Vasculogenic mimicry (VM) is the formation of vascular channels lacking endothelial cells. These channels are lined by tumor cells with cancer stem cell features, positive for periodic acid-Schiff, and negative for CD31 staining. The term VM was introduced by Maniotis et al. (1), who reported this phenomenon in highly aggressive uveal melanomas; since then, VM has been associated with poor prognosis, tumor aggressiveness, metastasis, and drug resistance in several tumors, including breast cancer. It is proposed that VM and angiogenesis (the de novo formation of blood vessels from the established vasculature by endothelial cells, which is observed in several tumors) rely on some common mechanisms. Furthermore, it is also suggested that VM could constitute a means to circumvent anti-angiogenic treatment in cancer. Therefore, it is important to determinant the factors that dictate the onset of VM. In this review, we describe the current understanding of VM formation in breast cancer, including specific signaling pathways, and cancer stem cells. In addition, we discuss the clinical significance of VM in prognosis and new opportunities of VM as a target for breast cancer therapy.
Omicron is the most mutated SARS-CoV-2 variant—a factor that can affect transmissibility, disease severity, and immune evasiveness. Its genomic surveillance is important in cities with millions of inhabitants and an economic center, such as Mexico City. Results. From 16 November to 31 December 2021, we observed an increase of 88% in Omicron prevalence in Mexico City. We explored the R346K substitution, prevalent in 42% of Omicron variants, known to be associated with immune escape by monoclonal antibodies. In a phylogenetic analysis, we found several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. A haplotype analysis revealed that there was no association between haplotype and vaccination status. Among the 66% of patients who have been vaccinated, no reported comorbidities were associated with Omicron; the presence of odynophagia and the absence of dysgeusia were significant predictor symptoms for Omicron, and the RT-qPCR Ct values were lower for Omicron. Conclusions. Genomic surveillance is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, and can inform public health decisions and detect the spread of any mutation that may affect therapeutic efficacy.
Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA‐seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α‐Satellite RNAs. We showed that α‐Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α‐Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α‐Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor‐binding motifs within α‐Satellite centromeric arrays. Using high‐resolution three‐dimensional immuno‐FISH and ChIP‐qPCR, we showed an association between the α‐Satellite upregulation and the recruitment of the transcription factor NFY‐A to the centromere upon MG132‐induced proteasome inhibition. Together, our results show that the proteasome controls α‐Satellite RNAs associated with the regulation of mitosis.
Background. Omicron is the most mutated SARS-CoV-2 variant that has emerged, resulting in viral phenotype alterations, which can affect transmissibility, disease severity, and immune evasiveness. Genomic surveillance of a highly transmissible variant is important in cities with millions of inhabitants and an economic center such as Mexico City. In this work, we describe the early effects of the Omicron variant in Mexico City, exploring its genomic profile and clinical description. Methodology. We sequenced SARS-CoV-2-positive samples in November and December 2021 using the public database GISAID. Haplotype and phylogenetic analyses were performed to genomically characterize Omicron. We used the Mexican federal database to explore the association with clinical information such as symptoms and vaccination status. Findings. The first case of Omicron was detected on November 16, 2022, and until December 31, 2021, we observed an increase from 88% in sequenced samples. Nineteen nonsynonymous mutations were found in the Omicron RBD, and we further explored the R346K substitution, which was prevalent in 42% of the samples and associated with immune escape by monoclonal antibodies. In the phylogenetic analysis, we found that there were several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. The haplotype analysis allowed us to observe that there was no association between haplotype and vaccination status. Of the patients with clinical data, 66% were vaccinated, none of the reported comorbidities were associated with Omicron, the presence of odynophagia and absence of dysgeusia were significant predictor symptoms for Omicron, and the Ct value on RT-qPCR was lower in Omicron. Conclusions. Genomic surveillance in highly populated and fast-moving urban regions such as Mexico City is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, to detect patterns that can inform public health decisions. It is also necessary to continue sequencing to detect the spread of any mutation that may affect the therapeutic efficacy or guide it.
