b453861834 . . _:b453861836 "2"^^ . _:b453861839 "2"^^ . _:b453861819 . _:b453861838 "2"^^ . . _:b453861535 . . _:b453861833 "2"^^ . _:b453861626 . _:b453861774 . _:b453861832 "2"^^ . _:b453861653 . _:b453861835 "2"^^ . _:b453861834 "2"^^ . . _:b453861845 "2"^^ . _:b453861876 . . _:b453861844 "2"^^ . _:b453861390 . . . _:b453861847 "2"^^ . _:b453861381 . _:b453861846 "2"^^ . . _:b453861841 "2"^^ . _:b453861840 "2"^^ . _:b453861588 . _:b453861720 . _:b453861835 . _:b453861843 "2"^^ . _:b453861708 . _:b453861842 . _:b453861842 "2"^^ . _:b453861853 "2"^^ . _:b453861852 "2"^^ . _:b453861690 . . _:b453861855 "2"^^ . _:b453861854 "2"^^ . _:b453861728 . _:b453861849 "2"^^ . _:b453861848 "2"^^ . _:b453861851 "2"^^ . _:b453861452 . . _:b453861850 "2"^^ . _:b453861436 . _:b453861861 "2"^^ . _:b453861705 . _:b453861860 "2"^^ . _:b453861863 "2"^^ . _:b453861862 "2"^^ . . _:b453861857 "2"^^ . . _:b453861856 "2"^^ . _:b453861859 "2"^^ . _:b453861768 . _:b453861858 "2"^^ . _:b453861869 "2"^^ . _:b453861827 . _:b453861868 "2"^^ . _:b453861871 "2"^^ . _:b453861679 . _:b453861593 . _:b453861870 "2"^^ . _:b10028490 . _:b453861865 "2"^^ . _:b453861864 "2"^^ . _:b453861867 "2"^^ . _:b453861866 "2"^^ . . . _:b453861877 "2"^^ . _:b453861799 . . _:b453861876 "2"^^ . _:b453861925 . _:b453861879 "2"^^ . _:b453861878 "2"^^ . . _:b453861549 . _:b453861873 "2"^^ . . _:b453861872 "2"^^ . _:b453861483 . _:b453861875 "2"^^ . _:b10028493 . . _:b453861434 . . _:b453861853 . _:b453861874 "2"^^ . _:b453861885 "2"^^ . . . _:b453861884 "2"^^ . . . _:b453861887 "2"^^ . _:b453861814 . _:b453861666 . _:b453861886 "2"^^ . _:b453861558 . _:b453861881 "2"^^ . _:b453861880 "2"^^ . . _:b453861883 "2"^^ . _:b453861882 "2"^^ . . . . _:b453861533 . _:b453861534 . _:b453861707 . _:b10028502 . . . . . . . . _:b10028503 "The activation of Akt phosphorylated and suppressed GSK-3\u03B2, which is the major kinase for the phosphorylation of \u03B2-catenin and Snail [>>30<<,33]. The phosphorylation of these molecules by GSK-3\u03B2 results in the consequent degradation of \u03B2-catenin and Snail by E3 ligase \u03B2-Trcp [30,33]. Consistent with these findings, we discovered that Akt was activated in Twist-overexpressing" . _:b10028527 . _:b453861497 . . . _:b10028521 . _:b453861732 . _:b453861889 . _:b453861506 . . _:b453861737 . _:b10028532 "Loss of E-cadherin expression is often correlated with the tumor grade and stage [>>20<<,21], because it results in the disruption of cell-cell adhesion and an increase in nuclear \u03B2-catenin, thus leading to cell growth and survival." . _:b453861484 . _:b453861554 . _:b10028518 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,4], brain [5], colon [6], and pancreas [>>7<<,8]. For example, breast cancer stem cells are characterized by low levels of heat stable antigen (CD24) and high levels of hyaluronan receptor (CD44) expression. This subpopulation of cells has the ability to self-renew, and to initiate" . . _:b453861569 . . _:b453861373 . _:b453861763 . _:b10028500 "Treating prostate cancer cells with stem cell-like characteristics with WNT inhibitors reduced both the size of tumorspheres and the ability of self-renewal, whereas Wnt3a stimulates them [>>32<<]. Consistent with previous reports [12-15], we found that over-expression of Twist induced EMT in Hela and MCF7 cells, which accompanied the gain-of-function of stem cell-like properties, such as high levels of ALDH1 expression," . . _:b453861372 . _:b453861375 . _:b453861482 . _:b453861818 . _:b453861374 . _:b453861373 . . _:b10028510 . _:b10028501 . . . . . . . _:b10028533 "Loss of E-cadherin expression is often correlated with the tumor grade and stage [20,>>21<<], because it results in the disruption of cell-cell adhesion and an increase in nuclear \u03B2-catenin, thus leading to cell growth and survival." . _:b10028497 . _:b453861895 . . _:b453861457 . . . . . _:b453861453 . _:b453861531 . . _:b453861711 . _:b453861571 . _:b453861562 . _:b10028509 "Cheng and her colleagues showed that the residual breast tumor cell populations that survived after conventional treatment were enriched for the subpopulation of cells with both tumor stem cell-like features and EMT characteristics [9,>>11<<]. Thus, more effective therapies will require the selective targeting of this crucial cell population." . _:b453861700 . _:b453861603 . _:b453861392 . _:b453861723 . . . _:b10028491 . _:b453861494 . _:b453861510 . . _:b10028503 . . _:b453861375 . . . . . . . "10.1186%2F1471-2407-11-49" . _:b453861778 . _:b453861877 . . _:b453861550 . _:b453861591 . _:b453861584 . _:b10028505 . _:b10028511 "background" . _:b453861694 . _:b453861479 . _:b453861548 . _:b10028488 "Over-expression of the CD44 family is an early event in the colorectal adenoma-carcinoma process, which suggests \u03B2-catenin/Tcf-4 signaling is crucial in initiating tumorigenesis [>>27<<]. Masaki et al supported this result with the immunostaining of \u03B2-catenin and CD44, suggesting that the up-regulation of CD44 through nuclear \u03B2-catenin contributed