Critical Reviews in Oncogenesis最新文献

DNA polymerase beta (Pol β) is a 39 kD vertebrate polymerase that lacks proofreading ability, yet still maintains a moderate fidelity of DNA synthesis. Pol β is a key enzyme that functions in the base excision repair and non-homologous end joining pathways of DNA repair. Mechanisms of fidelity for Pol β are still being elucidated but are likely to involve dynamic conformational motions of the enzyme upon its binding to DNA and deoxynucleoside triphosphates. Recent studies have linked germline and somatic variants of Pol β with cancer and autoimmunity. These variants induce genomic instability by a number of mechanisms, including error-prone DNA synthesis and accumulation of single nucleotide gaps that lead to replication stress. Here, we review the structure and function of Pol β, and we provide insights into how structural changes in Pol β variants may contribute to genomic instability, mutagenesis, disease, cancer development, and impacts on treatment outcomes.

Ovarian cancer manifests with early metastases and has an adverse outcome, impacting the health of women globally. Currently, this malignancy is often treated with cytoreductive surgery and platinum-based chemotherapy. This treatment option has a limited success rate due to tumor recurrence and chemoresistance. Consequently, the fundamental objective of ovarian cancer treatment is the development of novel treatment approaches. As a new robust tool, the CRISPR/Cas9 gene-editing system has shown immense promise in elucidating the molecular basis of all the facets of ovarian cancer. Due to the precise gene editing capabilities of CRISPR-Cas9, researchers have been able to conduct a more comprehensive investigation of the genesis of ovarian cancer. This gained knowledge can be translated into the development of novel diagnostic approaches and newer therapeutic targets for this dreadful malignancy. There is encouraging preclinical evidence that suggests that CRISPR/Cas9 is a powerful versatile tool for selectively targeting cancer cells and inhibiting tumor growth, establishing new signaling pathways involved in carcinogenesis, and verifying biomolecules as druggable targets. In this review, we analyzed the current research and progress made using CRISPR/Cas9-based engineering strategies in the diagnosis and treatment, as well as the challenges in bringing this method to clinics. This comprehensive analysis will lay the basis for subsequent research in the future for the treatment of ovarian cancer.

Androgen deprivation therapy (ADT) that antagonizes androgen receptor (AR) signaling has made significant increases to overall survival of prostate cancer patients. However, ADT is not curative, and patients eventually progress to castration resistant disease (CRPC). It has become evident that a subset of prostate cancers acquire ADT resistance through mechanisms independent of AR alteration or reprogramming of AR signaling. This approximately involves a quarter of prostate cancers progressing on ADT. Collectively, these tumors evolve via phenotypic plasticity and display the activation of developmental and stemness gene signatures as well as transitional programs including an epithelial-mesenchymal phenotype. Currently, no successful treatments exist for prostate cancer patients to inhibit or reverse prostate tumor progression that utilizes mechanisms of epi-plasticity. This overview will discuss epigenetic mechanisms that mediate phenotypic plasticity and the potential for targeting the epigenome to create a novel direction for combination strategies involving epigenetic therapy to provide durable response.

Inflammation is a key risk factor and functional driver in the initiation and progression of prostate cancer (PCa). De-regulated cytokine and chemokine signaling facilitates critical communication between tumor cells and multiple cell lineages within the tumor microenvironment (TME). Historical attempts at using targeted approaches to disrupt inflammation have been disappointing, with sub-optimal or negligible clinical benefit. Our increased awareness of the myeloid infiltrate in supporting the acquisition of castrate resistance and underpinning the abject response of advanced PCa to immunotherapy has re-focused attention on improved strategies to disrupt these complex cytokine and chemokine signaling networks within the TME. These ongoing and prospective strategies are principally focused on employing cytokine-/chemokine-directed therapies in informed combination with androgen signaling inhibitors or immunotherapeutic agents and, increasingly, with due consideration of the genetic context of the tumor. The availability of molecular-targeted therapeutic agents directed against the critical signal transduction nodes activated by cytokine and chemokine signaling in tumor cells provides opportunities to reduce the impacts of biological redundancy. Precision-based trials that deploy this latest generation of cytokine- and chemokine-directed therapeutics, directed to enriched patient cohorts in a biologically informed and biomarker-guided manner, have the potential to diversify the armamentarium of agents that is required in order to transform long-term outcomes for a currently incurable and genetically heterogenous disease.

Embryonic stem cells (ESCs) give rise to all cell types of the organism. Given the importance of these cells in this process, ESCs must employ robust mechanisms to protect genomic integrity or risk catastrophic propagation of mutations throughout the organism. Should such an event occur in daughter cells that will eventually contribute to the germline, the overall species health could dramatically decline. This review describes several key mechanisms employed by ESCs that are unique to these cells, in order to maintain their genomic integrity. Additionally, the contributions of cell cycle regulators in modulating ESC differentiation, after DNA damage exposure, are also examined. Where data are available, findings reported in ESCs are extended to include observations described in induced pluripotent stem cells (IPSCs).

