Hormonal Regulation of Patient-Derived Endometrial Cancer Stem-like Cells Generated by Three-Dimensional Culture

Abstract

Low-grade and early-stage endometrial cancer usually has a favorable prognosis, whereas recurrent or metastatic disease is often difficult to cure. Thus, the molecular mechanisms underlying advanced pathophysiology remain to be elucidated. From the perspective of the origin of advanced endometrial cancer, the characterization of cancer stem-like cells (CSCs) will be the first step toward the development of clinical management. We established long-term culturable patient-derived cancer cells (PDCs) from patient endometrial tumors by spheroid cell culture, which is favorable for the enrichment of CSCs. PDC-derived xenograft tumors were generated in immunodeficient NOD/Shi-scid, IL-2RγKO Jic mice. Morphologically, PDCs derived from three distinct patient samples and their xenograft tumors recapitulated the corresponding original patient tumors. Of note, CSC-related genes including ALDH1A1 were upregulated in all of these PDCs, and the therapeutic potentiality of aldehyde dehydrogenase inhibitors was demonstrated. In addition, these PDCs and their patient-derived xenograft (PDX) models exhibited distinct characteristics on the basis of their hormone responsiveness and metastatic features. Interestingly, genes associated with inflammation and tumor immunity were upregulated by 17β-estradiol in PDC lines with high estrogen receptor expression and were also overexpressed in secondary PDCs obtained from metastatic tumor models. These results suggest that PDC and PDX models from endometrial cancer specimens would be useful to elucidate CSC traits and to develop alternative diagnostic and therapeutic options for advanced disease.

Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications

“…Another target evaluated in preclinical setting was ALDH1. Inhibition of ALDH activity with disulfiram and N, N Diethylaminobenzaldehyde (DEAB) reduces proliferation of spheroids composed by CSCs [99]. On the other hand, an antibody directed against Epithelial membrane protein-2 (EMP2) (a protein involved in tumor migration and neoangiogenesis) reduces tumor formation and growth in ALDH1 + cells and indirectly downregulates ALDH1 expression although the precise mechanism of action is not clear [100].…”

“…Being known that estrogens stimulate growth of ER + CSC spheroids with upregulation of IL6, IL1B an IL18 [99], Guy and colleagues showed that MPA decrease CD133 + populations both in ER + /PgR + but also in ER − /PgR − cell lines. Moreover there was a reduction in CD133 + cells in samples of patients who responded to MPA treatment although number of samples was small (only 4 patients) and they all showed ER positivity [113].…”

“…Modulators of p53, like CP-31398 and PRIMA-1, reduce viability and growth of ALDH-expressing cells, suggesting an activity of these compounds on stemness related pathways [99].…”

Mechanisms of Apoptosis-Related Long Non-coding RNAs in Ovarian Cancer

“…Thus, lncRNA studies using ovarian tumor specimens or other ovarian cancer models are strongly demanded. Three-dimensional cultures of patient-derived cancer cells (PDCs) and cancer models established by transplanting tumor specimens into host mice (patient-derived xenograft [PDX] models) retain the properties of original tumors and have attracted attention as promising models for cancer research and drug screening ( Ishiguro et al, 2016 ; Maru and Hippo, 2019 ; Namekawa et al, 2019 ; Shiba et al, 2019 ). Further studies using PDC and PDX models would advance the application of apoptosis-related lncRNAs to ovarian cancer diagnosis, prognosis, and therapies.…”

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

“…In chemoresistant OC cell lines, DEAB treatment significantly inhibited P-glycoprotein (P-gp) protein and breast cancer resistance protein (BRCP) transcript and protein, re-sensitizing the cell lines to chemotherapy [82]. Similarly, DEAB effectively inhibited the proliferation of spheroids generated from patient-derived endometrial CSCs [104] (Table 2). However, it is also important to note that the selectivity of DEAB for different ALDH isoforms is low.…”