Targeting hypoxia-induced tumor stemness by activating pathogen-induced stem cell niche defense.

Tumor hypoxia and oxidative stress reprograms cancer stem cells (CSCs) to a highly aggressive and inflammatory phenotypic state of tumor stemness. Previously, we characterized tumor stemness phenotype in the ATP Binding Cassette Subfamily G Member 2 (ABCG2)-positive migratory side population (SPm) fraction of CSCs exposed to extreme hypoxia followed by reoxygenation. Here, we report that post-hypoxia/reoxygenation SPm+/ABCG2+ CSCs exerts defense against pathogen invasion that involves bystander apoptosis of non-infected CSCs. In an in vitro assay of cancer cell infection by Bacillus Calmette Guerin (BCG) or mutant Mycobacterium tuberculosis (Mtb) strain 18b (Mtb-m18b), the pathogens preferentially replicated intracellular to SPm+/ABCG2+ CSCs of seven cell lines of diverse cancer types including SCC-25 oral squamous cancer cell line. The conditioned media (CM) of infected CSCs exhibited direct anti-microbial activity against Mtb and BCG, suggesting niche defense against pathogen. Importantly, the CM of infected CSCs exhibited marked in vitro bystander apoptosis toward non-infected CSCs. Moreover, the CM-treated xenograft bearing mice showed 10- to 15-fold reduction (p < 0.001; n = 7) in the number of CSCs residing in the hypoxic niches. Our in vitro studies indicated that BCG-infected SPm+/ABCG2+ equivalent EPCAM+/ABCG2+ CSCs of SCC-25 cells underwent pyroptosis and released a high mobility group box protein 1 (HMGB1)/p53 death signal into the tumor microenvironment (TME). The death signal can induce a Toll-like receptor 2/4-mediated bystander apoptosis in non-infected CSCs by activating p53/MDM2 oscillation and subsequent activation of capase-3-dependent intrinsic apoptosis. Notably, SPm+/ABCG2+ but not SP cells undergoing bystander apoptosis amplified the death signal by further release of HMGB1/p53 complex into the TME. These results suggest that post-hypoxia SPm+/ABCG2+ CSCs serve a functional role as a tumor stemness defense (TSD) phenotype to protect TME against bacterial invasion. Importantly, the CM of TSD phenotype undergoing bystander apoptosis may have therapeutic uses against CSCs residing in the hypoxic niche.

Coronavirus Activates an Altruistic Stem Cell-Mediated Defense Mechanism that Reactivates Dormant Tuberculosis: Implications in Coronavirus Disease 2019 Pandemic.

We postulate that similar to bacteria, adult stem cells may also exhibit an altruistic defense mechanism to protect their niche against external threat. Herein, we report mesenchymal stem cell (MSC)-based altruistic defense against a mouse model of coronavirus, murine hepatitis virus-1 (MHV-1) infection of lung. MHV-1 infection led to reprogramming of CD271+ MSCs in the lung to an enhanced stemness phenotype that exhibits altruistic behavior, as per previous work in human embryonic stem cells. The reprogrammed MSCs exhibited transient expansion for 2 weeks, followed by apoptosis and expression of stemness genes. The conditioned media of the reprogrammed MSCs exhibited direct antiviral activity in an in vitro model of MHV-1-induced toxicity to type II alveolar epithelial cells by increasing their survival/proliferation and decreasing viral load. Thus, the reprogrammed MSCs can be identified as altruistic stem cells (ASCs), which exert a unique altruistic defense against MHV-1. In a mouse model of MSC-mediated Mycobacterium tuberculosis (MTB) dormancy, MHV-1 infection in the lung exhibited 20-fold lower viral loads than the MTB-free control mice on the third week of viral infection, and exhibited six-fold increase of ASCs, thereby enhancing the altruistic defense. Notably, these ASCs exhibited intracellular replication of MTB, and their extracellular release. Animals showed tuberculosis reactivation, suggesting that dormant MTB may exploit ASCs for disease reactivation.

Impact of Anti-Diabetic Medications on Quality of Life in Persons with Type 2 Diabetes Mellitus.

