Metastatic Process Research Articles

NGR-bearing human adenovirus type 5 infects cells in flotillin- or caveolin-mediated manner depending on the NGR insertion site

Human adenoviruses represent attractive candidates for the design of cancer gene therapy vectors. Modification of adenovirus tropism by incorporating a targeting ligand into the adenovirus capsid proteins allows retargeting of adenovirus towards the cells of interest. Human adenovirus type 5 (HAdV-C5) bearing NGR containing peptide (CNGRCVSGCAGRC) inserted into the fiber (AdFNGR) or the hexon (AdHNGR) protein demonstrated an increased transduction of endothelial cells showing expression of aminopeptidase N, also known as CD13, and αvβ3 integrin both present on tumor vasculature, indicating that NGR-bearing adenoviruses could be used as tools for anti-angiogenic cancer therapy. Here we investigated how AdFNGR and AdHNGR infect cells lacking HAdV-C5 primary receptor, coxsackie and adenovirus receptor, and we showed that both AFNGR and AdHNGR enter cells by dynamin- and lipid raft-mediated endocytosis, while clathrin is not required for endocytosis of these viruses. We present evidence that productive infection of both AdFNGR and AdHNGR involves lipid rafts, with usage of flotillin-mediated cell entry for AdFNGR and limited role of caveolin in AdHNGR transduction efficiency. Lipid rafts play important role in angiogenesis and process of metastasis. Therefore, the ability of AdFNGR and AdHNGR to use lipid raft-dependent endocytosis, involving respectively flotillin- or caveolin-mediated pathway, could give them an advantage in targeting tumor cells lacking HAdV-C5 primary receptor.

Exploration of aminopeptidase N as new biomarker for early diagnosis of thyroid cancer

False-positive diagnosis and overdiagnosis are ongoing issues in clinical diagnosis of thyroid cancer. Identifying new disease markers is crucial for early diagnosis and improved treatment. Aminopeptidase N (APN) is a promising biomarker for cancer diagnosis due to its critical roles in tumor invasion, metastasis, angiogenesis, and other processes. However, its potential as biomarker for thyroid cancer diagnosis needs further investigation. This study developed an ultra-sensitive near-infrared fluorescence probe, LAN-apn, to investigate the expression level of APN in thyroid cancer and evaluate its potential as biomarker of thyroid cancer. LAN-apn could accurately and sensitively determine APN through fluorescence method (DL = 0.069 ng/mL) and colorimetric method (DL = 4.5 ng/mL). In addition, LAN-apn allowed for successful fluorescence imaging of APN in thyroid cancer cells and thyroid cancer tumors both in vivo and in vitro, and confirmed that APN was significantly upregulated in thyroid cancer. Therefore, APN may become a new biomarker for thyroid cancer diagnosis, and LAN-apn could be used as a new imaging tool for the study of APN-thyroid cancer relationship and the early diagnosis of thyroid cancer.

Tumor Anti-angiogenesis: Nano-Arsenal will Kill the Crab

Angiogenesis: the process of developing new blood vessels from the pre-existing ones is a very crucial process in tumor formation, growth, progression and metastasis. The central role of angiogenesis in tumor growth and progression compels targeting tumor vasculature as a therapeutic mean. Nanoparticles have revolutionized the domain of cancer therapeutics, molecularly targeted anti-cancer drugs represents one of the most significant recent advances in clinical oncology. Various types of nano-drug complexes which targets tumor vasculature preferentially, are being increasingly tested for optimal therapeutic efficacy and minimal side-effects. Here, we review some of these anti-angiogenic nano-drug complexes.

OTHER-10 EARLY CLINICAL EXPERIENCE OF SRS AND SBRT STEREOTACTIC BODY RADIOTHERAPY FOR CENTRAL NERVOUS SYSTEM (CNS) CASE SERIES AT HCG CANCER CENTRE, NAIROBI.

