Bone Marrow Mesenchymal Stem Cells (BMSCs) Restrain the Malignant Behaviors of A549 Lung Cancer Cells Under Hypoxia via miR-145

Deriving from bone marrow, the bone marrow mesenchymal stem cells (BMSCs) possess multipolar chemotaxis, proliferation potential, along with the capability to differentiate into various types of cells. Moreover, the hypoxic stimulation can effectively induce BMSCs differentiation. This study intends to explore the impediment of BMSCs on malignant behaviors of lung cancer stem cells under hypoxia. A co-culture system of BMSCs with A549 cells was established and then assigned into normoxia group, hypoxia group (50, 100, and 200 nmol/L) followed by analysis of cell viability by CCK-8 assay and miR-145 expression by qRT-PCR. In addition, A549 cells were grouped into NC group, miR-145-mimics group, and miR-145-inhibitors group followed by analysis of cell invasion and levels of miR-145 and Oct4. Hypoxia group exhibited a reduced cell viability and higher miR-145 expression (146.01±21.23%) compared to normoxia group (P < 0.05). Transfection of miR-145-mimic significantly upregulated miR-145 and decreased cell invasion (7.49±1.43%) compared with miR-145-inhibitors group or NC group (P < 0.05). Meanwhile, Oct4 level in miR-145-mimics group (0.934±2.98) was significantly decreased (P < 0.05). In conclusion, under hypoxia condition, the co-culture with BMSCs can upregulated miR-145 level, effectively reduce the viability of lung cancer stem cells and restrain proliferation capability.

Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

Cancer tissue consists of heterogenous cell types, and cancer stem cells (CSCs) are a subpopulation of the tissue which possess therapy resistance, tumor reconstruction capability, and are responsible for metastasis. Intrahepatic cholangiocarcinoma (iCCA) is one of the most common type of liver cancer that is highly aggressive with poor prognosis. Since no target therapy is efficient in improving patient outcomes, new therapeutic approaches need to be developed. CSC is thought to be a promising therapeutic target because of its resistance to therapy. Accumulating evidences suggests that there are many factors (surface marker, stemness-related genes, etc.) and mechanisms (epithelial-mesenchymal transition, mitochondria activity, etc.) which are linked to CSC-like phenotypes. Nevertheless, limited studies are reported about the application of therapy using these mechanisms, suggesting that more precise understandings are still needed. In this review, we overview the molecular mechanisms which modulate CSC-like phenotypes, and discuss the future perspective for targeting CSC in iCCA.

Unexplored functions of sex hormones in glioblastoma cancer stem cells

Biological sex impacts a wide array of molecular and cellular functions that impact organismal development and can influence disease trajectory in a variety of pathophysiological states. In non-reproductive cancers, epidemiological sex differences have been observed in a series of tumors, and recent work has identified previously unappreciated sex differences in molecular genetics and immune response. However, the extent of these sex differences in terms of drivers of tumor growth and therapeutic response is less clear. In glioblastoma, the most common primary malignant brain tumor, there is a male bias in incidence and outcome, and key genetic and epigenetic differences, as well as differences in immune response driven by immune-suppressive myeloid populations, have recently been revealed. Glioblastoma is a prototypic tumor in which cellular heterogeneity is driven by populations of therapeutically resistant cancer stem cells (CSCs) that underlie tumor growth and recurrence. There is emerging evidence that GBM CSCs may show a sex difference, with male tumor cells showing enhanced self-renewal, but how sex differences impact CSC function is not clear. In this mini-review, we focus on how sex hormones may impact CSCs in GBM and implications for other cancers with a pronounced CSC population. We also explore opportunities to leverage new models to better understand the contribution of sex hormones versus sex chromosomes to CSC function. With the rising interest in sex differences in cancer, there is an immediate need to understand the extent to which sex differences impact tumor growth, including effects on CSC function.

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression

ObjectiveIntratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.DesignWe have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC). To determine the biological significance of the most frequent communication route, we used pancreatic ductal adenocarcinoma (PDAC) orthotopic models, patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs).ResultsWe demonstrate that PDAC tumours establish an organised communication network between subpopulations of cancer cells using EVs called the EVNet). The EVNet is plastic and reshapes in response to its environment. Communication within the EVNet occurs preferentially from CSC to NSCC. Inhibition of this communication route by impairing Rab27a function in orthotopic xenographs, GEMMs and PDXs is sufficient to hamper tumour growth and phenocopies the inhibition of communication in the whole tumour. Mechanistically, we provide evidence that CSC EVs use agrin protein to promote Yes1 associated transcriptional regulator (YAP) activation via LDL receptor related protein 4 (LRP-4). Ex vivo treatment of PDXs with antiagrin significantly impairs proliferation and decreases the levels of activated YAP.Patients with high levels of agrin and low inactive YAP show worse disease-free survival. In addition, patients with a higher number of circulating agrin+ EVs show a significant increased risk of disease progression.ConclusionPDAC tumours establish a cooperation network mediated by EVs that is led by CSC and agrin, which allows tumours to adapt and thrive. Targeting agrin could make targeted therapy possible for patients with PDAC and has a significant impact on CSC that feeds the tumour and is at the centre of therapy resistance.

The efficacy of PI3Kγ and EGFR inhibitors on the suppression of the characteristics of cancer stem cells

Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future.

Exome sequencing of glioblastoma-derived cancer stem cells reveals rare clinically relevant frameshift deletion in MLLT1 gene

Background Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC). Our experiments are focused on glioblastoma–IDH-wild type, and no disease-defining alterations were present in histone, BRAF or other genes. Methods In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of (1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; (2) identifying the variants affecting the function of genes known to be involved in cancer origin and development. Results By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency. Conclusions We discovered a potentially harmful frameshift deletion at Gln461fs in the MLLT1 gene. Further investigation is required to confirm the presence of the identified mutations in patient tissue samples, as well as the significance of the frameshift mutation in the MLLT1 gene on GBM biology and response to therapy based on genomic functional experiments.