The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.
The emergence of genetic engineering at the beginning of the 1970′s opened the era of biomedical technologies, which aims to improve human health using genetic manipulation techniques in a clinical context. Gene therapy represents an innovating and appealing strategy for treatment of human diseases, which utilizes vehicles or vectors for delivering therapeutic genes into the patients' body. However, a few past unsuccessful events that negatively marked the beginning of gene therapy resulted in the need for further studies regarding the design and biology of gene therapy vectors, so that this innovating treatment approach can successfully move from bench to bedside. In this paper, we review the major gene delivery vectors and recent improvements made in their design meant to overcome the issues that commonly arise with the use of gene therapy vectors. At the end of the manuscript, we summarized the main advantages and disadvantages of common gene therapy vectors and we discuss possible future directions for potential therapeutic vectors.
Considering the high mortality rate encountered in lung cancer, there is a strong need to explore new biomarkers for early diagnosis and also improved therapeutic targets to overcome this issue. The implementation of microRNAs as important regulators in cancer and other pathologies expanded the possibilities of lung cancer management and not only. MiR-21 represents an intensively studied microRNA in many types of cancer, including non-small cell lung cancer (NSCLC). Its role as an oncogene is underlined in multiple studies reporting the upregulated expression of this sequence in patients diagnosed with this malignancy; moreover, several studies associated this increased expression of miR-21 with a worse outcome within NSCLC patients. The same pattern is supported by the data existent in the Cancer Genome Atlas (TCGA). The carcinogenic advantage generated by miR-21 in NSCLC resides in the target genes involved in multiple pathways such as cell growth and proliferation, angiogenesis, invasion and metastasis, but also chemo- and radioresistance. Therapeutic modulation of miR-21 by use of antisense sequences entrapped in different delivery systems has shown promising results in impairment of NSCLC. Hereby, we review the mechanisms of action of miR-21 in cancer and the associated changes upon tumor cells together a focused perspective on NSCLC signaling, prognosis and therapy.
Purpose Surface-enhanced Raman scattering (SERS) spectroscopy on serum and other biofluids for cancer diagnosis represents an emerging field, which has shown promising preliminary results in several types of malignancies. The purpose of this study was to demonstrate that SERS spectroscopy on serum can be employed for the differential diagnosis between five of the leading malignancies, ie, breast, colorectal, lung, ovarian and oral cancer. Patients and methods Serum samples were acquired from healthy volunteers (n=39) and from patients diagnosed with breast (n=42), colorectal (n=109), lung (n=33), oral (n=17), and ovarian cancer (n=13), comprising n=253 samples in total. SERS spectra were acquired using a 532 nm laser line as excitation source, while the SERS substrates were represented by Ag nanoparticles synthesized by reduction with hydroxylamine. The classification accuracy yielded by SERS was assessed by principal component analysis–linear discriminant analysis (PCA-LDA). Results The sensitivity and specificity in discriminating between cancer patients and controls was 98% and 91%, respectively. Cancer samples were correctly assigned to their corresponding cancer types with an accuracy of 88% for oral cancer, 86% for colorectal cancer, 80% for ovarian cancer, 76% for breast cancer and 59% for lung cancer. Conclusion SERS on serum represents a promising strategy of diagnosing cancer which can discriminate between cancer patients and controls, as well as between cancer types such as breast, colorectal, lung ovarian and oral cancer.
Breast cancer represents one of the most common forms of cancer in women worldwide, with an increase in the number of newly diagnosed patients in the last decade. The role of fatty acids, particularly of a diet rich in ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), in breast cancer development is not fully understood and remains controversial due to their complex mechanism of action. However, a large number of animal models and cell culture studies have demonstrated that high levels of ω-3 PUFAs have an inhibitory role in the development and progression of breast cancer, compared to ω-6 PUFAs. The present review focused on recent studies regarding the correlation between dietary PUFAs and breast cancer development, and aimed to emphasize the main molecular mechanisms involved in the modification of cell membrane structure and function, modulation of signal transduction pathways, gene expression regulation, and antiangiogenic and antimetastatic effects. Furthermore, the anticancer role of ω-3 PUFAs through the modulation of microRNA expression levels was also reviewed.