Abstract BACKGROUND Stereotactic Radiosurgery (SRS), Stereotactic Radiotherapy(SRT) and Stereotactic Body Radiation Therapy (SBRT) delivers fewer high-dose fractions of radiation which may be radiobiologically favorable to conventional low-dose fractions commonly used for central nervous system. We report our early experience using SBRT in central nervous tumours (CNS). METHODS / INTRODUCTION Sequential patients treated with SBRT from December 2022 to May 2023 at HCG Cancer Care Kenya for CNS tumours will be included in this retrospective review of early clinical data collected in the institutional database. SBRT treatments were delivered using VersaHD Linac with doses ranging from 36.25Gy to 30Gy delivered in 3 to 5 fractions. Local guidelines have been developed to guide stereotactic radiotherapy treatments in Kenya. The national health insurer is currently reimbursing for stereotactic treatments would further increases the uptake. Discussion The CNS cases that has been treated locally with SRS/SRT/SBRT with CNS case series shall be evaluated under clinical presentation, treatment planning process in recurrent Meningioma, Glomus tymphanicum and brain metastasis. The radiobiological advantage of SRS/SRT/SBRT over conventional radiotherapy is the short course treatment with minimal toxicity. SRS/SBRT is not oxygen dependent tumor DNA damage but related to endothelial cell damage from apoptosis. The treatment volume margins in CNS cancers are tight to a millimeter hence rigid immobilization with head fraxion frame is required. The turnaround time from diagnosis, planning to treatment delivery for the patients is 72 hours. RESULTS 30 patients underwent SBRT treatment techniques varying from CNS and other sites. The case presentations in case series met the criteria and indications for SBRT treatment. The initial patient reported the treatment to be tolerable however currently we do have data on acute and long term in terms of both outcomes and toxicity. Follow up is needed to review and report on the outcomes.

Disulfidptosis-Related lncRNA for the Establishment of Novel Prognostic Signature and Therapeutic Response Prediction to Endometrial Cancer.

Disulfidptosis, a newly discovered cellular death mechanism initiated by disulfide stress, features elevated expression of SLC7A11 and restricted glucose availability, rendering it a possible therapeutic target for cancer. Endometrial cancer of the uterine corpus (ECUC) ranks among prevalent gynecological malignancies. Long non-coding RNAs (lncRNAs) have been implicated in ECUC's metabolic pathways, invasive capabilities, and metastatic processes. Yet, the prognostic implications of Disulfidptosis-Linked lncRNAs (DLLs) in ECUC remain ambiguous. Transcriptome and clinical datasets related to ECUC were sourced from The Cancer Genome Atlas (TCGA), while genes linked with disulfidptosis were identified from existing literature. A panel of ten DLLs was discerned through least absolute shrinkage and selection operator (LASSO) coupled with Cox regression methods to formulate and validate risk prognostic models. We engineered a nomogram for ECUC patient prognosis forecasting and further examined the model via gene set enrichment analysis (GSEA), principal component analysis (PCA), gene set analysis (GSA), immune profiling, and sensitivity to antineoplastic agents. Prognostic models employing a set of ten DLLs (including AC005034.2, AC020765.2, AL158071.4, AL161663.2, AP000787.1, CR392039.3, EMSLR, SEC24B-AS1, Z69733.1, Z94721.3) were established. Based on median risk values, patient samples were stratified into high- and low-risk cohorts, revealing notable differences in survival across both training and validation datasets. The risk scores, when amalgamated with clinical variables, acted as standalone predictors of prognosis. GSEA findings indicated that the high-risk category predominantly aligned with pathways like extracellular matrix interactions and cell adhesion molecules, suggesting a likely association with metastatic potential. Concurrently, we scrutinized disparities in immune function and tumor mutational burden across risk categories and identified anticancer drugs with likely efficacy. In summary, a set of ten DLLs proved useful in forecasting patient outcomes and holds potential for informing targeted therapeutic approaches in ECUC.

Management of arterial hypertension during therapy with antiangiogenic drugs in metastatic renal cell carcinoma

The use of antiangiogenic drugs in a single mode or in combination with immunotherapy in disseminated renal cell carcinoma has made it possible to achieve significant results in the therapy of the metastatic process. The flip side of effective therapy is the development of adverse events. An increase in blood pressure is one of the most frequent complications of antiangiogenic drug therapy with a frequency of up to 80 %.

