CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer

Cancer stem cells (CSCs), also known as tumor-initiating cells, are a sub-population of tumor cells found in many human cancers that are endowed with self-renewal and pluripotency. CSCs may be more resistant to conventional anticancer therapies than average cancer cells, as they can easily escape the cytotoxic effects of standard chemotherapy, thereby resulting in tumor relapse. Despite significant progress in related research, effective elimination of CSCs remains an unmet clinical need. CSCs are localized in a specialized microenvironment termed the niche, which plays a pivotal role in cancer multidrug resistance. The niche components of CSCs, such as the extracellular matrix, also physically shelter CSCs from therapeutic agents. Colorectal cancer is the most common malignancy worldwide and presents a relatively transparent process of cancer initiation and development, making it an ideal model for CSC niche research. Here, we review recent advances in the field of CSCs using colorectal cancer as an example to illustrate the potential therapeutic value of targeting the CSC niche. These findings not only provide a novel theoretical basis for in-depth discussions on tumor occurrence, development, and prognosis evaluation, but also offer new strategies for the targeted treatment of cancer.

Download Full-text

TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer

Nature Communications ◽

10.1038/s41467-021-24703-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jiahui Xu ◽

Xiaoli Yang ◽

Qiaodan Deng ◽

Cong Yang ◽

Dong Wang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Breast Tumor ◽

Breast Cancer Cells ◽

Triple Negative ◽

Vasculogenic Mimicry ◽

Regulatory Mechanisms ◽

Tumor Initiating Cells ◽

Self Renewal ◽

Tumor Endothelial Marker 8

AbstractEnhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.

Download Full-text

Neuregulin Autocrine Signaling Promotes Self-Renewal of Breast Tumor-Initiating Cells by Triggering HER2/HER3 Activation

Cancer Research ◽

10.1158/0008-5472.can-13-1055 ◽

2013 ◽

Vol 74 (1) ◽

pp. 341-352 ◽

Cited By ~ 23

Author(s):

Cleo Yi-Fang Lee ◽

Yuan Lin ◽

Scott V. Bratman ◽

Weiguo Feng ◽

Angera H. Kuo ◽

...

Keyword(s):

Breast Tumor ◽

Autocrine Signaling ◽

Tumor Initiating Cells ◽

Self Renewal

Download Full-text

Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712363115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5086-E5095 ◽

Cited By ~ 33

Author(s):

Liang Xu ◽

Ye Chen ◽

Anand Mayakonda ◽

Lynnette Koh ◽

Yuk Kien Chong ◽

...

Keyword(s):

Brain Tumor ◽

Acquired Resistance ◽

Transcriptional Network ◽

Next Generation ◽

Transcriptional Program ◽

Tumor Initiating Cells ◽

Self Renewal ◽

Brain Tumor Initiating Cells ◽

Bet Protein

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

Download Full-text

Polymethoxylated Flavones Target Cancer Stemness and Improve the Antiproliferative Effect of 5-Fluorouracil in a 3D Cell Model of Colorectal Cancer

Nutrients ◽

10.3390/nu11020326 ◽

2019 ◽

Vol 11 (2) ◽

pp. 326 ◽

Cited By ~ 6

Author(s):

Carolina Pereira ◽

Marlene Duarte ◽

Patrícia Silva ◽

Andreia Bento da Silva ◽

Catarina Duarte ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Colony Formation ◽

Cell Model ◽

Ht29 Cell ◽

Cancer Stemness ◽

Self Renewal ◽

Cell Spheroids ◽

Polymethoxylated Flavones ◽

The Impact

Polymethoxylated flavones (PMFs) from citrus fruits are reported to present anticancer potential. However, there is a lack of information regarding their effect on cancer stem cell (CSC) populations, which has been recognized as responsible for tumor initiation, relapse, and chemoresistance. In this study, we evaluated the effect of an orange peel extract (OPE) and its main PMFs, namely, nobiletin, sinensetin, tangeretin, and scutellarein tetramethylether in targeting cell proliferation and stemness using a 3D cell model of colorectal cancer composed of HT29 cell spheroids cultured for 7 days in stirred conditions. Soft agar assay, ALDH1 activity, and relative quantitative gene expression analysis of specific biomarkers were carried out to characterize the stemness, self-renewal, and mesenchymal features of HT29 cell spheroids. Then, the impact of OPE and PMFs in reducing cell proliferation and modulating cancer stemness and self-renewal was assessed. Results showed that, when compared with monolayer cultures, HT29 cell spheroids presented higher ALDH1 activity (81.97% ± 5.27% compared to 63.55% ± 17.49% for 2D), upregulation of CD44, PROM1, SOX9, and SNAI1 genes (1.83 ± 0.34, 2.54 ± 0.51, 2.03 ± 0.15, and 6.12 ± 1.59 times) and high self-renewal capability (352 ± 55 colonies compared to 253 ± 42 for 2D). Incubation with OPE (1 mg/mL) significantly inhibited cell proliferation and modulated cancer stemness and self-renewal ability: colony formation, ALDH1 activity, and the expression of cancer stemness biomarkers PROM1 and LGR5 were significantly reduced (0.66 ± 0.15 and 0.51 ± 0.14 times, respectively). Among all PMFs, tangeretin was the most efficient in targeting the CSC population by decreasing colony formation and the expression of PROM1 and LGR5. Scutellarein tetramethylether was shown to modulate markers of mesenchymal/metastatic transition (increasing CDH1 and reducing ZEB1 and SNAI1) and nobiletin was capable of downregulating PROM1 and SNAI1 expression. Importantly, all PMFs and OPE were shown to synergistically interact with 5-fluorouracil, improving the antiproliferative response of this drug.

Download Full-text