Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations

Abstract

Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution.

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

“…Considering that T-CDS17 displayed increased aggressiveness (higher invasion and tumor formation ability) than CDS-17 cells [45], the increase in SORE6+ cells could respond to an increase of the CSC burden during tumor progression and adaptation to new microenvironments. Similar findings regarding the gain of aggressiveness upon in vivo tumor growth associated to an increase of CSC markers, such as ALDH activity or OCT4 expression, have also been described in different types of sarcoma [22,35,45,46]. These findings support that serial transplantation could represent an efficient way of enriching/selecting CSC subpopulations [18].…”

“…We found that self-renewed tumorspheres formed by these cells showed increased expression of several CSC-related genes, including SOX2. Furthermore, by comparing the tumorigenic properties of these models with those of their xenograft-derived cell lines, we found that SOX2 expression was progressively enhanced in CSC-enriched tumorspheres during sarcoma progression toward more aggressive phenotypes, hence highlighting its potential applicability as CSC marker in sarcomas [35]. To further and significantly extend these data, herein we introduced a reporter system to monitor the transcriptional activity due to SOX2 and/or OCT4 (SORE6) [29] in a model of undifferentiated pleomorphic sarcoma (UPS) and chondrosarcoma patient-derived cell lines thus analyzing for the first time the ability of isolated SOX2/OCT4-positive cells as tumor-promoting CSCs in sarcoma.…”

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

“…Next, we tested the ability of these indolocarbazole analogs to target cancer stem cell (CSC)‐enriched tumorsphere cultures of MSC‐5H‐FC and T‐5H‐FC#1 cells . Again, EC‐70124 was more efficient than midostaurin in eliminating CSCs (Supporting Information Fig.…”

“…Tumorsphere formation protocol and the analysis of the effects of drugs on tumorsphere cultures were previously described …”

Study on Functional Monoclonal Antibodies of Anti-Human Uterine Sarcoma Stem Cell-Like Cells

“…of tumor stem cells; Oct4 abnormal expression is associated with self-renewal and unrestricted proliferative function of tumor stem cells, as well as epithelial-mesenchymal transition phenotype[47][48][49][50][51] ; ALDH1 abnormal expression enhances the cytotoxic effects of tolerant drugs of stem cells and tumor stem cells, as well as other compounds, contributing to and maintaining multidrug resistance of tumor stem cells and cell anoikis resistance[52][53][54][55] . Western blot analysis showed that the supernatants of 1-2F monoclonal cells with different dilution ratios reduced the expression levels of CD44, ABCG2, Bmi1, Nanog, Oct4 and ALDH1 proteins of HUSSLCs in concentrationdependent manner (P < 0.05).…”