3D bioprinted tumor-vessel-bone co-culture scaffold for breast cancer bone metastasis modeling and drug testing

Bone metastasis is one of the most common complications of advanced breast cancer (BrCa) with a poor clinical prognosis, due to the lack of effective drugs and therapeutics. Traditional screening systems for anti-cancer drugs are not capable of exactly reflecting the efficacy of drugs in vivo, mainly because they cannot replicate the dynamic metastasis process involving primary tumor, blood circulation and bone microenvironment. To precisely simulate the behavior of native BrCa cells, herein, a biomimetic 3D co-culture metastatic model composed of tumor, hollow vascular, and bone tissues is fabricated by one-step 3D bioprinting method for effective drug testing. Gelatin methacryloyl-based photocrosslinkable bioinks containing breast cancer cells (MDA-MB-231), human umbilical vein endothelial cells (HUVECs) and osteoblasts (h-OB) are applied to highly imitate the native metastatic niches with the formation of blood vessels, vascularized tumors, as well as vascularized bone tissues. The dynamic invasion behavior of BrCa cells from original sites to bone tissues through blood vessels is reproduced, and the interactive effect of cancer, vascular and bone cells are investigated. Moreover, the 3D co-culture metastatic model allows for higher drug resistance of BrCa cells than 2D culture and 3D mono-culture models. These results demonstrate that the 3D bioprinted co-culture metastatic model facilitates in-depth understanding of the basic mechanisms of BrCa migration and provides a physiologically relevant platform for the development of new therapeutic drugs.

Curcuminoid Nanovesicles as Advanced Therapeutics

AbstractTurmeric (Curcuma longa rhizome) is well‐known for its therapeutic properties in traditional Indian and Chinese medicines. It has preventive and therapeutic activity against diseases that target human body systems as well as various cancer types. This review focuses on the mechanism of action of curcumin against various factors involved in the metastatic process. The antimicrobial, antidiabetic, anti‐oxidant, and anti‐HIV activities and mechanism of curcumin‐functionalized nanovesicles are also reviewed. Despite the biocompatibility of curcumins, its medical applications are limited due to its low bioavailability, insolubility in water, and degradation at certain pH levels. Moreover, the low stability and rapid metabolism of curcumin limits its clinical applications. Therefore, it is imperative to design strategies to mitigate this shortfall which include the synthesis of curcumin glycosides or the development of curcumin delivery systems to improve the bioavailability and therapeutic efficacy of curcumin. This review provides insight into the different chemical methods for the synthesis and modification adopted to achieve these compounds.

The Metastasis Pattern of Renal Cell Carcinoma Is Influenced by Histologic Subtype, Grade, and Sarcomatoid Differentiation.

Background and Objectives: Metastasis is a major cause of death in renal cell carcinoma (RCC) patients; therefore, a better understanding of the metastatic process and the ability to predict metastasis in advance is important for treating patients with RCC. This study aimed to investigate whether histological subtypes of RCC and other factors, such as nuclear grade and sarcomatoid differentiation, could predict the probability and location of metastases in patients with RCC. Materials and Methods: Cases of clear-cell, papillary, chromophobe, and sarcomatoid RCC were retrieved and analyzed from the Surveillance, Epidemiology, and End Results databases. Results: When comparing the metastatic patterns among the three histologic subtypes, patients with clear-cell RCC were significantly more likely to have brain and lung metastases. Moreover, patients with papillary RCC were significantly less likely to develop bone metastases and more likely to develop lymph node metastases. Patients with chromophobe RCC are significantly more likely to develop liver metastases. As the nuclear grade increased, there was also a significantly increased tendency for clear-cell RCC to metastasize to the lungs. Patients with sarcomatoid RCC had a higher rate of metastasis, with a significantly higher probability of metastasis to the bone and lungs, than those with all three histological subtypes did. Conclusions: Histological subtype, nuclear grade, and sarcomatoid differentiation were significant predictors of metastasis in patients with RCC.

Recent Update Roles of Magnetic Nanoparticles in Circulating Tumor Cell (CTC)/Non-CTC Separation.