to the formation of the tumor [28]. Thus, we measured the CD44 luciferase" . _:b10028523 "EMT has been recognized not only as a physiological mechanism for development and tissue remodeling, but also as a pathological mechanism in the progression of various diseases including inflammation, fibrosis and cancer [>>16<<,17]. Weinberg and his colleagues showed that induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form tumorspheres, and in the expression of stem cell-like markers [13]. Specifically, cells" . _:b453861449 . _:b453861403 . _:b453861447 . _:b453861727 . _:b10028499 "For example, Wnt signaling is necessary for maintenance of stem cells in the intestinal crypts [>>31<<]. Treating prostate cancer cells with stem cell-like characteristics with WNT inhibitors reduced both the size of tumorspheres and the ability of self-renewal, whereas Wnt3a stimulates them [32]. Consistent with previous reports [12-15]," . _:b453861868 . _:b453861767 . . . . . . . . _:b453861704 . . . . . _:b10028497 "The gain-of-function of stem cell-like properties in EMT may confer tumor cells the survivability against chemo- and endocrine therapies, in addition to a distinct advantage for invasion and metastasis [13,>>14<<,19]. However, the molecular link between EMT and the gain of CSCs properties is unclear; whether a shared signaling pathway regulates both processes remains to be determined. The Wnt/\u03B2-catenin pathway mediates a wide variety of processes," . _:b10028528 "Consistent with this finding, tumor cells resistant to chemo- and endocrine therapies activate the EMT program, which results in the expansion of CSCs with CD44+CD24low expression [13,14,>>19<<]. However, it is unclear how the activation of the EMT program contributes to the expansion of CSCs with CD44+CD24low traits." . . . _:b453861387 . _:b453861754 . . _:b453861794 . _:b453861826 . _:b453861553 . _:b453861633 . . _:b453861563 . _:b453861475 . . _:b453861831 . _:b453861663 . _:b453861699 . . _:b453861820 . _:b453861780 . _:b453861775 . _:b453861792 . . _:b453861753 . . _:b453861689 . . _:b10028499 . . _:b453861637 . _:b453861636 . _:b453861639 . _:b453861607 . _:b453861638 . . _:b453861633 . _:b453861376 . _:b453861632 . _:b453861772 . _:b453861635 . . _:b453861634 . . _:b453861645 . _:b453861644 . _:b453861916 . _:b453861647 . _:b453861646 . _:b453861859 . _:b453861641 . _:b453861640 . _:b453861643 . . _:b453861642 . . _:b453861815 . _:b453861653 . . . _:b453861817 . _:b453861652 . _:b453861828 . _:b453861655 . _:b453861654 . _:b453861909 . _:b453861649 . _:b453861648 . . _:b453861617 . _:b453861691 . _:b453861651 . . _:b453861576 . _:b453861650 . _:b453861913 . . _:b453861661 . . _:b453861660 . _:b453861663 . . _:b453861832 . _:b453861662 . _:b453861657 . _:b10028535 "This, in turn, results in the stabilization and nuclear accumulation of \u03B2-catenin and leads to the activation of the Wnt/\u03B2-catenin signaling pathway [>>22<<], which has been implicated in stem cell maintenance and self-renewal." . . _:b453861656 . . _:b453861659 . _:b453861658 . . _:b453861423 . _:b453861669 . _:b10028508 "Cheng and her colleagues showed that the residual breast tumor cell populations that survived after conventional treatment were enriched for the subpopulation of cells with both tumor stem cell-like features and EMT characteristics [>>9<<,11]. Thus, more effective therapies will require the selective targeting of this crucial cell population." . _:b453861668 . _:b453861671 . _:b453861776 . . _:b453861670 . . . _:b453861665 . _:b453861734 . _:b453861745 . . _:b453861664 . _:b453861667 . _:b453861618 . _:b453861666 . _:b453861677 . . _:b453861765 . . . _:b453861676 . . . . _:b453861679 . _:b453861590 . _:b453861540 . _:b453861678 . _:b453861413 . . _:b453861673 . _:b453861672 . . _:b453861791 . _:b453861675 . _:b453861488 . . _:b453861674 . _:b453861685 . . _:b453861684 . _:b453861886 . _:b453861687 . _:b453861829 . _:b453861686 . _:b453861469 . _:b453861463 . _:b453861681 . _:b453861435 . . . _:b453861680 . _:b453861813 . _:b453861547 . _:b453861683 . _:b453861605 . . _:b453861682 . _:b453861802 . _:b453861693 . _:b453861692 . . _:b453861748 . _:b453861695 . . _:b453861565 . _:b453861599 . . _:b453861694 . _:b453861689 . . _:b453861688 . _:b453861691 . _:b453861690 . _:b10028535 . _:b453861448 . . . _:b453861701 . _:b10028534 . . _:b453861700 . . . _:b453861703 . _:b453861896 . . _:b453861702 . _:b453861893 "2"^^ . . _:b10028524 "EMT has been recognized not only as a physiological mechanism for development and tissue remodeling, but also as a pathological mechanism in the progression of various diseases including inflammation, fibrosis and cancer [16,>>17<<]. Weinberg and his colleagues showed that induction of EMT in immortalized human mammary epithelial cells results in an increased ability to form tumorspheres, and in the expression of stem cell-like markers [13]. Specifically, cells with" . _:b453861697 . _:b453861892 "2"^^ . _:b453861696 . _:b453861895 "2"^^ . _:b453861699 . _:b453861894 "2"^^ . _:b453861698 . _:b453861889 "2"^^ . _:b453861709 . _:b453861888 "2"^^ . _:b453861509 . _:b453861708 . _:b453861891 "2"^^ . _:b453861711 . _:b453861890 "2"^^ . _:b453861806 . . _:b453861710 . _:b453861901 "2"^^ . . . _:b453861705 . _:b453861900 "2"^^ . . _:b453861704 . _:b453861903 "2"^^ . . _:b453861707 . _:b453861902 "2"^^ . _:b453861706 . . _:b453861897 "2"^^ . _:b453861632 . . _:b453861382 . _:b453861717 . _:b453861896 "2"^^ . _:b453861671 . _:b453861790 . _:b453861716 . _:b453861899 "2"^^ . _:b453861719 . _:b453861898 "2"^^ . _:b453861852 . _:b453861718 . _:b453861909 "2"^^ . _:b453861713 . _:b453861908 "2"^^ . . _:b453861636 . _:b453861885 . _:b453861712 . _:b453861911 "2"^^ . . _:b453861394 . _:b453861461 . . _:b453861715 . _:b453861910 "2"^^ . _:b453861714 . _:b453861905 "2"^^ . _:b453861454 . _:b453861725 . _:b453861904 "2"^^ . . . . _:b453861724 . _:b453861907 "2"^^ . . _:b453861727 . _:b453861906 "2"^^ . _:b453861841 . _:b453861650 . _:b453861524 . _:b453861726 . _:b453861917 "2"^^ . _:b453861721 . _:b453861916 "2"^^ . . . _:b453861720 . _:b453861919 "2"^^ . _:b453861409 . _:b453861723 . _:b453861918 "2"^^ . _:b453861581 . _:b453861722 . _:b453861913 "2"^^ . _:b453861733 . _:b453861912 "2"^^ . _:b453861424 . _:b453861732 . _:b453861915 "2"^^ . . _:b453861446 . _:b453861735 . _:b453861914 "2"^^ . _:b453861734 . _:b453861925 "2"^^ . . _:b453861729 . _:b453861924 "2"^^ . . _:b453861728 . _:b453861927 "2"^^ . . _:b453861731 . _:b10028531 "E-cadherin is a cell-cell adhesion molecule that participates in homotypic, calcium-dependent interactions to form epithelial adherent junctions [20,>>21<<]. Loss of E-cadherin expression is often correlated with the tumor grade and stage [20,21], because it results in the disruption of cell-cell adhesion and an increase in nuclear \u03B2-catenin, thus leading to cell growth and survival. On one" . _:b453861926 "2"^^ . _:b10028514 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [>>3<<,4], brain [5], colon [6], and pancreas [7,8]." . . _:b453861730 . _:b453861921 "2"^^ . . _:b453861741 . _:b453861920 "2"^^ . _:b453861740 . _:b453861923 "2"^^ . _:b453861548 . _:b453861549 . _:b453861550 . _:b453861551 . _:b453861743 . _:b453861922 "2"^^ . _:b453861544 . _:b453861545 . . _:b453861546 . _:b453861547 . _:b453861742 . _:b453861540 . _:b453861541 . _:b453861542 . _:b453861543 . _:b453861737 . _:b453861536 . _:b453861537 . _:b453861538 . _:b453861539 . _:b453861736 . _:b453861564 . _:b10028515 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,>>4<<], brain [5], colon [6], and pancreas [7,8]." . _:b453861565 . _:b453861566 . _:b453861567 . _:b453861739 . _:b453861560 . _:b453861561 . _:b453861562 . _:b453861563 . _:b453861738 . _:b453861556 . _:b453861557 . _:b453861558 . _:b453861559 . _:b453861749 . _:b453861928 "2"^^ . _:b453861552 . _:b453861542 . . _:b453861553 . _:b453861554 . _:b453861555 . _:b453861748 . _:b453861516 . _:b453861902 . _:b453861517 . _:b453861518 . _:b453861519 . _:b453861751 . _:b453861512 . _:b453861513 . _:b453861514 . _:b453861733 . _:b453861515 . _:b453861750 . _:b453861508 . _:b453861509 . _:b453861779 . _:b453861510 . _:b453861511 . _:b453861745 . _:b453861504 . _:b453861505 . _:b453861506 . _:b453861507 . _:b453861744 . _:b453861532 . _:b453861533 . _:b453861534 . _:b453861535 . _:b453861747 . _:b453861528 . _:b453861529 . . _:b453861530 . _:b453861531 . _:b453861746 . _:b453861524 . _:b453861525 . _:b453861526 . _:b453861527 . _:b453861757 . _:b453861520 . _:b453861521 . _:b453861522 . . _:b453861523 . _:b453861756 . _:b453861612 . _:b453861613 . _:b453861614 . _:b453861615 . _:b453861759 . _:b453861608 . _:b453861609 . _:b453861610 . _:b453861611 . _:b453861758 . _:b453861604 . _:b453861605 . . _:b453861606 . _:b453861607 . _:b453861753 . _:b453861600 . _:b453861601 . _:b453861602 . _:b453861603 . _:b453861752 . _:b453861628 . _:b453861629 . _:b453861587 . _:b453861630 . _:b453861631 . _:b453861755 . _:b453861624 . _:b453861625 . . _:b453861626 . _:b453861654 . _:b453861627 . _:b453861754 . _:b10028530 . _:b453861620 . _:b453861608 . _:b453861621 . _:b453861622 . _:b453861623 . _:b453861765 . _:b453861616 . _:b453861617 . _:b453861618 . _:b453861619 . _:b453861764 . _:b453861580 . _:b453861845 . _:b453861581 . _:b453861582 . _:b453861583 . _:b453861767 . _:b453861576 . _:b453861577 . _:b453861578 . _:b453861579 . _:b453861766 . _:b453861572 . _:b453861573 . . _:b453861924 . _:b453861574 . _:b453861575 . _:b453861761 . _:b453861568 . . _:b453861569 . . _:b453861570 . _:b453861571 . _:b453861760 . _:b10028532 . _:b453861596 . _:b453861687 . _:b453861597 . . _:b453861598 . _:b453861599 . _:b453861763 . _:b453861592 . _:b453861593 . _:b453861594 . _:b453861595 . _:b453861762 . _:b453861588 . _:b453861589 . _:b453861590 . _:b453861591 . _:b453861630 . _:b453861773 . _:b453861584 . . _:b453861585 . _:b453861586 . _:b453861587 . _:b453861772 . _:b453861420 . _:b453861421 . _:b453861422 . _:b453861423 . _:b453861775 . _:b10028487 . _:b453861416 . _:b453861417 . _:b453861418 . _:b453861419 . _:b453861774 . _:b453861412 . _:b453861413 . _:b10028494 . _:b453861642 . _:b453861414 . _:b453861668 . _:b453861415 . _:b453861769 . _:b453861408 . _:b453861848 . _:b453861409 . _:b453861410 . _:b453861411 . _:b453861768 . _:b453861436 . _:b453861437 . _:b453861438 . _:b453861439 . _:b10028523 . _:b453861771 . _:b453861432 . _:b453861433 . _:b453861434 . _:b453861435 . _:b10028522 . _:b453861770 . _:b453861551 . _:b453861428 . _:b453861429 . _:b453861846 . _:b453861692 . _:b453861430 . _:b453861431 . _:b453861781 . . _:b453861424 . _:b453861425 . _:b453861426 . _:b453861427 . _:b453861780 . _:b453861388 . _:b453861389 . _:b453861393 . _:b453861390 . . _:b453861391 . _:b453861783 . _:b453861384 . _:b453861385 . _:b453861386 . _:b453861387 . _:b453861782 . _:b453861380 . _:b453861381 . _:b453861382 . _:b453861383 . _:b10028529 . . _:b453861777 . _:b453861376 . _:b453861377 . _:b453861378 . _:b453861379 . _:b453861776 . _:b453861404 . _:b453861405 . _:b453861406 . _:b453861407 . _:b453861779 . . _:b453861400 . _:b453861401 . _:b453861402 . _:b453861403 . _:b453861778 . _:b453861911 . _:b453861396 . _:b453861397 . _:b453861398 . . _:b453861399 . _:b453861789 . _:b453861392 . _:b453861393 . . _:b453861394 . _:b453861395 . _:b453861788 . _:b453861484 . _:b453861485 . _:b453861486 . _:b453861487 . _:b453861791 . _:b453861480 . _:b453861481 . _:b453861482 . _:b453861483 . _:b10028512 "It was not until 1994 that cancer stem cells (CSCs, also known as tumor-initiating cells) were first identified in human acute myeloid leukemia malignancies [>>1<<]. Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,4], brain [5], colon [6], and pancreas [7,8]. For example, breast cancer stem cells are characterized by low levels of heat stable antigen (CD24)" . _:b453861790 . _:b453861476 . _:b453861477 . _:b453861478 . _:b453861479 . _:b453861785 . _:b453861472 . _:b453861473 . _:b453861474 . _:b453861475 . _:b453861784 . _:b453861575 . _:b453861500 . _:b453861501 . _:b453861502 . _:b453861503 . _:b453861787 . _:b453861496 . _:b453861882 . _:b453861497 . _:b453861498 . _:b453861499 . _:b453861786 . _:b453861492 . _:b453861415 . _:b453861493 . _:b453861494 . _:b453861495 . _:b453861797 . _:b453861488 . _:b453861489 . _:b453861490 . _:b453861491 . _:b453861796 . _:b453861452 . _:b453861453 . . _:b453861454 . . _:b453861455 . _:b453861799 . _:b453861448 . _:b453861449 . _:b453861450 . _:b453861451 . _:b453861798 . _:b453861444 . _:b453861445 . . _:b453861446 . _:b453861447 . . _:b453861793 . _:b453861440 . _:b453861441 . _:b453861442 . _:b453861443 . _:b453861792 . _:b453861468 . _:b453861469 . _:b453861470 . _:b453861471 . _:b453861907 . _:b453861464 . . _:b453861795 . _:b453861465 . _:b453861840 . _:b453861466 . _:b453861583 . _:b453861880 . _:b453861467 . _:b453861794 . . _:b453861460 . _:b453861461 . _:b453861462 . _:b453861463 . _:b453861805 . _:b453861456 . _:b453861457 . _:b453861458 . . _:b453861459 . _:b453861804 . _:b10028519 . _:b453861804 . _:b453861805 . _:b453861806 . _:b453861807 . _:b453861807 . _:b453861800 . _:b453861801 . _:b453861802 . _:b453861803 . _:b453861806 . _:b453861796 . _:b453861797 . . _:b453861798 . _:b453861799 . _:b453861537 . _:b453861792 . _:b453861801 . _:b453861793 . _:b453861794 . . _:b453861795 . _:b453861800 . _:b453861820 . _:b453861900 . _:b453861821 . _:b453861822 . _:b453861861 . _:b453861823 . _:b453861803 . _:b453861816 . _:b453861817 . _:b453861818 . _:b453861819 . _:b453861762 . _:b453861384 . _:b453861802 . _:b453861812 . _:b453861813 . _:b453861814 . _:b453861815 . _:b453861813 . _:b453861808 . _:b453861809 . _:b453861810 . _:b453861811 . _:b453861812 . _:b453861772 . . _:b453861773 . _:b453861774 . _:b453861775 . _:b453861815 . _:b453861768 . _:b453861769 . _:b453861770 . _:b453861771 . _:b453861814 . _:b453861764 . _:b453861765 . . _:b453861766 . _:b453861767 . _:b453861809 . _:b453861760 . _:b453861761 . _:b453861762 . _:b453861763 . _:b453861808 . _:b453861788 . _:b453861789 . _:b453861790 . _:b453861791 . _:b453861811 . _:b453861784 . . _:b453861785 . _:b453861786 . _:b453861787 . _:b453861810 . _:b453861780 . _:b453861781 . . _:b453861782 . . _:b453861783 . _:b453861821 . _:b453861776 . _:b453861777 . _:b453861778 . _:b453861779 . _:b453861820 . _:b453861868 . . _:b453861869 . _:b453861870 . _:b453861871 . _:b453861823 . _:b453861864 . _:b453861865 . _:b453861866 . _:b453861867 . _:b453861822 . _:b453861860 . _:b10028485 "results" . _:b453861861 . _:b453861568 . _:b453861862 . . _:b453861863 . _:b453861817 . . _:b453861856 . . _:b453861857 . _:b453861624 . _:b453861858 . _:b453861859 . _:b453861816 . _:b453861884 . _:b10028517 . _:b453861885 . _:b453861886 . _:b453861887 . _:b453861819 . _:b453861880 . _:b453861881 . _:b453861882 . _:b453861883 . _:b453861818 . _:b453861876 . _:b453861877 . _:b453861878 . _:b453861879 . _:b453861829 . _:b453861872 . _:b453861873 . _:b453861874 . _:b453861875 . _:b453861828 . _:b453861836 . _:b453861837 . _:b453861838 . . _:b453861839 . _:b453861831 . _:b453861832 . _:b453861833 . _:b453861596 . _:b453861834 . _:b453861835 . _:b453861830 . _:b453861828 . _:b453861829 . _:b453861830 . _:b453861831 . _:b453861825 . _:b453861824 . _:b453861825 . _:b453861826 . _:b453861827 . _:b453861824 . _:b453861852 . _:b453861853 . _:b453861854 . . _:b453861855 . _:b453861827 . _:b453861848 . _:b453861849 . _:b453861850 . _:b453861389 . _:b453861851 . _:b10028513 "Subsequent studies have identified CSCs in solid tumors, including breast [>>2<<], prostate [3,4], brain [5], colon [6], and pancreas [7,8]." . _:b453861826 . _:b453861844 . _:b453861845 . . _:b453861846 . _:b453861847 . _:b453861837 . _:b453861840 . . _:b453861841 . . _:b453861842 . _:b453861843 . _:b453861836 . _:b453861676 . _:b453861677 . _:b453861678 . _:b453861679 . _:b453861839 . _:b453861672 . . _:b453861673 . _:b453861674 . _:b453861675 . _:b453861893 . _:b453861668 . _:b453861838 . _:b453861669 . _:b453861670 . . _:b453861671 . _:b453861833 . _:b453861664 . _:b453861665 . _:b453861666 . _:b453861667 . _:b453861832 . _:b453861692 . _:b453861693 . _:b453861694 . _:b453861695 . _:b453861835 . _:b453861688 . _:b453861667 . _:b453861689 . _:b453861690 . _:b453861915 . _:b453861691 . _:b453861834 . _:b453861684 . _:b453861685 . _:b453861686 . _:b453861687 . _:b453861845 . _:b453861680 . _:b453861375 "13"^^ . _:b453861425 . _:b453861681 . _:b453861682 . _:b453861683 . _:b453861844 . _:b453861644 . _:b453861374 "13"^^ . _:b453861645 . _:b453861646 . _:b453861647 . _:b453861847 . _:b453861847 . _:b453861640 . . _:b453861641 . . _:b453861642 . _:b453861643 . _:b453861846 . _:b453861636 . _:b453861637 . _:b453861638 . _:b453861639 . _:b453861841 . _:b453861632 . _:b453861633 . _:b453861373 "15"^^ . _:b453861634 . _:b453861635 . _:b453861840 . _:b453861660 . _:b453861661 . _:b453861662 . _:b453861663 . _:b453861750 . _:b453861656 . _:b453861843 . _:b453861657 . _:b453861658 . _:b453861372 "28"^^ . _:b453861659 . _:b453861842 . _:b453861652 . _:b453861653 . _:b453861654 . _:b453861655 . _:b453861853 . _:b453861648 . _:b453861649 . _:b453861650 . _:b453861651 . _:b453861852 . _:b453861740 . _:b453861741 . _:b453861742 . _:b453861743 . _:b10028520 "The cancer stem cell hypothesis has fundamental clinical implications, as current treatment strategies may affect the bulk of the tumor cells but leave CSCs behind, serving as a reservoir for disease recurrence and metastasis [>>9<<-11]. Therefore, the elucidation of molecular pathways, which regulate self-renewal activity of CSCs and their interaction with niche, will provide potential therapeutic targets." . _:b453861855 . _:b453861736 . . _:b453861737 . _:b453861738 . _:b453861739 . _:b453861854 . _:b453861611 . _:b453861732 . _:b453861733 . _:b453861734 . _:b453861615 . _:b453861735 . _:b453861431 . . _:b453861849 . _:b453861728 . _:b453861729 . _:b453861730 . _:b453861731 . _:b453861848 . _:b453861756 . _:b453861757 . _:b453861710 . _:b453861758 . _:b453861759 . _:b453861851 . _:b453861752 . _:b453861753 . _:b453861754 . _:b453861755 . _:b453861850 . _:b453861748 . _:b453861749 . _:b453861750 . _:b453861751 . _:b453861861 . _:b453861744 . _:b453861745 . . _:b453861746 . . _:b453861747 . _:b453861860 . _:b453861708 . _:b453861709 . _:b453861428 . _:b453861710 . _:b453861711 . _:b453861863 . _:b453861704 . _:b453861705 . _:b453861440 . _:b453861706 . _:b453861707 . _:b453861862 . _:b453861700 . _:b453861701 . _:b453861702 . _:b453861703 . _:b453861857 . _:b453861696 . . _:b453861697 . _:b453861698 . _:b453861699 . _:b453861856 . _:b453861724 . _:b453861725 . _:b453861726 . _:b453861727 . _:b453861859 . _:b453861720 . _:b453861721 . _:b453861722 . _:b453861723 . _:b453861858 . _:b453861716 . _:b453861884 . _:b453861717 . . _:b453861718 . _:b453861747 . _:b453861719 . _:b453861869 . _:b453861712 . _:b453861713 . _:b453861714 . _:b453861477 . _:b453861715 . _:b453861868 . . . _:b453861871 . . _:b453861870 . _:b453861865 . . _:b453861864 . . _:b453861437 . _:b453861867 . _:b453861866 . _:b453861808 . _:b453861398 . _:b453861877 . _:b453861620 . . _:b10028507 "This speculation is consistent with the fact that EMT also correlates with the presence of \u03B2-catenin in the nucleus [>>34<<]. Thus, activation of \u03B2-catenin and Akt pathways is a synergistic event at EMT and is critical for generating high-grade invasive cells with stem cell-like features (Figure 7b)." . _:b453861876 . _:b453861879 . . . . . _:b453861878 . _:b453861873 . _:b453861872 . _:b453861875 . _:b453861875 . _:b453861874 . _:b453861885 . _:b453861388 . _:b453861884 . . . _:b453861887 . _:b453861886 . . _:b453861538 . _:b453861881 . _:b453861433 . . _:b453861880 . _:b453861883 . . _:b453861882 . _:b453861381 . _:b453861380 . _:b453861602 . _:b453861383 . _:b453861665 . _:b453861382 . . . _:b453861377 . . _:b453861376 . _:b453861646 . _:b453861874 . _:b453861379 . _:b453861527 . _:b453861378 . _:b453861647 . _:b453861389 . _:b453861614 . _:b453861516 . . _:b453861388 . _:b453861739 . _:b453861391 . _:b453861928 . . _:b453861924 . _:b453861390 . _:b453861925 . _:b453861926 . _:b453861927 . _:b453861385 . _:b453861920 . _:b453861921 . _:b453861922 . . _:b453861923 . _:b453861384 . . . _:b453861387 . . _:b453861386 . . _:b10028495 _:b10028504 . _:b10028495 _:b10028505 . _:b453861397 . _:b10028495 _:b10028506 . . _:b453861471 . . _:b10028495 _:b10028507 . _:b10028495 _:b10028508 . _:b453861693 . . _:b453861742 . _:b10028495 _:b10028509 . _:b453861396 . _:b453861900 . _:b10028495 _:b10028510 . _:b453861901 . . _:b453861902 . _:b10028495 _:b10028496 . _:b10028495 _:b10028497 . _:b453861903 . _:b453861430 . _:b453861836 . _:b453861896 . _:b10028495 _:b10028498 . _:b453861399 . _:b10028495 _:b10028499 . _:b453861897 . _:b10028495 _:b10028500 . _:b453861898 . _:b10028495 _:b10028501 . _:b453861899 . _:b453861398 . _:b453861892 . _:b10028495 _:b10028502 . . _:b453861893 . _:b10028495 _:b10028503 . _:b453861735 . _:b453861894 . _:b453861895 . _:b453861393 . _:b453861888 . _:b453861889 . _:b453861890 . _:b453861891 . _:b453861392 . _:b453861916 . _:b453861917 . _:b453861918 . . _:b453861919 . _:b10028492 _:b10028493 . _:b453861395 . _:b453861912 . _:b10028492 _:b10028494 . _:b10028494 "Wnt3A-conditioned media was prepared as described by Willert et al [>>25<<]. Briefly, stable murine L-cells (ATCC, Manassas, VA) that overexpress Wnt3A were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 1% L-glutamine, and 0.4 mg/ml Geneticin." . _:b453861913 . _:b453861914 . _:b453861915 . _:b453861394 . _:b453861908 . . _:b453861909 . _:b453861910 . _:b453861911 . . _:b453861904 . _:b453861405 . _:b453861696 . _:b453861905 . _:b453861906 . _:b453861907 . _:b453861404 . . _:b453861407 . _:b453861544 . _:b453861406 . . _:b453861401 . _:b453861784 . _:b453861400 . _:b10028485 _:b10028486 . _:b10028485 _:b10028487 . _:b10028485 _:b10028488 . . _:b10028485 _:b10028489 . _:b453861403 . _:b453861557 . _:b10028485 _:b10028490 . _:b453861496 . _:b10028485 _:b10028491 . _:b453861402 . _:b453861638 . _:b453861413 . . _:b453861412 . _:b453861415 . . _:b453861414 . _:b453861798 . _:b453861409 . _:b453861408 . _:b453861411 . _:b453861566 . _:b453861410 . . _:b453861421 . . _:b453861420 . _:b10028511 _:b10028528 . _:b10028511 _:b10028529 . _:b453861423 . _:b10028511 _:b10028530 . _:b453861803 . . _:b10028511 _:b10028531 . _:b10028511 _:b10028532 . . _:b10028511 _:b10028533 . _:b453861422 . _:b10028511 _:b10028534 . _:b10028511 _:b10028535 . _:b10028511 _:b10028520 . _:b10028511 _:b10028521 . _:b453861417 . _:b10028511 _:b10028522 . _:b10028511 _:b10028523 . _:b10028511 _:b10028524 . _:b10028511 _:b10028525 . _:b453861416 . _:b10028511 _:b10028526 . _:b10028511 _:b10028527 . _:b10028511 _:b10028512 . _:b10028511 _:b10028513 . _:b453861419 . . _:b10028511 _:b10028514 . _:b10028511 _:b10028515 . _:b10028511 _:b10028516 . _:b10028511 _:b10028517 . _:b453861418 . _:b10028511 _:b10028518 . _:b10028511 _:b10028519 . . _:b453861429 . . . _:b453861428 . _:b10028487 "CD44 expression was part of a genetic program controlled by the \u03B2-catenin/Tcf-4 signaling pathway [>>26<<]. Over-expression of the CD44 family is an early event in the colorectal adenoma-carcinoma process, which suggests \u03B2-catenin/Tcf-4 signaling is crucial in initiating tumorigenesis [27]." . _:b453861401 . _:b453861431 . _:b453861430 . . _:b453861425 . . _:b453861424 . _:b453861427 . _:b453861380 . _:b453861426 . _:b453861437 . _:b453861436 . . . _:b453861439 . . . _:b453861669 . _:b453861489 . _:b453861438 . _:b453861433 . _:b453861546 . _:b453861432 . _:b453861435 . _:b453861434 . . _:b10028522 . _:b453861445 . _:b453861444 . _:b453861447 . _:b453861446 . . . _:b453861441 . _:b453861499 . _:b453861440 . . _:b453861443 . _:b453861919 . . _:b453861622 . _:b453861442 . _:b453861453 . _:b453861595 . . _:b453861452 . _:b453861455 . _:b10028529 . _:b453861454 . . _:b453861801 . _:b453861449 . _:b453861764 . _:b453861448 . _:b453861451 . _:b453861715 . _:b453861881 . _:b453861450 . _:b453861461 . . . . _:b453861460 . _:b453861463 . _:b453861462 . _:b453861457 . . _:b453861456 . . _:b453861904 . _:b453861459 . _:b453861458 . _:b453861469 . . _:b453861468 . _:b453861471 . _:b453861470 . . . _:b453861504 . _:b453861465 . _:b453861464 . _:b453861467 . _:b453861466 . _:b453861477 . . _:b453861476 . _:b453861479 . _:b453861849 . . _:b453861478 . _:b453861473 . _:b453861472 . _:b453861475 . . _:b453861474 . . _:b453861674 . _:b453861485 . _:b453861484 . _:b453861922 . _:b453861487 . _:b453861486 . _:b453861481 . _:b453861480 . _:b453861466 . . _:b453861483 . . _:b453861482 . . _:b453861493 . . _:b453861492 . . _:b453861495 . _:b453861494 . _:b453861649 . _:b453861489 . _:b453861488 . . _:b453861491 . . _:b453861490 . _:b453861706 . _:b10028504 "The activation of Akt phosphorylated and suppressed GSK-3\u03B2, which is the major kinase for the phosphorylation of \u03B2-catenin and Snail [30,>>33<<]. The phosphorylation of these molecules by GSK-3\u03B2 results in the consequent degradation of \u03B2-catenin and Snail by E3 ligase \u03B2-Trcp [30,33]. Consistent with these findings, we