Merkel Cell Polyomavirus: Oncogenesis in a Stable Genome

Merkel cell polyomavirus (MCV) is the causative agent for the majority of Merkel cell carcinoma (MCC) cases. Polyomavirus-associated MCC (MCCP) is characterized by the integration of MCV DNA into the tumor genome and a low tumor mutational burden. In contrast, nonviral MCC (MCCN) is characterized by a high tumor mutational burden induced by UV damage. Since the discovery of MCV, much work in the field has focused on understanding the molecular mechanisms of oncogenesis driven by the MCV tumor (T) antigens. Here, we review our current understanding of how the activities of large T (LT) and small T (ST) promote MCC oncogenesis in the absence of genomic instability. We highlight how both LT and ST inhibit tumor suppressors to evade growth suppression, an important cancer hallmark. We discuss ST interactions with cellular proteins, with an emphasis on those that contribute to sustaining proliferative signaling. Finally, we examine active areas of research into open questions in the field, including the origin of MCC and mechanisms of viral integration.

Returning to the Hallmarks of Cancer: A Brief Review and Revision

The hallmarks of cancer represent principals and mechanisms on which, different types of cancers function and proliferate, These principals which also include the revised edition include sustained proliferative signaling, Evading growth suppressors , avoiding immune destruction, enabling replicative immortality, tumor promoting inflammation, activating invasion and metastasis, Inducing angiogenesis, genome instability and mutation, resisting cell death, deregulating cellular energetics. This article reviews these hallmarks and suggests any additional hallmark that can be further investigated and integrated into the revised edition , Hanahan and Weinberg’s hallmark of cancer are great pillars of understanding for modern cancer study and are open to modification , making it easily approachable ,critiqued and adds the possibility of additions in the near future. The role of exosomes are discussed with the potential to categorize drug resistance as a separate hallmark to assist us in developing therapeutics that can counter or bypass these mechanisms that assist cancer cells to proliferate even further.

Hallmarks of Cancers: Primary Antibody Deficiency Versus Other Inborn Errors of Immunity

Inborn Errors of Immunity (IEI) comprise more than 450 inherited diseases, from which selected patients manifest a frequent and early incidence of malignancies, mainly lymphoma and leukemia. Primary antibody deficiency (PAD) is the most common form of IEI with the highest proportion of malignant cases. In this review, we aimed to compare the oncologic hallmarks and the molecular defects underlying PAD with other IEI entities to dissect the impact of avoiding immune destruction, genome instability, and mutation, enabling replicative immortality, tumor-promoting inflammation, resisting cell death, sustaining proliferative signaling, evading growth suppressors, deregulating cellular energetics, inducing angiogenesis, and activating invasion and metastasis in these groups of patients. Moreover, some of the most promising approaches that could be clinically tested in both PAD and IEI patients were discussed.

The biogenesis and biological function of PIWI-interacting RNA in cancer

Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24–31 nucleotides), bind to PIWI proteins, and show 2′-O-methyl modification at the 3′-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.

Up-regulation of DNA2 results in cell proliferation and migration in endometriosis

Accumulating evidence has suggests that women with advanced endometriosis exhibit alterations in the expression of genes in the endometrium compared to healthy controls. Furthermore, replication stress is a characteristic feature of cancer cells, which results from sustained proliferative signaling induced by either the activation of oncogenes or the loss of tumor suppressors. In the present study, we propose that DNA replication ATP-dependent helicase/nuclease 2 (DNA2) might be upregulated in endometriosis. Immunohistochemical staining results confirmed the hypothesis that DNA2 is overexpressed in the eutopic/ectopic endometrium compared to that in a control endometrium from a healthy donor. Subsequently, ectopic endometrium-derived endometrial mesenchymal stem cells (EMSCs) showed the highest level of DNA2 and checkpoint kinase 1 (CHK1), as well as the strongest proliferation and migration capabilities, followed by eutopic endometrium-derived EMSCs, and then control EMSCs. To further analyze the function of DNA2, we knocked-down DNA2 expression in KLE cells. As expected, proliferation and migration declined when cells were transfected with DNA2 small interfering RNA. Taken together, our study demonstrated the overexpression of DNA2 in human endometriosis, which might be responsible for the upregulated cell proliferation and migration. This study provides insights into the mechanisms underlying human endometriosis.

A Systematic Review of MicroRNAs Involved in Cervical Cancer Progression

To obtain a better understanding on the role of microRNAs in the progression of cervical cancer, a systematic review was performed to analyze cervical cancer microRNA studies. We provide an overview of the studies investigating microRNA expression in relation to cervical cancer (CC) progression, highlighting their common outcomes and target gene interactions according to the regulatory pathways. To achieve this, we systematically searched through PubMed MEDLINE, EMBASE, and Google Scholar for all articles between April 2010 and April 2020, in accordance with the PICO acronym (participants, interventions, comparisons, outcomes). From 27 published reports, totaling 1721 cases and 1361 noncancerous control tissue samples, 26 differentially expressed microRNAs (DEmiRNAs) were identified in different International Federation of Gynecology and Obstetrics (FIGO) stages of cervical cancer development. It was identified that some of the dysregulated microRNAs were associated with specific stages of cervical cancer development. The results indicated that DEmiRNAs in different stages of cervical cancer were functionally involved in several key hallmarks of cancer, such as evading growth suppressors, enabling replicative immortality, activation of invasion and metastasis, resisting cell death, and sustained proliferative signaling. These dysregulated microRNAs could play an important role in cervical cancer’s development. Some of the stage-specific microRNAs can also be used as biomarkers for cancer classification and monitoring the progression of cervical cancer.

Wnt/β-Catenin Signaling Regulates CXCR4 Expression and [68Ga] Pentixafor Internalization in Neuroendocrine Tumor Cells

Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [68Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [68Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.

ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation

The role of the amino acid transporters ASCT2 and LAT1 in cancer has been explored throughout the years. In this review, we report their impact on the hallmarks of cancer, as well as their clinical significance. Overall, both proteins have been associated with cell death resistance through dysregulation of caspases and sustainment of proliferative signaling through mTOR activation. Furthermore, ASCT2 appears to play an important role in cellular energetics regulation, whereas LAT1 expression is associated with angiogenesis and invasion and metastasis activation. The molecular impact of these proteins on the hallmarks of cancer translates into various clinical applications and both transporters have been identified as prognostic factors in many types of cancer. Concerning their role as therapeutic targets, efforts have been undertaken to synthesize competitive or irreversible ASCT2 and LAT1 inhibitors. However, JHP203, a selective inhibitor of the latter, is, to the best of our knowledge, the only compound included in a Phase 1 clinical trial. In conclusion, considering the usefulness of ASCT2 and LAT1 in a variety of cancer-related pathways and cancer therapy/diagnosis, the development and testing of novel inhibitors for these transporters that could be evaluated in clinical trials represents a promising approach to cancer prognosis improvement.

Myeloproliferative Neoplasms: Emerging Treatment Options for Myelofibrosis

Myelofibrosis (MF) is a symptom-forward disease, and its treatment focuses on alleviating those symptoms, as well as improving survival. An initial disease risk assessment is critical for deciding on a course of therapy (and a number of models can be used depending on the available patient information), and anemia can be considered a special case within the treatment algorithms for MF. JAK-STAT inhibition is currently the cornerstone of treatment for MF, but these inhibitors are not perfect. Future research will focus on the microenvironment in reversing fibrosis, immunotherapies, proliferative signaling pathways, epigenetic regulators, and stem cells.