CD98 heavy chain as a prognostic biomarker and target for cancer treatment

The SLC3A2 gene encodes for a cell-surface transmembrane protein CD98hc (4F2). CD98hc serves as a chaperone for LAT1 (SLC7A5), LAT2 (SLC7A8), y+LAT1 (SLC7A7), y+LAT2 (SLC7A6), xCT (SLC7A11) and Asc1 (SLC7A10) providing their recruitment to the plasma membrane. Together with the light subunits, it constitutes heterodimeric transmembrane amino acid transporters. CD98hc interacts with other surface molecules, such as extracellular matrix metalloproteinase inducer CD147 (EMMPRIN) and adhesion receptors integrins, and regulates glucose uptake. In this way, CD98hc connects the signaling pathways sustaining cell proliferation and migration, biosynthesis and antioxidant defense, energy production, and stem cell properties. This multifaceted role makes CD98hc one of the critical regulators of tumor growth, therapy resistance, and metastases. Indeed, the high expression levels of CD98hc were confirmed in various tumor tissues, including head and neck squamous cell carcinoma, glioblastoma, colon adenocarcinoma, pancreatic ductal adenocarcinoma, and others. A high expression of CD98hc has been linked to clinical prognosis and response to chemo- and radiotherapy in several types of cancer. In this mini-review, we discuss the physiological functions of CD98hc, its role in regulating tumor stemness, metastases, and therapy resistance, and the clinical significance of CD98hc as a tumor marker and therapeutic target

Discovery of the cancer stem cell related determinants of radioresistance

AbstractTumors are known to be heterogeneous containing a dynamic mixture of phenotypically and functionally different tumor cells. The two concepts attempting to explain the origin of intratumor heterogeneity are the cancer stem cell hypothesis and the clonal evolution model. The stochastic model argues that tumors are biologically homogenous and all cancer cells within the tumor have equal ability to propagate the tumor growth depending on continuing mutations and selective pressure. By contrast, the stem cells model suggests that cancer heterogeneity is due to the hierarchy that originates from a small population of cancer stem cells (CSCs) which are biologically distinct from the bulk tumor and possesses self-renewal, tumorigenic and multilineage potential. Although these two hypotheses have been discussed for a long time as mutually exclusive explanations of tumor heterogeneity, they are easily reconciled serving as a driving force of cancer evolution and diversity. Recent discovery of the cancer cell plasticity and heterogeneity makes the CSC population a moving target that could be hard to track and eradicate. Understanding the signaling mechanisms regulating CSCs during the course of cancer treatment can be indispensable for the optimization of current treatment strategies

Polyphenols delivery by polymeric materials: challenges in cancer treatment

Nanotechnology can offer different solutions for enhancing the therapeutic efficiency of polyphenols, a class of natural products widely explored for a potential applicability for the treatment of different diseases including cancer. While possessing interesting anticancer properties, polyphenols suffer from low stability and unfavorable pharmacokinetics, and thus suitable carriers are required when planning a therapeutic protocol. In the present review, an overview of the different strategies based on polymeric materials is presented, with the aim to highlight the strengths and the weaknesses of each approach and offer a platform of ideas for researchers working in the field

An epigenetic reprogramming strategy to re-sensitize radioresistant prostate cancer cells

Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations

CXCR4 Expression in Prostate Cancer Progenitor Cells

Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44+/CD133+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy

The Role of lncRNAs TAPIR-1 and -2 as Diagnostic Markers and Potential Therapeutic Targets in Prostate Cancer

In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa

Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release

The transcription factor Hes3 is a component of a signaling pathway that supports the growth of neural stem cells with profound consequences in neurodegenerative disease models. Here we explored whether Hes3 also regulates pancreatic islet cells. We showed that Hes3 is expressed in human and rodent pancreatic islets. In mouse islets it co-localizes with alpha and beta cell markers. We employed the mouse insulinoma cell line MIN6 to perform in vitro characterization and functional studies in conditions known to modulate Hes3 based upon our previous work using neural stem cell cultures. In these conditions, cells showed elevated Hes3 expression and nuclear localization, grew efficiently, and showed higher evoked insulin release responses, compared with serum-containing conditions. They also exhibited higher expression of the transcription factor Pdx1 and insulin. Furthermore, they were responsive to pharmacological treatments with the GLP-1 analog Exendin-4, which increased nuclear Hes3 localization. We employed a transfection approach to address specific functions of Hes3. Hes3 RNA interference opposed cell growth and affected gene expression as revealed by DNA microarrays. Western blotting and PCR approaches specifically showed that Hes3 RNA interference opposes the expression of Pdx1 and insulin. Hes3 overexpression (using a Hes3-GFP fusion construct) confirmed a role of Hes3 in regulating Pdx1 expression. Hes3 RNA interference reduced evoked insulin release. Mice lacking Hes3 exhibited increased islet damage by streptozotocin. These data suggest roles of Hes3 in pancreatic islet function