discovered that Akt was activated in Twist-overexpressing" . _:b453861501 . . _:b453861500 . _:b10028501 "Consistent with previous reports [>>12<<-15], we found that over-expression of Twist induced EMT in Hela and MCF7 cells, which accompanied the gain-of-function of stem cell-like properties, such as high levels of ALDH1 expression, tumorsphere-formation and high levels of CD44." . . _:b453861503 . _:b453861502 . _:b453861492 . _:b453861497 . _:b453861476 . . _:b453861496 . _:b453861785 . _:b453861499 . _:b453861498 . _:b453861509 . _:b453861508 . _:b453861511 . _:b453861510 . _:b453861726 . _:b453861505 . _:b453861504 . _:b453861507 . _:b453861736 . _:b453861506 . . _:b453861517 . _:b453861395 . . _:b10028489 "Masaki et al supported this result with the immunostaining of \u03B2-catenin and CD44, suggesting that the up-regulation of CD44 through nuclear \u03B2-catenin contributed to the formation of the tumor [>>28<<]. Thus, we measured the CD44 luciferase in Twist-overexpressing cells stimulated with Wnt3a. We found that CD44 luciferase levels were further elevated by Wnt3a (Figure 5c), indicating that the activation of the \u03B2-catenin pathway plays a" . _:b453861610 . _:b453861516 . _:b453861657 . _:b453861519 . _:b453861518 . _:b453861714 . _:b10028513 . _:b453861513 . _:b453861891 . _:b453861512 . _:b453861515 . . _:b453861514 . . _:b453861525 . _:b453861524 . _:b453861527 . _:b453861526 . _:b453861508 . . _:b453861521 . _:b453861556 . _:b453861520 . _:b453861523 . _:b453861522 . . _:b453861533 . . . _:b453861426 . _:b453861532 . _:b453861535 . _:b453861534 . _:b453861529 . _:b453861528 . _:b453861531 . _:b453861412 . _:b453861530 . _:b453861541 . . _:b453861540 . . _:b453861543 . _:b453861542 . . _:b453861625 . _:b453861537 . _:b453861850 . . _:b453861672 . _:b453861536 . _:b453861539 . . . _:b453861538 . _:b453861549 . _:b453861486 . _:b453861548 . _:b453861825 . _:b453861551 . _:b453861550 . _:b453861545 . _:b453861888 . _:b10028511 . _:b10028493 "Flow Cytometry Analysis was performed as described previously [>>23<<]. Cells were harvested by trypsinization and washed twice with PBS." . . _:b10028486 . _:b453861544 . _:b453861766 . . _:b453861515 . . _:b453861903 . _:b453861547 . . _:b453861546 . _:b10028492 . . _:b453861557 . _:b10028495 . _:b453861556 . . _:b10028485 . . _:b453861559 . . _:b453861558 . _:b453861545 . _:b453861553 . _:b10028488 . _:b453861485 . _:b453861552 . _:b453861555 . . _:b453861554 . . _:b453861565 . _:b453861564 . _:b453861681 . _:b453861567 . _:b453861566 . _:b453861561 . . _:b453861890 . _:b453861560 . _:b453861563 . _:b453861468 . _:b453861562 . _:b453861573 . _:b453861465 . _:b453861572 . . _:b10028495 "discussion" . _:b453861575 . _:b453861574 . _:b453861569 . _:b453861568 . . . _:b10028521 . . _:b453861571 . _:b453861570 . . . _:b453861581 . _:b453861580 . _:b453861709 . _:b453861583 . . _:b453861582 . _:b453861577 . _:b10028526 "Consistent with this finding, tumor cells resistant to chemo- and endocrine therapies activate the EMT program, which results in the expansion of CSCs with CD44+CD24low expression [>>13<<,14,19]. However, it is unclear how the activation of the EMT program contributes to the expansion of CSCs with CD44+CD24low traits." . _:b453861576 . _:b453861579 . _:b453861578 . _:b453861589 . _:b453861675 . _:b453861588 . _:b453861591 . _:b453861786 . _:b453861590 . . _:b453861585 . _:b453861584 . _:b453861587 . _:b453861586 . . _:b453861406 . . _:b453861597 . _:b10028510 "Gupta et al. recently implemented a chemical screen and discovered compounds showing selective toxicity for breast CSCs, including salinomycin [>>35<<]. It would be interesting to test whether Salinomycin inhibits the activation of \u03B2-catenin and Akt pathways in the near future." . _:b453861596 . . _:b453861599 . . _:b453861598 . _:b453861377 . . . _:b453861593 . . . _:b453861751 . _:b453861592 . . _:b453861595 . _:b453861594 . . _:b453861605 . _:b10028516 . . _:b453861604 . . _:b453861607 . _:b453861862 . . _:b453861676 . _:b453861606 . _:b453861601 . . _:b453861600 . _:b453861603 . . . _:b453861602 . _:b453861872 . . _:b453861613 . _:b453861612 . _:b453861637 . _:b453861615 . _:b453861927 . _:b453861614 . _:b453861609 . _:b453861520 . _:b453861608 . _:b453861503 . _:b453861837 . _:b453861611 . . _:b453861610 . _:b453861661 . . _:b453861621 . _:b453861821 . _:b453861620 . _:b453861623 . _:b453861622 . _:b453861616 . _:b453861617 . _:b453861616 . _:b453861860 . . . _:b453861619 . _:b453861618 . _:b453861629 . _:b453861769 . _:b453861478 . _:b453861628 . _:b453861631 . _:b453861908 . _:b453861630 . _:b453861625 . _:b453861717 . _:b453861624 . _:b453861631 . _:b453861627 . _:b453861626 . _:b453861857 . . . _:b10028501 . _:b10028502 "The expression of Twist also has been shown to activate the Akt pathway to promote migration, invasion and paclitaxel resistance [>>29<<]. The activation of Akt phosphorylated and suppressed GSK-3\u03B2, which is the major kinase for the phosphorylation of \u03B2-catenin and Snail [30,33]." . _:b453861810 . _:b453861906 . _:b453861451 . _:b453861641 . . . _:b453861698 . . _:b453861741 . _:b10028491 "The activation of Akt and suppression of GSK-3\u03B2 in Twist-expressing cells were quite interesting, as we showed previously that GSK-3\u03B2 is the major kinase regulating the protein stability and the cellular localization of Snail [>>30<<]. To further extend this finding, we examined the expression of Snail in these cells. We found that the level of Snail was significantly higher in Twist-overexpressing cells than that of parental cells (Figure 6b). Together, our results" . _:b453861421 . . _:b453861758 . _:b453861866 . _:b453861543 . . . _:b453861493 . _:b453861523 . . _:b453861869 . _:b453861795 . . . . . _:b453861427 . _:b453861901 . . . _:b10028496 "The gain-of-function of stem cell-like properties in EMT may confer tumor cells the survivability against chemo- and endocrine therapies, in addition to a distinct advantage for invasion and metastasis [>>13<<,14,19]. However, the molecular link between EMT and the gain of CSCs properties is unclear; whether a shared signaling pathway regulates both processes remains to be determined. The Wnt/\u03B2-catenin pathway mediates a wide variety of" . _:b453861411 . _:b453861685 . . . . _:b10028520 . _:b453861635 . _:b453861555 . . _:b453861391 . _:b453861870 . _:b453861530 . _:b453861386 . _:b453861816 . _:b453861480 . . _:b453861643 . . _:b453861777 . . . . . . . _:b453861858 . _:b453861408 . _:b453861382 "7"^^ . . . . _:b453861438 . _:b453861383 "7"^^ . _:b453861871 . . _:b453861380 "9"^^ . _:b453861580 . _:b453861381 "8"^^ . _:b453861378 "9"^^ . _:b453861379 "9"^^ . _:b453861377 "12"^^ . . _:b453861894 . _:b453861498 . _:b453861376 "12"^^ . _:b10028519 "Subsequent studies have identified CSCs in solid tumors, including breast [2], prostate [3,4], brain [5], colon [6], and pancreas [7,>>8<<]. For example, breast cancer stem cells are characterized by low levels of heat stable antigen (CD24) and high levels of hyaluronan receptor (CD44) expression. This subpopulation of cells has the ability to self-renew, and to initiate" . _:b453861628 . _:b453861390 "6"^^ . _:b453861391 "6"^^ . _:b453861388 "6"^^ . . _:b453861487 . . . _:b453861389 "6"^^ . . _:b10028485 . _:b453861386 "7"^^ . _:b453861731 . _:b10028486 . _:b453861387 "6"^^ . . . _:b453861914 . _:b10028487 . _:b453861384 "7"^^ . _:b453861385 "7"^^ . _:b453861398 "6"^^ . _:b453861399 "6"^^ . _:b453861402 . _:b453861396 "6"^^ . _:b453861552 . _:b10028492 . _:b453861397 "6"^^ . _:b10028493 . _:b453861394 "6"^^ . _:b453861809 . _:b10028494 . _:b453861395 "6"^^ . _:b453861589 . . _:b453861680 . _:b453861659 . _:b10028495 . _:b453861392 "6"^^ . _:b10028488 . _:b453861393 "6"^^ . _:b10028489 . _:b10028490 . _:b453861405 "5"^^ . _:b10028489 . . _:b453861404 "5"^^ . _:b10028491 . . _:b453861407 "5"^^ . _:b10028500 . . _:b10028501 . _:b453861406 "5"^^ . _:b10028502 . _:b453861401 "5"^^ . _:b453861771 . _:b10028503 . _:b453861921 . _:b453861400 "6"^^ . _:b453861854 . _:b10028496 . _:b453861403 "5"^^ . _:b10028497 . _:b453861402 "5"^^ . . _:b453861822 . _:b10028498 . _:b453861413 "5"^^ . _:b10028499 . _:b453861412 "5"^^ . _:b10028508 . _:b453861415 "5"^^ . . . _:b10028509 . _:b453861414 "5"^^ . _:b10028510 . _:b453861409 "5"^^ . _:b453861683 . _:b453861408 "5"^^ . _:b10028511 . _:b10028504 . _:b453861411 "5"^^ . . _:b10028505 . _:b453861410 "5"^^ . _:b453861560 . . _:b10028506 . _:b453861421 "5"^^ . . _:b453861379 . _:b10028507 . _:b453861420 "5"^^ . _:b10028516 . _:b453861423 "5"^^ . _:b10028517 . _:b453861422 "5"^^ . _:b453861417 "5"^^ . _:b10028518 . _:b453861416 "5"^^ . _:b10028519 . _:b453861592 . _:b453861419 "5"^^ . _:b10028512 . _:b453861824 . _:b10028513 . _:b453861418 "5"^^ . _:b453861419 . _:b453861429 "4"^^ . _:b10028514 . . _:b453861428 "4"^^ . _:b10028515 . _:b453861431 "4"^^ . . _:b10028524 . _:b453861430 "4"^^ . _:b10028525 . _:b453861425 "4"^^ . _:b453861843 . _:b10028526 . _:b453861424 "4"^^ . _:b10028527 . . _:b453861730 . . _:b453861427 "4"^^ . _:b453861578 . _:b10028520 . _:b453861426 "4"^^ . _:b10028518 . _:b10028521 . _:b453861532 . _:b453861437 "4"^^ . _:b10028522 . _:b453861436 "4"^^ . _:b10028523 . . _:b453861439 "4"^^ . . _:b10028532 . _:b453861781 . _:b453861438 "4"^^ . _:b10028533 . _:b453861433 "4"^^ . . _:b10028534 . _:b453861755 . _:b453861863 . _:b453861645 . _:b453861472 . _:b453861432 "4"^^ . _:b10028535 . . _:b453861435 "4"^^ . _:b453861400 . _:b10028528 . _:b453861434 "4"^^ . _:b453861807 . _:b10028529 . . . _:b453861445 "4"^^ . _:b10028530 . _:b453861444 "4"^^ . _:b10028531 . . _:b453861447 "4"^^ . . _:b453861455 . . _:b10028504 . _:b453861372 . _:b453861446 "4"^^ . _:b453861373 . _:b453861374 . _:b453861375 . _:b453861639 . _:b453861441 "4"^^ . _:b10028506 . _:b453861440 "4"^^ . . _:b453861770 . _:b453861443 "4"^^ . . . _:b453861442 "4"^^ . . _:b453861453 "4"^^ . _:b453861879 . _:b453861452 "4"^^ . _:b453861455 "4"^^ . _:b453861454 "4"^^ . . _:b453861449 "4"^^ . _:b453861448 "4"^^ . _:b453861451 "4"^^ . _:b453861586 .