During carcinogenesis, advanced tumors are surrounded by both stromal and immune cells, which support tumor development. In addition, inflammation and angiogenesis are processes that play important roles in the development of cancer, from the initiation of carcinogenesis, tumor in situ and advanced stages of cancer. During acute inflammation, vascular hyperpermeability allows inflammatory mediators and immune response cells, including leukocytes and monocytes/macrophages, to infiltrate the site of damage. As a factor that regulates vascular permeability, vascular endothelial growth factor (VEGF) also plays a vital role as a multifunctional molecule and growth factor. Furthermore, stromal and immune cells secrete soluble factors that activate endothelial cells and favor their transmigration to eliminate the aggressive agent. In this review, we present a comprehensive view of both the relationship between chronic inflammation and angiogenesis during carcinogenesis and the participation of endothelial cells in the inflammatory process. In addition, the regulatory mechanisms that contribute to the endothelium returning to its basal permeability state after acute inflammation are discussed. Moreover, the manner in which immune cells participate in pathological angiogenesis release pro-angiogenic factors that contribute to early tumor vascularization, even before the angiogenic switch occurs, is also examined. Also, we discuss the role of hypoxia as a mechanism that drives the acquisition of tumor hallmarks that make certain cancers more aggressive. Finally, some combinations of therapies that inhibit the angiogenesis process and that may be a successful strategy for cancer patients are indicated.

Epigenetic mechanisms control gene expression during normal development and their aberrant regulation may lead to human diseases including cancer. Natural phytochemicals can largely modulate mammalian epigenome through regulation of mechanisms and proteins responsible for chromatin remodeling. Phytochemicals are mainly contained in fruits, seeds, and vegetables as well as in foods supplements. These compounds act as powerful cellular antioxidants and anti-carcinogens agents. Several dietary compounds such as catechins, curcumin, genistein, quercetin and resveratrol, among others, exhibit potent anti-tumor activities through the reversion of epigenetic alterations associated to oncogenes activation and inactivation of tumor suppressor genes. In this review, we summarized the actual knowledge about the role of dietary phytochemicals in the restoration of aberrant epigenetic alterations found in cancer cells with a particular focus on DNA methylation and histone modifications. Furthermore, we discussed the mechanisms by which these natural compounds modulate gene expression at epigenetic level and described their molecular targets in diverse types of cancer. Modulation of epigenetic activities by phytochemicals will allow the discovery of novel biomarkers for cancer prevention, and highlights its potential as an alternative therapeutic approach in cancer.

Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.

Vasculogenic mimicry (VM) is a mechanism whereby cancer cells form microvascular structures similar to three-dimensional channels to provide nutrients and oxygen to tumors. Unlike angiogenesis, VM is characterized by the development of new patterned three-dimensional vascular-like structures independent of endothelial cells. This phenomenon has been observed in many types of highly aggressive solid tumors. The presence of VM has also been associated with increased resistance to chemotherapy, low survival, and poor prognosis. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level through different pathways. In recent years, these tiny RNAs have been shown to be expressed aberrantly in different human malignancies, thus contributing to the hallmarks of cancer. In this context, miRNAs and lncRNAs can be excellent biomarkers for diagnosis, prognosis, and the prediction of response to therapy. In this review, we discuss the role that the tumor microenvironment and the epithelial-mesenchymal transition have in VM. We include an overview of the mechanisms of VM with examples of diverse types of tumors. Finally, we describe the regulation networks of lncRNAs-miRNAs and their clinical impact with the VM. Knowing the key genes that regulate and promote the development of VM in tumors with invasive, aggressive, and therapy-resistant phenotypes will facilitate the discovery of novel biomarker therapeutics against cancer as well as tools in the diagnosis and prognosis of patients.

In tumor cells the effectiveness of anti-neoplastic agents that cause cell death by induction of DNA damage is influenced by DNA repair activity. RAD50 protein plays key roles in DNA double strand breaks repair (DSBs), which is crucial to safeguard genome integrity and sustain tumor suppression. However, its role as a potential therapeutic target has not been addressed in breast cancer. Our aim in the present study was to analyze the expression of RAD50 protein in breast tumors, and evaluate the effects of RAD50-targeted inhibition on the cytotoxicity exerted by cisplatin and anthracycline and taxane-based therapies in breast cancer cells. Immunohistochemistry assays on tissue microarrays indicate that the strong staining intensity of RAD50 was reduced in 14% of breast carcinomas in comparison with normal tissues. Remarkably, RAD50 silencing by RNA interference significantly enhanced the cytotoxicity of cisplatin. Combinations of cisplatin with doxorubicin and paclitaxel drugs induced synergistic effects in early cell death of RAD50-deficient MCF-7, SKBR3, and T47D breast cancer cells. Furthermore, we found an increase in the number of DSBs, and delayed phosphorylation of histone H2AX after cisplatin treatment in RAD50-silenced cells. These cellular events were associated to a dramatical increase in the frequency of chromosomal aberrations and a decrease of cell number in metaphase. In conclusion, our data showed that RAD50 abrogation impairs DNA damage response and sensitizes breast cancer cells to cisplatin-combined therapies. We propose that the development and use of inhibitors to manipulate RAD50 levels might represent a promising strategy to sensitize breast cancer cells to DNA damaging agents.

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Cancer patients who better benefit from neoadjuvant chemotherapy (NeoCh) are those who achieve a successful pathological complete response (pCR) represented by the absence of residual disease. Unfortunately, no highly sensitive and specific tumor biomarkers for predicting the clinical response to NeoCh have yet been defined. The aim of the present study was to ascertain whether miR-145-5p could discriminate between pCR and no-pCR in triple-negative breast cancer patients that received a cisplatin/doxorubicin-based neoadjuvant treatment. miR-145-5p expression was determined in breast tumors by quantitative RT-PCR. Our data showed that miR-145-5p had a significant low expression (P<0.005) in patients that achieved pCR in comparison to the non-responder group. Kaplan Meier analysis indicated that low levels of miR-145-5p were associated with increased disease-free survival. In addition, receiver operating characteristic (ROC) curve analysis suggested that miR-145-5p is a good predictor of pCR (P<0.003, AUC= 0.7899, 95% CI, 0.6382-0.9416). Quantitative RT-PCR expression analysis also revealed that miR-145-5p was downregulated in four breast cancer cell lines relative to normal cells. To study the functions of miR-145-5p, its expression was restored in triple-negative MDA-MB-231 cells and its effects in cell proliferation were evaluated by MTT assays and in apoptosis using Annexin V experiments. Data revealed that ectopic expression of miR-145-5p resulted in a significant inhibition of cell proliferation and also induced apoptosis. Moreover, miR-145-5p led to sensitization of breast cancer cells to cisplatin therapy. In addition, western blot assays indicated that miR-145-5p downregulated the TGFβR2 protein. In conclusion, miR-145-5p could be a potential biomarker of clinical response to NeoCh in triple-negative breast cancer. Functionally miR-145-5p may regulate cell proliferation, at least in part, by targeting TGFβR2.

Our data suggest for the first time that abrogation of HDGF by EGCG enhances cisplatin-induced apoptosis and sensitize A549 cells to chemotherapy. Therefore, we propose that decreasing the HDGF levels by using EGCG may represent a novel strategy in lung cancer therapy.