DNA Methylation as a Diagnostic, Prognostic, and Predictive Biomarker in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a term collectively used to describe all cancers that develop in the oral and nasal cavities, the paranasal sinuses, the salivary glands, the pharynx, and the larynx. The majority (75%) of all newly diagnosed cases are observed in patients with locally advanced and aggressive disease, associated with significant relapse rates (30%) and poor prognostic outcomes, despite advances in multimodal treatment. Consequently, there is an unmet need for the identification and application of tools that would enable diagnosis at the earliest possible stage, accurately predict prognostic outcomes, contribute to the timely detection of relapses, and aid in the decision for therapy selection. Recent evidence suggests that DNA methylation can alter the expression of genes in a way that it favors tumorigenesis and tumor progression in HNSCC, and therefore represents a potential source for biomarker identification. This study summarizes the current knowledge on how abnormally methylated DNA profiles in HNSCC patients may contribute to the pathogenesis of HNSCC and designate the methylation patterns that have the potential to constitute clinically valuable biomarkers for achieving significant advances in the management of the disease and for improving survival outcomes in these patients.

miRNA-Guided Regulation of Mesenchymal Stem Cells Derived from the Umbilical Cord: Paving the Way for Stem-Cell Based Regeneration and Therapy.

The human body is an abundant source of multipotent cells primed with unique properties that can be exploited in a multitude of applications and interventions. Mesenchymal stem cells (MSCs) represent a heterogenous population of undifferentiated cells programmed to self-renew and, depending on their origin, differentiate into distinct lineages. Alongside their proven ability to transmigrate toward inflammation sites, the secretion of various factors that participate in tissue regeneration and their immunoregulatory function render MSCs attractive candidates for use in the cytotherapy of a wide spectrum of diseases and conditions, as well as in different aspects of regenerative medicine. In particular, MSCs that can be found in fetal, perinatal, or neonatal tissues possess additional capabilities, including predominant proliferation potential, increased responsiveness to environmental stimuli, and hypoimmunogenicity. Since microRNA (miRNA)-guided gene regulation governs multiple cellular functions, miRNAs are increasingly being studied in the context of driving the differentiation process of MSCs. In the present review, we explore the mechanisms of miRNA-directed differentiation of MSCs, with a special focus on umbilical cord-derived mesenchymal stem cells (UCMSCs), and we identify the most relevant miRNAs and miRNA sets and signatures. Overall, we discuss the potent exploitations of miRNA-driven multi-lineage differentiation and regulation of UCMSCs in regenerative and therapeutic protocols against a range of diseases and/or injuries that will achieve a meaningful clinical impact through maximizing treatment success rates, while lacking severe adverse events.

DNA Damage Response Mechanisms in Head and Neck Cancer: Significant Implications for Therapy and Survival.

Head and neck cancer (HNC) is a term collectively used to describe a heterogeneous group of tumors that arise in the oral cavity, larynx, nasopharynx, oropharynx, and hypopharynx, and represents the sixth most common type of malignancy worldwide. Despite advances in multimodality treatment, the disease has a recurrence rate of around 50%, and the prognosis of metastatic patients remains poor. HNCs are characterized by a high degree of genomic instability, which involves a vicious circle of accumulating DNA damage, defective DNA damage repair (DDR), and replication stress. Nonetheless, the damage that is induced on tumor cells by chemo and radiotherapy relies on defective DDR processes for a successful response to treatment, and may play an important role in the development of novel and more effective therapies. This review summarizes the current knowledge on the genes and proteins that appear to be deregulated in DDR pathways, their implication in HNC pathogenesis, and the rationale behind targeting these genes and pathways for the development of new therapies. We give particular emphasis on the therapeutic targets that have shown promising results at the pre-clinical stage and on those that have so far been associated with a therapeutic advantage in the clinical setting.

The Intricate Interplay between Cancer Stem Cells and Oncogenic miRNAs in Breast Cancer Progression and Metastasis.

Complex signaling interactions between cancer cells and their microenvironments drive the clonal selection of cancer cells. Opposing forces of antitumor and tumorigenic potential regulate the survival of the fittest clones, while key genetic and epigenetic alterations in healthy cells force them to transform, overcome cell senescence, and proliferate in an uncontrolled manner. Both clinical samples and cancer cell lines provide researchers with an insight into the complex structure and hierarchy of cancer. Intratumor heterogeneity allows for multiple cancer cell subpopulations to simultaneously coexist within tumors. One category of these cancer cell subpopulations is cancer stem cells (CSCs), which possess stem-like characteristics and are not easily detectable. In the case of breast cancer, which is the most prevalent cancer type among females, such subpopulations of cells have been isolated and characterized via specific stem cell markers. These stem-like cells, known as breast cancer stem cells (BCSCs), have been linked to major events during tumorigenesis including invasion, metastasis and patient relapse following conventional therapies. Complex signaling circuitries seem to regulate the stemness and phenotypic plasticity of BCSCs along with their differentiation, evasion of immunosurveillance, invasiveness and metastatic potential. Within these complex circuitries, new key players begin to arise, with one of them being a category of small non-coding RNAs, known as miRNAs. Here, we review the importance of oncogenic miRNAs in the regulation of CSCs during breast cancer formation, promotion and metastasis, in order to highlight their anticipated usage as diagnostic and prognostic tools in the context of patient stratification and precision medicine.

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets.

Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.