RAS oncogenes are chief tumorigenic drivers, and their mutation constitutes a universal predictor of poor outcome and treatment resistance. Despite more than 30 years of intensive research since the identification of the first RAS mutation, most attempts to therapeutically target RAS mutants have failed to reach the clinic. In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021. However, since Sotorasib targets the KRAS G12C mutant with high specificity, relatively few patients will benefit from this therapy. On the other hand, indirect approaches to inhibit the RAS pathway have revealed very intricate cascades involving feedback loops impossible to overcome with currently available therapies. Some of these mechanisms play different roles along the multistep carcinogenic process. For instance, although mutant RAS increases replicative, metabolic and oxidative stress, adaptive responses alleviate these conditions to preserve cellular survival and avoid the onset of oncogene-induced senescence during tumorigenesis. The resulting rewiring of cellular mechanisms involves the DNA damage response and pathways associated with oxidative stress, which are co-opted by cancer cells to promote survival, proliferation, and chemo- and radioresistance. Nonetheless, these systems become so crucial to cancer cells that they can be exploited as specific tumor vulnerabilities. Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.
Background It has been reported that the oncoprotein E7 from human papillomavirus type 16 (HPV16-E7) can induce the excessive synthesis of centrosomes through the increase in the expression of PLK4, which is a transcriptional target of E2F1. On the other hand, it has been reported that increasing MPS1 protein stability can also generate an excessive synthesis of centrosomes. In this work, we analyzed the possible role of MPS1 in the amplification of centrosomes mediated by HPV16-E7. Results Employing qRT-PCR, Western Blot, and Immunofluorescence techniques, we found that E7 induces an increase in the MPS1 transcript and protein levels in the U2OS cell line, as well as protein stabilization. Besides, we observed that inhibiting the expression of MPS1 in E7 protein-expressing cells leads to a significant reduction in the number of centrosomes. Conclusions These results indicate that the presence of the MPS1 protein is necessary for E7 protein to increase the number of centrosomes, and possible implications are discussed.
Introduction. Lung cancer is the most common malignancy in the world including Mexico [1, 2]. Smoking is the main risk factor for the development of different types of lung cancer, about 70–80% of lung cancer cases are associated with smoking and approximately 50% of new cancer cases are diagnosed in ex-smokers. Current therapies rarely cure the disease, and the high relapse rate with the delay in diagnosis results in a poor prognosis and overall survival rates of 10% [1]. Several ion channels are over-expressed in cancer including Kv1.3, K2p9.1, Kv10.1 (Eag1) and Kv11.1 (HERG) channels. These channels are expressed in different cell types and tumor tissues and have been shown to increase cell proliferation. Eag1 is expressed aberrantly with a high frequency (75%) in tumor cells of different histological origins including sarcomas, carcinomas of the breast, colon, and cervix. Eag1 inhibition by either astemizole, imipramine, or Eag1 specific monoclonal antibodies reduces tumor cell proliferation in vitro and in vivo [3, 4, 5]. Eag1 channels are over-expressed in lung cancer [6]. However, a detailed study of Eag1 expression in the different types of lung cancer is missing. Materials and Methods: Lung biopsies: 44 Lung biopsies were obtained from patients attending the Instituto Nacional de Enfermedades Respiratorias (National Institute for Respiratory Diseases) in Mexico City following local ethical considerations. Patients had no prior treatment (chemotherapy or radiotherapy). 37 biopsies were classified as lung cancer samples and included adenocarcinoma, epidermoid, small cell, adenosquamous and neuroendocrine tumors. 5 samples were diagnosed as inflammatory disease and 2 were form patients with thyroid carcinoma. RNA extraction was performed with TRIzol (Life Technologies, Invitrogene) according to the manufacturer's recommendation. cDNA was synthesized by reverse transcription under the manufacturer's recommendations (New England BioLabs). Eag1 gene expression was assessed by real-time PCR under the manufacturer's recommendations (Fermentas SYBR Green/ROX qPCR Master Mix). Eag1 expression in lung biopsies was compared to Eag1 basal expression in fibroblasts from normal lung (WI-38) which was given the value of 1. Results: Eag1 expression was found in 81% of the cancer biopsies while 8% of the samples did not showed changes and in 10% of the biopsies Eag1 was found to be under-expressed. Interestingly, Eag1 was over-expressed in 80% of the samples from chronic inflammation while no changes were observed in the samples from thyroid carcinoma. Conclusions: Our results suggest Eag1 as a tumor marker for different types of lung cancer and as a potential early marker of the disease. References: 1. MacKinnon C A et al. British Medical Bulletin. 95: 47–61. 2010. 2. Molina-Alavez A et al. Gaceta mexicana de oncología. 7(5): 169–173. 2008. 3. Pardo A L et al. The journal of membrane biology. 205: 115–124. 2005. 4. Blackiston J D et al. Cell cycle. 8(21): 3527–3536. 2009. 5. Camacho J. Cancer letters. 233: 1–9. 2006. 6. Hemmerlein et al. Molecular cancer. 5(41): 1–13. 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C13.
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