Search Results (638)

The morphogenesis of the primordial gut relies on signaling pathways such as Wnt, FGF, Notch, Hedgehog, and Hippo. Reciprocal crosstalk between the endoderm and mesoderm is integrated into the signaling pathways, resulting in craniocaudal patterning. These pathways are also involved in adult intestinal homeostasis including cell proliferation and specification of cell fate. Perturbations in this process can cause growth disturbances manifesting as adenomas, serrated lesions, and cancer. Significant differences have been observed between right and left colon cancers in the hindgut, and between the jejunoileum, appendix, and right colon in the midgut. The question is to what extent the embryology of the mid- and hindgut contributes to differences in the underlying tumor biology. This review examines the precursor lesions and consensus molecular subtypes (CMS) of colorectal cancer (CRC) to highlight the significance of embryology and tumor microenvironment (TME) in CRC. The three main precursor lesions, i.e., adenomas, serrated lesions, and inflammatory bowel disease-associated dysplasia, are linked to the CMS classification, which is based on transcriptomic profiling and clinical features. Both embryologic and micro-environmental underpinnings of the mid- and hindgut contribute to the differences in the tumors arising from them, and they may do so by recapitulating embryonic signaling cascades. This manifests in the range of CRC CMS and histologic cancer subtypes and in tumors that show multidirectional differentiation, the so-called stem cell carcinomas. Emerging evidence shows the limitations of CMS particularly in patients on systemic therapy who develop drug resistance. The focus is thus transitioning from CMS to specific components of the TME. Full article

Tenascin-C (TNC) is an extracellular matrix (ECM) protein with key roles in various biological processes, such as embryonic development and tissue regeneration. However, its deregulated expression can contribute to pathological responses, promoting chronic inflammation, fibrosis, or tumor progression. It belongs to the tenascin family, a class of extracellular proteins that interfere with cellular events in both physiological and pathological contexts, interacting specifically with cells and other components of the ECM. TNC has emerged as a key player in the pathogenesis of chronic respiratory diseases (CRDs), including asthma, chronic obstructive pulmonary disease (COPD), lung cancer (LC), pulmonary hypertension (PH), and idiopathic pulmonary fibrosis (IPF). The influence of TNC on cellular responses, which is mediated by precise interactions with cellular receptors and ligands, triggers complex intracellular signaling cascades associated with the inflammatory response, fibrosis, and tumorigenesis in these CRDs. This review synthesizes recent evidence highlighting the multifaceted roles and underlying mechanisms of TNC in the context of these CRDs. Full article

A complex and gradual process, the epithelial–mesenchymal transition (EMT) occurs both during embryonic development and tumor progression. Cells undergo a transition from an epithelial to a mesenchymal state throughout this process. More and more evidence points to EMT as a cause of increased metastatic spread of prostate cancer (PCa), along with stemness enhancement and therapy resistance. Here, we used bioinformatic methods to analyze gene expression microarray data, single-cell RNA sequencing, oncogenes, and tumor suppressor genes (TSGs) in order to reconstruct the network of differentially expressed genes (DEGs) involved in the epithelial–mesenchymal transition with PCa. No prior study has documented this sort of analysis. We next validated our results using data from the Cancer Genome Atlas (TCGA), which included microarray and single-cell RNA sequencing. Potentially useful in PCa diagnosis and treatment are extracellular matrix in epithelial–mesenchymal transition genes, including ITGBL1, DSC3, COL4A6, ANGPT1, ARMCX1, MICAL2, and EPHA5. In this study, we aimed to shed light on the molecular characteristics and pathways of DEGs in PCa, as well as to identify possible biomarkers that are important in the development and advancement of this cancer. These insights have important implications for understanding prostate cancer progression and for the development of therapeutic strategies targeting ECM-mediated pathways. Full article

