scholarly journals Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2063
Author(s):  
Shreya Raghavan ◽  
Catherine S. Snyder ◽  
Anni Wang ◽  
Karen McLean ◽  
Dmitriy Zamarin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Tumor Cells ◽  
Hedgehog Signaling ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Potential ◽  
Malignant Ascites ◽  
Ovarian Cancer Stem Cells ◽  
Mesenchymal Transition ◽  
Pdgf Signaling

Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.

scholarly journals Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1058 ◽  
Author(s):  
Gener ◽  
Rafael ◽  
Seras-Franzoso ◽  
Perez ◽  
Pindado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Distant Metastases ◽  
Metastatic Potential ◽  
Phenotypic Change ◽  
Primary Tumors ◽  
Mesenchymal Transition

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of ALDH1A 1(aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.

scholarly journals Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1973
Author(s):  
Yoann Daniel ◽  
Elise Lelou ◽  
Caroline Aninat ◽  
Anne Corlu ◽  
Florian Cabillic
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Mesenchymal Transition ◽  
Energy Needs ◽  
New Strategies ◽  
Pro Inflammatory Cytokines

Tumor cells display important plasticity potential, which contributes to intratumoral heterogeneity. Notably, tumor cells have the ability to retrodifferentiate toward immature states under the influence of their microenvironment. Importantly, this phenotypical conversion is paralleled by a metabolic rewiring, and according to the metabostemness theory, metabolic reprogramming represents the first step of epithelial-to-mesenchymal transition (EMT) and acquisition of stemness features. Most cancer stem cells (CSC) adopt a glycolytic phenotype even though cells retain functional mitochondria. Such adaptation is suggested to reduce the production of reactive oxygen species (ROS), protecting CSC from detrimental effects of ROS. CSC may also rely on glutaminolysis or fatty acid metabolism to sustain their energy needs. Besides pro-inflammatory cytokines that are well-known to initiate the retrodifferentiation process, the release of catecholamines in the microenvironment of the tumor can modulate both EMT and metabolic changes in cancer cells through the activation of EMT transcription factors (ZEB1, Snail, or Slug (SNAI2)). Importantly, the acquisition of stem cell properties favors the resistance to standard care chemotherapies. Hence, a better understanding of this process could pave the way for the development of therapies targeting CSC metabolism, providing new strategies to eradicate the whole tumor mass in cancers with unmet needs.

scholarly journals Relationship between ovarian cancer stem cells, epithelial mesenchymal transition and tumour recurrence

2019 ◽  
Author(s):  
Monica Angelica Amaya Padilla ◽  
Mudra Binju ◽  
Graeme Wan ◽  
Yohan Suryo Rahmanto ◽  
Pritinder Kaur ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tumour Recurrence ◽  
Ovarian Cancer Stem Cells ◽  
Mesenchymal Transition

scholarly journals EBV latent membrane proteins promote hybrid epithelial-mesenchymal and extreme mesenchymal states of nasopharyngeal carcinoma cells for tumorigenicity

2021 ◽  
Vol 17 (8) ◽  
pp. e1009873
Author(s):  
Nannan Zhu ◽  
Xiaoting Xu ◽  
Yan Wang ◽  
Musheng Zeng ◽  
Yan Yuan
Keyword(s):  
Stem Cells ◽  
Nasopharyngeal Carcinoma ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Metastatic Potential ◽  
Carcinoma Cells ◽  
Tumor Xenograft ◽  
Additional Function ◽  
Mesenchymal Transition

EBV-encoded LMPs are consistently detected in nasopharyngeal carcinoma (NPC). Recent evidence suggests potential roles of LMP1 and LMP2A in Epithelial-to-mesenchymal transition (EMT) process in NPC. EMT engages in the generation and maintenance of cancer stem cells (CSCs) and confers on cancer cells increased tumor-initiating and metastatic potential, and higher resistance to anticancer therapies. However, how LMP1 and LMP2A regulate the EMT process to generate cells with different EMT states and its implications for tumor progression remain unclear. Here we report that LMP1 and LMP2A promote EMT that drives NPC cells from the epithelial-like state (CD104+, CD44low) to epithelial-mesenchymal hybrid (E/M) state (CD104+, CD44high). Furthermore, LMP2A possesses an additional function in stabilizing LMP1 and increasing the level of LMP1 in NPC cells. The elevated LMP1 further forces the EMT to generate extreme-mesenchymal (xM) state cells (CD104-, CD44high). To define the tumorigenic features of cancer stem cells at different states in the EMT spectrum, E, E/M and xM subpopulations were isolated and tested for tumorigenic capability in a tumor xenograft animal model. We found that the cells with E/M phenotypes possess the highest tumor initiating capacity. However, the xM subpopulation exhibits increased vasculogenic mimicry, a hallmark of metastatic cancers. Taken together, coordinated action of LMP1 and LMP2A generates an array of intermediate subpopulations in the EMT spectrum that are responsible for distinct tumorigenic features of NPC such as tumor-initiation, vasculogenesis, and metastasis.

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