Breast cancer (BC) is the most common malignancy among women, with over one million cases occurring annually worldwide. Although therapies against estrogen receptors and HER2 have improved response rate and survival, patients with advanced disease, who are resistant to anti-hormonal therapy and/or to chemotherapy, have limited treatment options for reducing morbidity and mortality. These limitations provide major incentives for developing new, effective, and personalized therapeutic interventions. This review presents evidence on the involvement of dopamine (DA) and its type 1 receptors (D1R) in BC. DA is produced in multiple peripheral organs and is present in the systemic circulation in significant amounts. D1R is overexpressed in ~ 30% of BC cases and is associated with advanced disease and shortened patient survival. Activation of D1R, which signals via the cGMP/PKG pathway, results in apoptosis, inhibition of cell invasion, and increased chemosensitivity in multiple BC cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in mouse models with D1R-expressing BC xenografts. It is proposed that D1R should serve as a novel diagnostic/prognostic factor through the use of currently available D1R detection methods. Fenoldopam, which is FDA-approved to treat renal hypertension, could be repurposed as an effective therapeutic agent for patients with D1R-expressing tumors. Several drugs that interfere with the cGMP/PKG pathway and are approved for treating other diseases should also be considered as potential treatments for BC.

Oral cancer is a heterogeneous, aggressive, and complex entity. Current major treatment options for the disease are surgery, chemo, and/or radiotherapy either alone or in combination with each other. Each treatment method has its own limitations such as a significant journey with deformities and a protracted rehabilitation process leading to loss of self-esteem, loss of tolerance, and therapeutic side effects. Conventional therapies are frequently experienced with regimen resistance and recurrence attributed to the cancer stem cells (CSCs). Given that CSCs exert their tumorigenesis by affecting several cellular and molecular targets and pathways an improved understanding of CSCs' actions is required. Hence, more research is recommended to fully understand the fundamental mechanisms driving CSC-mediated treatment resistance. Despite the difficulties and disagreements surrounding the removal of CSCs from solid tumors, a great amount of knowledge has been derived from the characterization of CSCs. Various efforts have been made to identify the CSCs using several cell surface markers. In the current review, we will discuss numerous cell surface markers such as CD44, ALDH1, EPCAM, CD24, CD133, CD271, CD90, and Cripto-1 for identifying and isolating CSCs from primary oral squamous cell carcinoma (OSCC). Further, a spectrum of embryonic signaling pathways has been thought to be the main culprit of CSCs' active state in cancers, resulting in conventional therapeutic resistance. Hence, we discuss the functional and molecular bases of several signaling pathways such as the Wnt/beta;-catenin, Notch, Hedgehog, and Hippo pathways and their associations with disease aggressiveness. Moreover, numerous inhibitors targeting the above mentioned signaling pathways have already been identified and some of them are already undergoing clinical trials. Hence, the present review encapsulates the characterization and effectiveness of the prospective potential targeted therapies for eradicating CSCs in oral cancers.

Hepatocellular carcinoma (HC) is a malignant primary liver cancer which has poor treatment outcomes in advanced stages, and many of the HC patients present with advanced stages. The incidence of death due to HC increase as a result of ineffective treatments for advanced stage disease. Early diagnosis and management has proven benefits in both survival and quality of life. Currently very few biomarkers are available to provide diagnostic and prognostic benefits in HC patients. The present review elaborates the association of cardiac markers in HC disease. The HC disease pathology includes many cardiovascular events like hypoxia and other parameters discussed in this review which have a role in disease advancement, and also may help as diagnostic and / or prognostic markers. The scientific lacuna in association / role of cardiac markers in HC disease is also stated in this review which may be helpful for future research studies and develop cost effective biomarker for early diagnosis of HC.

Liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, can be devastating if not treated early. The risk factors of liver cancer include alcoholic liver disease, non-alcoholic fatty liver disease, disruption of melatonin levels, and dysregulated circadian rhythm. The circadian rhythm is a 24-hour biological clock that regulates the physiological activities at both central and peripheral levels. Its molecular mechanism exists in every cell in mammals. Disruption of the circadian rhythm has found in liver cancers as an independent risk factor. This review summarized the most recent findings about the molecular mechanisms of circadian rhythm, the crosstalk between core clock genes and melatonin, as well as the role of circadian rhythm and melatonin played in chronic liver diseases and liver cancer. Finally, we discussed the potential clinical application of circadian rhythm and melatonin for the treatment of liver cancer and discussed future perspectives of how understanding the circadian rhythm in liver cancer progression could provide new clinical applications for liver cancer treatment and diagnosis.