DICER1 syndrome is a hereditary cancer predisposition syndrome, characterized by a large range of benign and malignant neoplasms. Patients with DICER1 syndrome have a broad phenotype, with pleuropulmonary blastoma, Sertoli–Leydig cell tumor, cystic nephroma, cervical embryonal rhabdomyosarcoma, cystic lung lesions, and thyroid follicular nodular disease being the most prevalent manifestations. The syndrome is caused by loss-of-function germline variants in the DICER1 gene, and DICER1-related tumors are characterized by second somatic hotspot variants in the RNase IIIb domain of DICER1. DICER1 encodes an endoribonuclease, which is important for RNA interference. This review describes the molecular mechanism of DICER1 function and the pathogenetic mechanisms of tumorigenesis. The purpose of this review is to describe the pathogenesis, genotype–phenotype correlation and tissue specificity of DICER1 syndrome. We conclude that there is a lack of knowledge about the exact molecular mechanisms of DICER1 function and more research is needed to determine the exact role of this altered protein in relation to pathogenesis. Full article

Angiogenesis, the formation of new blood vessels from pre-existing ones, is crucial for various physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration and tumor progression. While traditionally attributed to the actions of growth factors and their receptors, emerging evidence highlights the crucial regulatory roles of mitochondria in angiogenesis. This narrative review explores the multifaceted functions of mitochondria in endothelial cells, which are central to blood vessel formation. Beyond their classical role in ATP production, mitochondria contribute to angiogenesis through redox signaling, calcium homeostasis, biosynthetic activity, and reactive oxygen species (ROS) generation. These organelles help regulate key endothelial behaviors such as proliferation, migration, and tube formation through mechanisms that include mitochondrial calcium signaling and ROS-mediated stabilization of hypoxia-inducible factor-1α (HIF-1α), leading to increased vascular endothelial growth factor (VEGF) expression. Additionally, mitochondrial dynamics, dysfunction, and genetic factors are discussed for their influence on angiogenic outcomes. Understanding these complex mitochondrial functions opens new therapeutic avenues for modulating angiogenesis in diseases such as cancer and cardiovascular disorders. Full article

Background/Objectives: Cadherin-6 (CDH6), also known as K-cadherin, is a type II classic cadherin molecule that plays an important role in the embryonic development of the kidney but has very limited expression in adult tissues. It is overexpressed in several human malignancies, primarily in ovarian cancer, renal cell carcinoma, as well as, less frequently, cholangiocarcinoma, uterine serous carcinoma, glioma, lung, pancreatic and thyroid cancers. The characteristic of limited expression in normal tissues, high expression in tumor tissues, and rapid internalization upon antibody binding makes CDH6 a well-suited antibody-drug conjugate (ADC) target. Methods: We developed a novel CDH6-targeting ADC, CUSP06, consisting of a proprietary humanized antibody selective for CDH6, a protease cleavable linker, and an exatecan payload, with a drug-to-antibody ratio (DAR) of 8. We further characterized the pharmacological activities of CUSP06 in multiple in vitro and in vivo models. Results: CUSP06 was selectively bound to cell surface CDH6 and was efficiently internalized into CDH6-positive ovarian cancer cells, and led to the induction of DNA damage and apoptosis of CDH6-positive cancer cells. CUSP06 exhibited strong antiproliferative activity against several CDH6-positive cancer cell lines and demonstrated strong bystander cell killing effect in the cell mixing experiments in vitro. CUSP06 exhibits excellent in vivo antitumor efficacy in CDH6-high or -low cell line-derived xenograft (CDX) or patient-derived xenograft (PDX) models from human ovarian, renal and uterine cancers, as well as cholangiocarcinoma. CUSP06 demonstrated a favorable safety profile in GLP-compliant toxicology studies in Sprague Dawley rats and cynomolgus monkeys. Conclusions: The preclinical data highlighted the therapeutic potential of CUSP06 in multiple CDH6-positive human cancers. Full article

