Highly aggressive tumors are characterized by a highly invasive phenotype, and they display chemoresistance. Furthermore, some of the tumors lack expression of biomarkers for target therapies. This is the case of small-cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, glioblastoma, metastatic melanoma, and advanced ovarian cancer. Unfortunately, these patients show a low survival rate and most of the available drugs are ineffective. In this context, epigenetic modifications have emerged to provide the causes and potential treatments for such types of tumors. Methylation and hydroxymethylation of DNA, and histone modifications, are the most common targets of epigenetic therapy, to influence gene expression without altering the DNA sequence. These modifications could impact both oncogenes and tumor suppressor factors, which influence several molecular pathways such as epithelial-to-mesenchymal transition, WNT/β–catenin, PI3K–mTOR, MAPK, or mismatch repair machinery. However, epigenetic changes are inducible and reversible events that could be influenced by some environmental conditions, such as UV exposure, smoking habit, or diet. Changes in DNA methylation status and/or histone modification, such as acetylation, methylation or phosphorylation, among others, are the most important targets for epigenetic cancer therapy. Therefore, the present review aims to compile the basic information of epigenetic modifications, pathways and factors, and provide a rationale for the research and treatment of highly aggressive tumors with epigenetic drugs.
In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt et al. 2015 and Bailey et al. 2016 have found specific gene signatures, which identify different molecular subtypes of pancreatic cancer and provide a comprehensive stratification for both a personalized treatment or to identify potential druggable targets. However, the routine clinical management of pancreatic cancer does not consider a broad molecular analysis of each patient, due probably to the lack of target therapies for this tumor. Therefore, the current treatment decision is taken based on patients´ clinicopathological features and performance status. Histopathological evaluation of tumor samples could reveal many other attributes not only from tumor cells but also from their microenvironment specially about the presence of pancreatic stellate cells, regulatory T cells, tumor-associated macrophages, myeloid derived suppressor cells and extracellular matrix structure. In the present article, we revise the four molecular subtypes proposed by Bailey et al. and associate each subtype with other reported molecular subtypes. Moreover, we provide for each subtype a potential description of the tumor microenvironment that may influence treatment response according to the gene expression profile, the mutational landscape and their associated histology.
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