Association of Tat with Promoters of PTEN and PP2A Subunits Is Key to Transcriptional Activation of Apoptotic Pathways in HIV-Infected CD4+ T Cells

Apoptosis in HIV-1-infected CD4+ primary T cells is triggered by the alteration of the PI3K and p53 pathways, which converge on the FOXO3a transcriptional activator. Tat alone can cause activation of FOXO3a and of its proapoptotic target genes. To understand how Tat affects this pathway, we carried out ChIP-Chip experiments with Tat. Tat associates with the promoters of PTEN and two PP2A subunit genes, but not with the FOXO3a promoter. PTEN and PP2A encode phosphatases, whose levels and activity are increased when Tat is expressed. They counteract phosphorylation of Akt1 and FOXO3a, and so activate transcriptional activity of FOXO3a. FOXO3a promotes increased transcription of Egr-1, which can further stimulate the transcription of PTEN, thereby reinforcing the pathway that leads to FOXO3a transcriptional activation. RNAi experiments support the role of PTEN and PP2A in the initiation of the Tat-mediated cascade, which is critical to apoptosis. The increased accumulation of PTEN and PP2A subunit mRNAs during Tat expression is more likely to be the result of increased transcription initiation and not relief of promoter-proximal pausing of RNAPII. The Tat-PTEN and -PP2A promoter interactions provide a mechanistic explanation of Tat-mediated apoptosis in CD4+ T cells

Modulation of vascular reactivity by perivascular adipose tissue (PVAT)

Purpose of Review: In this review we discuss the role of perivascular adipose tissue (PVAT) in the modulation of vascular contractility and arterial pressure, focusing on the role of the renin-angiotensin-aldosterone system and oxidative stress/inflammation. Recent Findings: PVAT possesses an relevant endocrine-paracrine activity, which may be altered in several pathophysiological and clinical conditions. During the last two decades it has been shown PVAT may modulate vascular reactivity. It has also been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction. In particular, adipocytes secrete a number of adipokines with various functions, as well as several vasoactive factors, together with components of the renin-angiotensin system which may act at local or at systemic level. It has been shown that the anticontractile effect of PVAT is lost in obesity, probably as a consequence of the development of adipocyte hypertrophy, inflammation, and oxidative stress. Summary: Adipose tissue dysfunction is interrelated with inflammation and oxidative stress, thus contributing to endothelial dysfunction observed in several pathological and clinical conditions such as obesity and hypertension. Decreased local adiponectin level, macrophage recruitment and infiltration, and activation of renin-angiotensin-aldosterone system could play an important role in this regards

Expression of the transcription factor Hes3 in the mouse and human ocular surface, and in pterygium

Purpose: In this work we examined the presence of the neural stem cell biomarker Hairy and Enhancer of Split 3 (Hes3) in the anterior eye segment and in the aberrant growth condition of the conjunctiva pterygium. Further, we studied the response of Hes3 to irradiation. Materials and methods: Adult mouse and human corneoscleral junction and conjunctiva, as well as human pterygium were prepared for immunohistochemical detection of Hes3 and other markers. Total body irradiation was used to study the changes in the pattern of Hes3 expression. Results: The adult rodent and human eye as well as pterygium, contain a population of cells expressing Hes3. In the human eye, Hes3-expressing (Hes3+) cells are found predominantly in the subconjunctival space spanning over the limbus where they physically associate with blood vessels. The cytoarchitecture of Hes3 + cells is similar to those previously observed in the adult central nervous system. Furthermore, irradiation reduces the number of Hes3 + cells in the subconjunctival space. In contrast, irradiation strongly promotes the nuclear localization of Hes3 in the ciliary body epithelium. Conclusions: Our results suggest that a recently identified signal transduction pathway that regulates neural stem cells and glioblastoma cancer stem cells also operates in the ocular surface, ciliary body, and in pterygium