Background/Objectives: Copper levels are significantly elevated in both the sera and tumor tissues of various cancers, including prostate cancer. It has therefore been suggested that targeting the elevated copper levels with copper chelators could lead to selective cancer treatment. Thus, several classes of low molecular weight copper-coordinating lipophilic compounds, as well as the newly developed copper complexes of appropriately functionalized polymers, are being investigated as promising novel anticancer therapeutics. Particularly, metal-containing polymers, or metallopolymers, are systematically investigated as anticancer agents or as drug delivery systems. This study aims to utilize the strong copper-chelating properties of hyperbranched polyethyleneimine (PEI) to develop PEI:Cu metallopolymers and evaluate their selectivity and anticancer properties against several prostate cancer cell lines. Methods: A series of PEI:Cu complexes at PEI/Cu ratios that ensure that no free copper ions are present in the solution are prepared and investigated against a human non-cancerous cell line and three prostate cancer cell lines of increasing metastatic potential. Results: PEI:Cu derivatives are cytotoxic against the human prostate carcinoma metastatic PC3 and DU145 cell lines, even at the lowest tested concentrations of 5 μg/mL, while against the non-cancerous HEK293 cells, all metallopolymer derivatives exhibit insignificant cytotoxicity up concentrations of 50 μg/mL. Their cytotoxic effect is associated with mitochondria membrane potential loss and ROS production increase. Conclusions: Hyperbranched polyethyleneimine–coordinated copper(II) metallopolymers, at low concentrations, selectively induce cytotoxicity in metastatic prostate cancer cell lines without compromising the viability of non-cancerous embryonic kidney cells. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM. Full article

Malignant mediastinal tumors are a group representing some of the most demanding oncological challenges for early, multi-level, and successful management. The timely identification of any suspicious clinical symptomatology is urgent in achieving an accurate, staged histological diagnosis, in order to follow up with an equally detailed medical therapeutic plan (interventional or not) and determine the principal goals regarding efficient overall treatment in these patients. We report a case of a 24-year-old male patient with an incident-free prior medical history. An initial chest X-ray was performed after the patient reported short-term, consistent moderate chest pain symptomatology, early work fatigue, and shortness of breath. The following imaging procedures (chest CT, PET-CT) indicated the presence of an anterior mediastinal mass (meas. ~11 cm × 10 cm × 13 cm, SUV: 8.7), applying additional pressure upon both right heart chambers. The Alpha-Fetoprotein (aFP) blood levels had exceeded at least 50 times their normal range. Two consecutive diagnostic attempts with non-specific histological results, a negative-for-malignancy fine-needle aspiration biopsy (FNA-biopsy), and an additional tumor biopsy, performed via mini anterior (R) thoracotomy with “suspicious” cellular gatherings, were performed elsewhere. After admission to our department, an (R) Video-Assisted Thoracic Surgery (VATS) was performed, along with multiple tumor biopsies and moderate pleural effusion drainage. The tumor’s measurements had increased to DMax: 16 cm × 9 cm × 13 cm, with a severe degree of atelectasis of the Right Lower Lobe parenchyma (RLL) and a pressure-displacement effect upon the Superior Vena Cava (SVC) and the (R) heart sinus, based on data from the preoperative chest MRA. The histological report indicated elements of a combined, non-seminomatous germ-cell mediastinal tumor, posthuberal-type teratoma, and embryonal carcinoma. The imminent chemotherapeutic plan included a “BEP” (Bleomycin^®/Cisplatin^®/Etoposide^®) scheme, which needed to be modified to a “VIP” (Cisplatin^®/Etoposide^®/Ifosfamide^®) scheme, due to an acute pulmonary embolism incident. While the aFP blood levels declined, even reaching normal measurements, the tumor’s size continued to increase significantly (DMax: 28 cm × 25 cm × 13 cm), with severe localized pressure effects, rapid weight loss, and a progressively worsening clinical status. Thus, an emergency surgical intervention took place via median sternotomy, extended with a complementary “T-Shaped” mini anterior (R) thoracotomy. A large, approx. 4 Kg mediastinal tumor was extracted, with additional RML and RUL “en-bloc” segmentectomy and partial mediastinal pleura decortication. The following histological results, apart from verifying the already-known posthuberal-type teratoma, indicated additional scattered small lesions of combined high-grade rabdomyosarcoma, chondrosarcoma, and osteosarcoma, as well as numerous high-grade glioblastoma cellular gatherings. No visible findings of the previously discovered non-seminomatous germ-cell and embryonal carcinoma elements were found. The patient’s postoperative status progressively improved, allowing therapeutic management to continue with six “TIP” (Cisplatin^®/Paclitaxel^®/Ifosfamide^®) sessions, currently under his regular “follow-up” from the oncological team. This report underlines the importance of early, accurate histological identification, combined with any necessary surgical intervention, diagnostic or therapeutic, as well as the appliance of any subsequent multimodality management plan. The diversity of mediastinal tumors, especially for young patients, leaves no place for complacency. Such rare examples may manifest, with equivalent, unpredictable evolution, obliging clinical physicians to stay constantly alert and not take anything for granted. Full article