Introduction: Type 2 diabetes mellitus (T2DM) has been found to be associated with poor quality of life (QOL). The aim of this study was to measure QOL in T2DM patients and examine if the patients' socio demographic, diabetes-related clinical characteristics and insulin usage are associated with better quality of life. Materials and Methods: This clinic based cross-sectional study analyzed data from outpatients with T2DM attending a referral clinic between January and June 2016. Association between Diabetes Attitudes, Wishes and Needs (DAWN) QOL and few demographic, socioeconomic, clinical and biochemical predictors were examined using multivariate logistic regression model. A total of 518 patients completed the interview. Results: The HbA1c level of insulin ± oral anti-diabetic (OAD) cohort was significantly lower (7.89 ± 1.98) than the OAD cohort (8.79 ± 1.96), P < 0.001. Compared to their counterparts in the OAD cohort, patients on insulin were older with longer duration of diabetes mellitus. Co-morbid confounders like obesity, hypoglycemia, and blood pressure control or socio demographic confounders like income, education were almost similar in both the cohorts. The incidence of hypertension, coronary artery disease (CAD) and statin usage was significantly higher in the insulin cohort. The overall composite DAWN QOL scores of the insulin ± OAD cohort (25.42 ± 4.35) was marginally higher than that of the OAD cohort (23.62 ± 5.06) (P = 0.067). Analog insulin users were also found to have significantly higher composite DAWN QOL scores compared to human insulin users (25.77 ± 5.73 vs.24.13 ± 4.88, P = 0.037). Conclusions: The insulin cohort, despite being older and having longer duration of diabetes, had significantly higher diet compliance score, and enhanced QOL owing to better diabetes-related knowledge and treatment adherence characteristics than non-insulin users. Questionnaires-based evaluation of QOL can provide better understanding of the patient's experience of the illness, self-care, psychological and emotional functioning, and choice of therapeutic modality enhancing the quality of care.

MYC Regulates the HIF2α Stemness Pathway via Nanog and Sox2 to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells.

Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T-cell leukemia, MYC, maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated hypoxia-inducible factor-2α (HIF2α) in Sca-1+ cells only. Furthermore, the reprogramming factors, Nanog and Sox2, facilitated MYC regulation of HIF2α in Sca-1+ versus Sca-1- cells. Reduced expression of HIF2α inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown of p53, Nanog, or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T-cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF2α stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the HIF2α stemness pathway maintains leukemic stem cells downstream of MYC in human and mouse T-cell leukemias. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4015/F1.large.jpg.

Preclinical and Clinical Evidence of Mycobacterium tuberculosis Persistence in the Hypoxic Niche of Bone Marrow Mesenchymal Stem Cells after Therapy.

Mycobacterium tuberculosis (MTB), the causative agent of pulmonary tuberculosis, is difficult to eliminate by antibiotic therapy. We recently identified CD271(+) bone marrow-mesenchymal stem cells (BM-MSCs) as a potential site of MTB persistence after therapy. Herein, we have characterized the potential hypoxic localization of the post-therapy MTB-infected CD271(+) BM-MSCs in both mice and human subjects. We first demonstrate that in a Cornell model of MTB persistence in mice, green fluorescent protein-labeled virulent MTB-strain H37Rv was localized to pimonidazole (an in vivo hypoxia marker) positive CD271(+) BM-MSCs after 90 days of isoniazid and pyrazinamide therapy that rendered animal's lung noninfectious. The recovered CD271(+) BM-MSCs from post-therapy mice, when injected into healthy mice, caused active tuberculosis infection in the animal's lung. Moreover, MTB infection significantly increased the hypoxic phenotype of CD271(+) BM-MSCs. Next, in human subjects, previously treated for pulmonary tuberculosis, the MTB-containing CD271(+) BM-MSCs exhibited high expression of hypoxia-inducible factor 1α and low expression of CD146, a hypoxia down-regulated cell surface marker of human BM-MSCs. These data collectively demonstrate the potential localization of MTB harboring CD271(+) BM-MSCs in the hypoxic niche, a critical microenvironmental factor that is well known to induce the MTB dormancy phenotype.