Clinical & Experimental Metastasis最新文献

Colorectal cancer (CRC) presents a growing concern globally, marked by its escalating incidence and mortality rates, thus imposing a substantial health burden. This investigation delves into the role of nuclear receptor subfamily 3 group C member 1 (NR3C1) in CRC metastasis and explores the associated mechanism. Through a comprehensive bioinformatics analysis, NR3C1 emerged as a gene with diminished expression levels in CRC. This finding was corroborated by observations of a low-expression pattern of NR3C1 in both CRC tissues and cells. Furthermore, experiments involving NR3C1 knockdown revealed an exacerbation of proliferation, migration, and invasion of CRC cells in vitro. Subsequent assessments in mouse xenograft tumor models, established by injecting human HCT116 cells either through the tail vein or at the cecum termini, demonstrated a reduction in tumor metastasis to the lung and liver, respectively, upon NR3C1 knockdown. Functionally, NR3C1 (glucocorticoid receptor) suppressed SET binding protein 1 (SETBP1) transcription by binding to its promoter region. Notably, mouse double minute 4 (MDM4) was identified as an upstream regulator of NR3C1, orchestrating its downregulation via ubiquitination-dependent proteasomal degradation. Further investigations unveiled that SETBP1 knockdown suppressed migration and invasion, and epithelial to mesenchymal transition of CRC cells, consequently impeding in vivo metastasis in murine models. Conversely, upregulation of MDM4 exacerbated the metastatic phenotype of CRC cells, a propensity mitigated upon additional upregulation of NR3C1. In summary, this study elucidates a cascade wherein MDM4-mediated ubiquitination of NR3C1 enables the transcriptional activation of SETBP1, thereby propelling the dissemination of CRC cells.

To develop a clinical-radiomics nomogram based on spectral CT multi-parameter images for predicting lymph node metastasis in colorectal cancer. A total of 76 patients with colorectal cancer and 156 lymph nodes were included. The clinical data of the patients were collected, including gender, age, tumor location and size, preoperative tumor markers, etc. Three sets of conventional images in the arterial, venous, and delayed phases were obtained, and six sets of spectral images were reconstructed using the arterial phase spectral data, including virtual monoenergetic images (40 keV, 70 keV, 100 keV), iodine density maps, iodine no water maps, and virtual non-contrast images. Radiomics features of lymph nodes were extracted from the above images, respectively. Univariate analysis and least absolute shrinkage and selection operator (LASSO) regression were used to select features. A clinical model was constructed based on age and carcinoembryonic antigen (CEA) levels. The radiomics features selected were used to generate a composed radiomics signature (Com-RS). A nomogram was developed using age, CEA, and the Com-RS. The models' prediction efficiency, calibration, and clinical application value were evaluated by the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis, respectively. The nomogram outperforms the clinical model and the Com-RS (AUC = 0.879, 0.824). It is well calibrated and has great clinical application value. This study developed a clinical-radiomics nomogram based on spectral CT multi-parameter images, which can be used as an effective tool for preoperative personalized prediction of lymph node metastasis in colorectal cancer.

Although progress has been made in the treatment of cancer, particularly for the four major types of cancers affecting the lungs, colon, breast and prostate, resistance to cancer treatment often emerges upon inhibition of major signaling pathways, which leads to the activation of additional pathways as a last-resort survival mechanism by the cancer cells. This signaling plasticity provides cancer cells with a level of operational freedom, reducing treatment efficacy. Plasticity is a characteristic of cancer cells that are not only able to switch signaling pathways but also from one cellular state (differentiated cells to stem cells or vice versa) to another. It seems implausible that the inhibition of one or a few signaling pathways of heterogeneous and plastic tumors can sustain a durable effect. We propose that inhibiting molecules with pleiotropic functions such as cell surface co-receptors can be a key to preventing therapy escape instead of targeting bona fide receptors. Therefore, we ask the question whether co-receptors often considered as "accessory molecules" are an overlooked key to control cancer cell behavior.

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.

Epigenetic mechanisms have been shown to play an important role in the development of cancer. These include the activation of chromatin remodeling factors in various malignancies, including bromodomain plant homeodomain (PHD) finger transcription factor (BPTF), the largest component of the human nucleosome remodeling factor (NURF). In the last few years, BPTF has been identified as a pro-tumorigenic factor in melanoma, stimulated by research into the molecular mechanisms underlying BPTF function. Developing therapy targeting the BPTF bromodomain would represent a significant advance. Melanoma therapy has been revolutionized by the efficacy of immunotherapeutic and targeted strategies, but the development of drug resistance calls for alternative therapeutic approaches. Recent work has shown both a biomarker as well as functional role for BPTF in melanoma progression and as a possible target for its therapy. BPTF was shown to stimulate the mitogen-activated protein kinase pathway, which is targeted by selective BRAF inhibitors. The advent of small molecule inhibitors that target bromodomain motifs has shown that bromodomains are druggable. By combining the bromodomain inhibitor bromosporine with existing treatments that target mutant BRAF, BPTF targeting has emerged as a novel and promising therapeutic approach for metastatic melanoma. This article summarizes the functional role of BPTF in tumor progression, reviews the clinical experience to date with bromodomain inhibitors, and discusses the promise of BPTF targeting in melanoma and other solid tumors.