Background: Often, neoadjuvant therapy, which relies on the induction of double-strand breaks (DSBs), is used prior to surgery to shrink tumors by inducing cancer cell apoptosis. However, recent studies have suggested that this treatment may also induce a fluctuating state between senescence and stemness in PA-1 embryonal carcinoma cells, potentially affecting therapeutic outcomes. Thus, the respective epigenetic pathways are up or downregulated over a time period of days. These fluctuations go hand in hand with changes in spatial DNA organization. Methods: By means of Single-Molecule Localization Microscopy in combination with mathematical evaluation tools for pointillist data sets, we investigated the organization of euchromatin and heterochromatin at the nanoscale on the third and fifth day after etoposide treatment. Results: Using fluorescently labeled antibodies against H3K9me3 (heterochromatin tri-methylation sites) and H3K4me3 (euchromatin tri-methylation sites), we found that the induction of DSBs led to the de-condensation of heterochromatin and compaction of euchromatin, with a peak effect on day 3 after the treatment. On day 3, we also observed the co-localization of euchromatin and heterochromatin, which have marks that usually occur in exclusive low-overlapping network-like compartments. The evaluation of the SMLM data using topological tools (persistent homology and persistent imaging) and principal component analysis, as well as the confocal microscopy analysis of H3K9me3- and H3K4me3-stained PA-1 cells, supported the findings that distinct shifts in euchromatin and heterochromatin organization took place in a subpopulation of these cells during the days after the treatment. Furthermore, by means of flow cytometry, it was shown that the rearrangements in chromatin organization coincided with the simultaneous upregulation of the stemness promotors OCT4A and SOX2 and senescence promotors p21Cip1 and p27. Conclusions: Our findings suggest potential applications to improve cancer therapy by inhibiting chromatin remodeling and preventing therapy-induced senescence. Full article

Conventional chemotherapy continues to form the backbone of treatment for many pediatric central nervous system (CNS) tumors. Advances have been made especially in the molecular underpinning of certain pediatric CNS tumors, allowing for advancement and consideration in incorporating this molecular information in molecular targeted therapy or appropriate de-escalation or escalation of therapy. In very young children with embryonal CNS tumors, intensive high-dose chemotherapy approaches have been used with varied increased survival in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and rare embryonal subtypes, but there are certain molecular risk groups that require new therapies, such as the ATRT MYC subtype. Some CNS tumors remain resistant or refractory to conventional chemotherapy, especially in relapsed disease. Strategies to explore combination therapies with chemotherapy, novel agents, and novel approaches are needed to improve survival in this population in the future. Full article

Pluripotent stem cell (PSC)-based therapies are currently in clinical trials. However, one of the main safety concerns includes the potential for cancer formation of the PSC-derived products. Currently, the teratoma in vivo assay is accepted by regulatory agencies for identifying whether PSCs have the potential to become malignant. Yolk sac elements (YSE) are one of the elements that could arise from PSC. Whereas the other malignant element, embryonal carcinoma, is thoroughly studied, this is not the case for YSE. Therefore, more research is needed to assess the nature of YSE. We propose that it is imperative to include the formation of YSE in the safety assessment of PSC due to their close resemblance to the clinical entity of yolk sac tumor (YST), a human malignant germ cell tumor (hGCT). In this review, we extrapolate knowledge from YST to better understand YSE derived from PSC. We demonstrate that both share a similar morphology and that the same characteristic immunohistochemical markers can be used for their identification. We discuss the risk these tumors pose, thereby touching upon genetic abnormalities and gene expression that characterize them, as well as possible disease mechanisms. Integrating the molecular and immunohistochemical markers identified in this review into future research will help to better address the potential malignancy associated with PSC. Full article

