Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24− immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and β-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.

Vasculogenic mimicry (VM) has recently been discovered as an alternative mechanism for nourishing cancer cells in vivo. During VM, tumor cells align and organize themselves into three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism mainly occurs in aggressive solid tumors and has been associated with poor prognosis in oncologic patients. Long non-coding RNAs (lncRNAs) are essential regulators of protein-encoding genes involved in cancer development and progression. These single-stranded RNA molecules regulate critical cellular functions in cancer cells including cell proliferation, apoptosis, angiogenesis, VM, therapy response, migration, invasion, and metastasis. Recently, high-throughput RNA-sequencing technologies have identified thousands of lncRNAs, but only a small percentage of them have been functionally characterized in human cancers. The vast amount of data about its genomic expression in tumors can allow us to dissect their functions in cancer biology and make them suitable biomarkers for cancer diagnosis and prognosis. In this study, we reviewed the current knowledge about the role of lncRNAs in regulating VM in cancer. We also examined the molecular mechanisms of lncRNAs and highlight several commonalities in the cellular functions associated with VM between diverse cancer types. Future directions for research focused on deciphering their function in VM are delineated. Finally, the potential of selected lncRNAs as novel therapeutic targets in RNA-based molecular interventions is also discussed.

Breast cancer remains the leading cause of cancer-related death in women worldwide. This disease is characterized by its molecular and phenotypic heterogeneity, which hinders the development of effective therapies. While two-dimensional (2D) monolayer cell cultures are widely used, they are insufficient to reproduce the characteristics of the tumor microenvironment, thus limiting our understanding of cancer biology. In this context, three-dimensional (3D) models have emerged as representative tools that more accurately reproduce tissue architecture, cell signaling, and nutrients and oxygen gradients. These cellular models offer greater similarity to primary tissues, improving the study of relevant biological processes. Although 3D cultures provide numerous advantages in cancer research, there is no unified model that standardizes the matrix type and parameters such as gelation time or porosity, hindering the reproducibility and interpretability of the data. This review integrates evidence from various studies to evaluate the effect of epigenetic variations generated by 3D culture methods, which are regulated by mechanotransduction and, consequently, by signaling pathways such as integrin/FAK-ILK/Rho-YAP derived from interactions of cells with extracellular matrix-enriched scaffolds. This affects processes such as DNA methylation, histone coding, and the regulation of non-coding RNAs such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in different molecular subtypes of breast cancer. Overall, the evidence highlights that 3D culture methods are not equivalent but rather generate distinct epigenetic signatures at the non-coding RNA level that influence the proliferation, differentiation, therapeutic resistance, and metastatic potential of tumor cells. Furthermore, the evidence suggests that histone coding patterns, primarily through the reduction of acetylation marks, are conserved regardless of the type of 3D culture. In summary, the study highlights that the microarchitectural and compositional characteristics of 3D scaffolds are key determinants of epigenetic plasticity.

Vasculogenic mimicry (VM) has been recently discovered as an alternative mechanism to nourish cancer cells in vivo. During VM, tumor cells align and organize in three-dimensional (3D) channel-like structures to transport nutrients and oxygen to the internal layers of tumors. This mechanism occurs mainly in aggressive solid tumors and has been associated with poor prognosis in oncologic patients. Long non-coding RNAs (lncRNAs) are essential regulators of protein-encoding genes involved in cancer development and progression. These single-stranded RNA molecules regulate critical cellular functions in cancer cells, including cell proliferation, apoptosis, angiogenesis, VM, therapy response, migration, invasion, and metastasis. Recently, high-throughput RNA sequencing technologies have identified thousands of lncRNAs, but only a tiny percentage have been functionally characterized in human cancers. The vast amount of data about its genomic expression in tumors can allow us to dissect their functions in cancer biology and make them suitable biomarkers for cancer diagnosis and prognosis. Here, we have reviewed the current knowledge about the role of lncRNAs in VM in human cancers, with a special emphasis on their potential to be used as novel therapeutic targets in RNA-based molecular interventions.

Background/Objectives: B-cell acute lymphoblastic leukemia (B-ALL) remains the most common pediatric malignancy. This study aimed to evaluate clinical outcomes in pediatric B-ALL in Southern Mexico and determine how socioeconomic vulnerabilities—specifically indigenous status and treatment non-adherence—independently drive relapse and compromise survival in a resource-limited setting. Methods: A retrospective cohort study was conducted, including 146 patients (0–17 years) treated between 2010 and 2024 using modified Total XIII and XV protocols. Survival was estimated via Kaplan–Meier. Independent prognostic factors for overall survival (OS) and relapse were identified using multivariable Cox proportional hazards models. Results: The 5-year OS was 50%, and event-free survival (EFS) was 37.6%. Survival varied significantly by clinical risk: 88% for low-risk, 77% for standard-risk, and 31% for high-risk patients. Relapse occurred in 45.8% of patients. Beyond established biological predictors like hyperleukocytosis and high-risk cytogenetics, socioeconomic vulnerabilities profoundly impacted outcomes. Documented treatment non-adherence significantly reduced 5-year OS (23.4% vs. 56.1%, p = 0.001) and disproportionately affected indigenous patients (55.5% vs. 10.1% in non-indigenous). Multivariable analysis identified indigenous status as an independent predictor of increased relapse hazard (HR = 1.89, p = 0.049), alongside male sex and high leukocyte count. Conclusions: Survival outcomes in this cohort are markedly lower than in high-income countries. The high incidence of relapse is deeply intertwined with local structural inequities. Improving survival requires complementing biological risk stratification with targeted strategies to overcome socioeconomic barriers and prevent treatment non-adherence.

Background: B-cell acute lymphoblastic leukemia (B-ALL) is the most frequent malignancy of childhood; worldwide, 487,294 new cases and 305,405 deaths were reported in 2022, including more than 5000 new cases in Mexico. Chemotherapy, delivered in induction, consolidation and maintenance phases, remains the mainstay of treatment, yet 10–20% of patients relapse after induction because of chemoresistance, whose molecular basis is still incompletely understood. Methods: This retrospective study aimed to identify proteins associated with resistance to vincristine (VCR) and methotrexate (MTX) administered during the induction phase, using LC–MS/MS proteomics and bioinformatic analysis of treatment-naive bone marrow aspirates from responders and nonresponders. Results: Nonresponders showed a distinct proteomic profile, with deregulated processes converging on cytoskeletal structure and dynamics, nucleic acid metabolism, DNA repair and RNA processing. Within these processes, thymidine phosphorylase (TYMP) and gelsolin (GSN) emerged as differentially expressed proteins, both consistently overexpressed in nonresponders at the individual-patient level. Conclusions: We conclude that cytoskeletal remodeling and nucleotide metabolism are prominent features of intrinsic chemoresistance in pediatric B-ALL, and that TYMP and GSN represent candidate biomarkers of nonresponse to VCR- and MTX-based induction that warrant validation by orthogonal methods in independent, adequately powered cohorts.