Background

Neuroblastoma (NB) is the most prevalent solid extracranial malignancy in children, often with bone marrow metastases (BMM) are present. The conventional approach for detecting BMM is bone marrow biopsy and aspiration (BMBA). 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (18 F-FDG PET/CT) has become a staple for staging and is also capable of evaluating marrow infiltration. The consensus on the utility of 18 F-FDG PET/CT for assessing BMM in NB patients is still under deliberation.

Methods

This retrospective study enrolled 266 pediatric patients with pathologically proven NB. All patients had pretherapy FDG PET/CT. BMBA, clinical, radiological, and follow-up data were also collected. The diagnostic accuracy of BMBA and 18 F-FDG PET/CT was assessed.

Results

BMBAs identified BMM in 96 cases (36.1%), while 18 F-FDG PET/CT detected BMI in 106 cases (39.8%) within the cohort. The initial sensitivity, positive predictive value (PPV), specificity, and negative predictive value (NPV) of 18 F-FDG PET/CT were 93.8%, 84.9%, 90.6%, and 96.3%, respectively. After treatment, these values were 92.3%, 70.6%, 97.3%, and 99.4%, respectively. The kappa statistic, which measures agreement between BMBA and 18 F-FDG PET/CT, was 0.825 before treatment and 0.784 after treatment, with both values indicating a substantial agreement (P = 0.000). Additionally, the amplification of MYCN and a positive initial PET/CT scan were identified as independent prognostic factors for overall survival (OS).

Conclusion

18 F-FDG-PET/CT is a valuable method for evaluating BMM in NB. The routine practice of performing a BMBA without discrimination may need to be reassessed. Negative result from 18 F-FDG-PET/CT could potentially spare children with invasive bone marrow biopsies.

Chemotherapy drugs efficiently eradicate rapidly dividing differentiated cells by inducing cell death, but poorly target slowly dividing cells, including cancer stem cells and dormant cancer cells, in the later course of treatment. Prolonged exposure to chemotherapy results in a decrease in the proportion of apoptotic cells in the tumour mass. To investigate and characterize the molecular basis of this phenomenon, microarray-based expression analysis was performed to compare tHcred²-DEVD-EGFP-caspase 3-sensor transfected C-26 tumour cells that were harvested after engraftment into mice treated with or without 5-FU. Peritoneal metastasis was induced by intraperitoneal injection of C-26 cells, which were subsequently reisolated from omental metastatic tumours after the mice were sacrificed by the end of the 10th day after tumour injection. The purity of reisolated tHcred2-DEVD-EGFP-caspase 3-sensor-expressing C-26 cells was confirmed using FLIM, and total RNA was extracted for gene expression profiling. The validation of relative transcript levels was carried out via real-time semiquantitative RT‒PCR assays. Our results demonstrated that chemotherapy induced the differential expression of mediators of cancer cell dormancy and cell survival-related genes and downregulation of both intrinsic and extrinsic apoptotic signalling pathways. Despite the fact that some differentially expressed genes, such as BMP7 and Prss11, have not been thoroughly studied in the context of chemoresistance thus far, they might be potential candidates for future studies on overcoming drug resistance.

In several cancer types, metastasis is associated with poor prognosis, survival, and quality of life, representing a life risk more significant than the primary tumor itself. Metastasis is a multi-step process that spreads tumor cells from primary sites to surrounding or distant organs, originating secondary tumors. The interconnected steps that drive metastasis depend of several capabilities that enable cells to detach from the primary tumor, acquire motility and migrate through the basal membrane; invade and spread through the vascular system, and finally settle and originate a new tumor. Recently, stress-induced phosphoprotein 1 (STIP1) has emerged as a protein capable of driving tumor cells through these metastasis steps by mediating several biological processes and signaling pathways. This protein is mainly known for its function as a co-chaperone, acting as a scaffold for the interaction of its client heat-shock proteins Hsp70/90 chaperones; however, it is also known that STIP1 can act independently of chaperones to activate downstream phosphorylation pathways. The over-expression of STIP1 has been reported across various cancer types, identifying it as a potential biomarker for predicting patient prognosis and monitoring the progression of metastasis. Here, we present a discussion on how this co-chaperone mediates the initial steps of metastasis (cell adhesion loss, epithelial-to-mesenchymal transition, and angiogenesis), highlighting the biological mechanisms in which STIP1 plays a vital role, also presenting an overview of the current knowledge regarding its clinical relevance.

Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDH^hiCD44⁺ breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can ‘prime’ the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDH^hiCD44⁺ TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDH^hiCD44⁺ cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDH^hiCD44⁺ phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.