Over the years, nutrition and environmental factors have been demonstrated to influence human health, specifically cancer. Owing to the fact that cancer is a leading cause of death worldwide, efforts are being made to elucidate molecular mechanisms that trigger or delay carcinogenesis. Phytochemicals, in particular, have been shown to modulate oncogenic processes through their antioxidant and anti-inflammatory activities and their ability to mimic the chemical structure and activity of hormones. These compounds can act not only by influencing oncogenic proteins, but also by modulating noncoding RNAs such as microRNAs and long noncoding RNAs. Although we are only beginning to understand the complete effects of many natural compounds, such as phytochemicals, researchers are motivated to combine these agents with traditional, chemo-based, or hormone-based therapies to fight against cancer. Since ongoing studies continue to prove effective, herein we exalt the importance of improving dietary choices as a chemo-preventive strategy.
EMT represents the dominant program within advanced stages of colon cancer, where cells acquire migratory characteristics in order to invade secondary tissues and form metastasis. Where the majority of the therapeutic strategies are concentrated on the reduction of the tumor mass through different apoptotic mechanisms, the present study advocates an important role for miR-205-5p in impairment of colon cancer cells migration and restoration of the epithelial phenotype. Upon identification of a homogenous downregulated profile for miR-205-5p in colon adenocarcinoma patients, functional studies demonstrated that experimental upregulation of this sequence is able to significantly raise the levels of E-cadherin through direct inhibition of ZEB1. Moreover, the elevation in CDH1 expression was translated into functional parameters where cells lost their invasion and migratory characteristics and formed homogenous clusters through adhesion interactions. Survival analysis of colon adenocarcinoma patients revealed that low levels of miR-205-5p are associated with an unfavorable prognostic compared to those with increased expression, demonstrating the possible clinical utility of miR-205-5p replacement. Exogenous administration of miRNA mimics was not associated with significant changes in cell viability or inflammatory pathways. Therefore, the proposed strategy is aiming towards inhibition of metastasis and limitation of the tumor borders in advanced stages patients in order to prolong the survival time and to increase the efficiency of the current therapeutic strategies.
BackgroundBreast cancer is a highly heterogeneous pathology, exhibiting a number of subtypes commonly associated with a poor outcome. Due to their high stability, microRNAs are often regarded as non-invasive cancer biomarkers, having an expression pattern specific for their ‘cell of origin’.MethodTriple negative breast cancer (TNBC: ER-, PR-, Her-2-) and double positive breast cancer (DPBC: ER+, PR+, Her-2) miRNA expression patterns were obtained by analysis of the TCGA (The Cancer Genome Atlas) data, followed by PCR-array analysis on plasma samples from 20 TNBC patients, 14 DPBC patients and 11 controls.ResultsThree downregulated and nine upregulated miRNAs were obtained from the TNBC analysis. Five overexpressed miRNAs were identified in the DPBC group. Four of the dysregulated miRNAs (miR-10a, miR-125b, miR-210 and miR-489) were common for both groups. The cluster miR-17-92 (miR-17, miR-20a, miR-20b, and miR-93), along with miR-130, miR-22 and miR-29a/c, were found to differentiate between TNBC and DPBC. A panel of five transcripts (miR-10a, miR-125, miR-193b, miR-200b and miR-489) was validated in a new set of plasma samples. The overlapping of TCGA and plasma profiling data revealed miR-200b, miR-200c, miR-210 and miR-29c as common signature. MiR-200b was validated on additional normal and tumor tissue samples. The expression level of this transcript from the TCGA data was correlated with lung and bone metastatic genes.ConclusionThe miR-200b presents a great potential for the future advancements in the diagnostic/prognostic and therapeutic approach of TNBC, along with other coding or non-coding transcripts. However, this needs to be further integrated in a regulatory network that acts in conjunction with other markers that affect the patients’ prognosis or response to therapy.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0920-2) contains supplementary material, which is available to authorized users.
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