Dietary marine lipids enriched in ω-3 polyunsaturated fatty acids (PUFAs) are spotlighted for favorable effects in neurodegenerative conditions and tumor cell proliferation. Commercial marine oils, with high EPA and DHA content, consist of non-polar lipids constituted by triacylglycerols or polar oils composed of phospholipids. Both classes have shown different activities to significantly inhibit proliferation and migration, and induce apoptosis in cancer cells. This work was aimed at testing marine oils’ associated effects on neuroblastoma (NB) and glioblastoma (GB). Commercial non-polar and polar marine oils were studied in 3D spheroid models developed with human neuroblastoma, GB, and non-nervous embryonic kidney cell lines. This study also included results provided by a new sustainable polar marine oils source: fishery side-streams. Cell viability and mitochondrial activity assessments demonstrated that both marine oils dramatically reduced NB cells’ metabolism, proliferation, and viability. Effects on GB and epithelial cells were different, including a metabolic increase. Marine oils also induce cell differentiation and selectively modulate the activity of neurons and glia, depending on the oils’ chemical form. Sustainable polar oil showed bioactive characteristics similar to commercial krill oil. We propose that marine oils rich in triacylglycerols and phospholipids with high EPA and DHA levels may be a useful tool in NB antiproliferative therapies. Full article

Medulloblastoma represents a rare yet complex embryonal tumor of the posterior cranial fossa that, while predominantly affecting pediatric populations, occurs with increasing recognition among adolescents and young adults (AYAs, 15–39 years). The scarcity of medulloblastoma within this demographic creates substantial obstacles in diagnosis, treatment selection, and psychosocial management that differ markedly from established pediatric approaches. Emerging data reveal that AYA patients exhibit distinctive tumor biology, including altered molecular subgroup patterns, variable therapeutic responses, and unique survival trajectories when compared to younger patients. Current investigations examining autologous stem cell transplantation following intensive chemotherapy protocols in metastatic cases demonstrate encouraging preliminary results. Evidence increasingly supports adapting pediatric treatment paradigms for adult application, potentially improving therapeutic outcomes while reducing treatment burden. These cross-disciplinary approaches between pediatric and adult oncology demonstrate considerable promise for enhancing clinical results and minimizing therapy-associated morbidity, emphasizing the critical need for collaborative care models in managing this challenging malignancy across diverse age groups. Full article

Background: Ovarian cancer remains the most lethal gynecological cancer, primarily due to its asymptomatic nature in early stages and consequent late diagnosis. Early detection improves survival, but current biomarkers lack sensitivity and specificity. Cell-free DNA (cfDNA) released from tumor cells captures tumor-associated epigenetic alterations and represents a promising source for minimally invasive biomarkers. Among these, aberrant DNA methylation occurs early in tumorigenesis and may reflect underlying disease biology. This study aimed to investigate genome-wide cfDNA methylation profiles in patients with ovarian cancer, benign ovarian conditions, and healthy controls to identify cancer-associated methylation patterns that may inform future biomarker development. Results: We performed genome-wide cfDNA methylation profiling using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) on plasma samples from 40 patients with high-grade serous ovarian carcinoma, 38 patients with benign ovarian conditions, and 38 healthy postmenopausal women. A total of 536 differentially methylated regions (DMRs) were identified between ovarian cancer and controls (n = 76), with 97% showing hypermethylation in ovarian cancer. DMRs were enriched in CpG islands and gene bodies and depleted in repetitive elements, consistent with known cancer-associated methylation patterns. Fifteen genes showed robust hypermethylation across analyses. These genes exhibited methylation across intronic, exonic, and upstream regulatory regions. Separate comparisons of ovarian cancer to each control group (benign and healthy) supported the reproducibility of these findings. Gene Ontology enrichment analysis revealed enrichment in gland development, embryonic morphogenesis, and endocrine regulation, suggesting biological relevance to ovarian tumorigenesis. Conclusions: This study identifies consistent cfDNA hypermethylation patterns in ovarian cancer, affecting genes involved in developmental regulation and hormone-related processes. Our findings underscore the potential of cfMeDIP-seq for detecting tumor-specific methylation signatures in plasma and highlight these 15 hypermethylated genes as biologically relevant targets for future studies on cfDNA methylation in ovarian cancer. Full article