Inhibitory effect of Nodal on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma of uterus.

Cancers consist of heterogeneous populations. Recently, it has been demonstrated that cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs). Aldehyde dehydrogenase 1 (ALDH1) is one of the markers of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and ALDH1-high population of endometrioid adenocarcinoma cell line was more tumorigenic, resistant to anti-cancer drugs, and invasive than ALDH1-low population. Here, the regulatory signaling for ALDH1 was examined. The inhibition of TGF-β signaling increased ALDH1-high population. Among TGF-β family members, Nodal expression and ALDH1 expression levels were mutually exclusive. Immunohistochemical analysis on clinical samples revealed Nodal-high tumor cells to be ALDH-low and vise versa, suggesting that Nodal may inhibit ALDH1 expression via stimulating TGF-β signaling in uterine endometrioid adenocarcinoma. In fact, the addition of Nodal to endometrioid adenocarcinoma cell line reduced ALDH1-high population. Although ALDH1 mRNA level was not affected, the amount of ALDH1 protein appeared to be reduce by Nodal through ubiquitine-proteasome pathway. The regulation of TGF-β signaling might be a novel therapeutic target of CICs in endometrioid adenocarcinoma.

Wang Y ，Jiang Y ，Tian T ，Hori Y ，Wada N ，Ikeda J ，Morii E ... -  《-》

Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications.

Aldehyde dehydrogenase 1 (ALDH1) is expressed in stem/progenitor cells, including cancer-initiating cells (CIC) of various organs. In the present study, ALDH1 expression was immunohistochemically examined in uterine endometrioid adenocarcinoma. The ALDH1 was expressed in a small portion of tumor cells, and these ALDH1-expressing cells were less mature than ALDH1-non-expressing cells. The ALDH1-expressing (ALDH1-hi) cells were more tumorigenic, resistant to anti-cancer agents and more invasive than ALDH1-lo cells. Culture of the sorted ALDH1-hi cells yielded both ALDH1-hi and ALDH1-lo cells, whereas ALDH1-lo cells yielded ALDH-lo cells alone. Clinically, a high-level of ALDH1 expression in tumor cells was correlated with T category, lymphatic invasion, recurrence and prognosis of patients. Patients with high ALDH1 expression showed poorer prognoses than those with low expression (P = 0.015 for disease-free survival [DFS] and P = 0.010 for overall survival [OS]), and high ALDH1 expression was an independent factor for poor prognosis. Aldehyde dehydrogenase 1 is a candidate for CIC marker for uterine endometrioid adenocarcinoma.

Rahadiani N ，Ikeda J ，Mamat S ，Matsuzaki S ，Ueda Y ，Umehara R ，Tian T ，Wang Y ，Enomoto T ，Kimura T ，Aozasa K ，Morii E ... -  《-》

Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumourigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-β.

Aldehyde dehydrogenase 1 (ALDH1) has been shown to serve as a marker for cancer-initiating cells (CICs), but little is known about the regulation of the CIC functions of ALDH1+ cancer cells. We isolated ALDH1+ cells from human diffuse-type gastric carcinoma cells and characterized these cells using an Aldefluor assay. ALDH1+ cells constituted 5-8% of the human diffuse-type gastric carcinoma cells, OCUM-2MLN and HSC-39; were more tumourigenic than ALDH1- cells; and were able to self-renew and generate heterogeneous cell populations. Using gene expression microarray analyses, we identified REG4 (regenerating islet-derived family, member 4) as one of the genes up-regulated in ALDH1+ cells, and thus as a novel marker for ALDH1+ tumour cells. Induced expression of REG4 enhanced the colony-forming ability of OCUM-2MLN cells, while knockdown of REG4 inhibited the tumourigenic potential of ALDH1+ cells. We further found that TGF-β signalling reduces the expression of ALDH1 and REG4, and the size of the ALDH1+ cell population. In human diffuse-type gastric carcinoma tissues, the expression of ALDH1 and REG4 correlated with each other, as assessed by immunohistochemistry, and ALDH1 expression correlated inversely with Smad3 phosphorylation as a measure of TGF-β signalling. These findings illustrate that, in diffuse-type gastric carcinoma, REG4 is up-regulated in ALDH1+ CICs, and that the increased tumourigenic ability of ALDH1+ cells depends on REG4. Moreover, TGF-β down-regulates ALDH1 and REG4 expression, which correlates with a reduction in CIC population size and tumourigenicity. Targeting REG4 in ALDH1+ CICs may provide a novel strategy in the treatment of diffuse-type gastric carcinoma.

Katsuno Y ，Ehata S ，Yashiro M ，Yanagihara K ，Hirakawa K ，Miyazono K ... -  《-》

Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line.

Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine.

Wang Y ，Jiang Y ，Ikeda J ，Tian T ，Sato A ，Ohtsu H ，Morii E ... -  《-》

ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis.

Kuroda T ，Hirohashi Y ，Torigoe T ，Yasuda K ，Takahashi A ，Asanuma H ，Morita R ，Mariya T ，Asano T ，Mizuuchi M ，Saito T ，Sato N ... -  《-》