Metastasis of cancer is a major cause of death worldwide. Circulating tumor cells (CTCs) are important in the metastatic process of cancer. CTCs are able to circulate in the bloodstream. Therefore, they can be used as biomarkers of metastasis. However, CTCs are rare when compared to a large number of blood cells in the blood. Many CTC detection methods have been developed to increase CTC detection efficiency. Magnetic nanoparticles (MNPs) have attracted immense attention owing to their potential medical applications. They are particularly appealing as a tool for cell separation. Because of their unique properties, MNPs are of considerable interest for the enrichment of CTCs through CTC or non-CTC separation. Herein, we review recent developments in the application of MNPs to separate CTCs or non-CTCs in samples containing CTCs. This review provides information on new approaches that can be used to detect CTCs in blood samples. The combination of MNPs with other particles for magnetic-based cell separation for CTC detection is discussed. Furthermore, different approaches for synthesizing MNPs are included in this review.

Armillaria ostoyae extracts inhibit EMT of cancer cell lines via TGF-β and Wnt/β-catenin signaling components

Armillaria ostoyae is an edible mushroom, appreciated in human nutrition, with several medicinal properties already proven. However, its phenolic composition and effects on cancer have never been investigated so far, especially regarding specific signaling pathways included in first steps of cancer metastatic process, epithelial-mesenchymal transition (EMT) and migration. We report phenolic profile of two Armillaria ostoyae extracts, ethanol and diethyl ether (E and DE) and their effects on colorectal carcinoma (HCT-116) and cervical adenocarcinoma (HeLa) cells. Phenolics were detected using HPLC, while effects on cancer cells were investigated using MTT test; expression of markers related to EMT on gene and protein level by flow cytometry, immunofluorescence and qRT-PCR method. Antimigratory potential was assessed on collective and individual type of migration by Wound healing assay and RTCA technique. Sinapic acid was detected as the main phenolic component in E, while rutin and naringin were dominant in DE type of extract. Extracts notably suppressed pro-EMT markers: vimentin, N-cadherin, β-catenin, Snail, Smad2 and MMP-9, and elevated anti-EMT marker E-cadherin. Consequently, collective and single cell migration were significantly inhibited via regulation of TGF-β and Wnt/β-catenin signaling components. DE extract was more efficient in suppression of EMT and migration of colorectal and cervical cancer cells.

Mixed neuroendocrine-non-neuroendocrine neoplasm (minen) of the duodenum: a rare clinical case

The study presents a rare case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) of the duodenum in a somatically aggravated patient. Endoscopic, ultrasound, and CT diagnostic studies, which were performed during hospitalization for examination, could not unequivocally detect the exact organ location of the tumor. Due to the prevalence of liver metastasis processes, surgical methods of treatment were not indicated. The final diagnosis of a rare type of malignant neoplasm was made only by the results of a postmortem examination.

Molecular interaction of metastasis suppressor genes and tumor microenvironment in breast cancer

Breast cancer (BC) is a leading cause of cancer-related deaths in women worldwide where the process of metastasis is a major contributor to the mortality associated with this disease. Metastasis suppressor genes are a group of genes that play a crucial role in preventing or inhibiting the spread of cancer cells. They suppress the metastasis process by inhibiting colonization and by inducing dormancy. These genes function by regulating various cellular processes in the tumor microenvironment (TME), such as cell adhesion, invasion, migration, and angiogenesis. Dysregulation of metastasis suppressor genes can lead to the acquisition of an invasive and metastatic phenotype and lead to poor prognostic outcomes. The components of the TME generally play a necessary in the metastasis progression of tumor cells. This review has identified and elaborated on the role of a few metastatic suppressors associated with the TME that have been shown to inhibit metastasis in BC by different mechanisms, such as blocking certain cell signaling molecules involved in cancer cell migration, invasion, enhancing immune surveillance of cancer cells, and promoting the formation of a protective extracellular matrix (ECM). Understanding the interaction of metastatic suppressor genes and the components of TME has important implications for the development of novel therapeutic strategies to target the metastatic cascade. Targeting these genes or their downstream signaling pathways offers a promising approach to inhibiting the spread of cancer cells and improves patient outcomes.

New Therapeutic Perspectives in Prostate Cancer: Patient-Derived Organoids and Patient-Derived Xenograft Models in Precision Medicine.

One of the major goals in the advancement of basic cancer research focuses on the development of new anticancer therapies. To understand the molecular mechanisms of cancer progression, acquired drug resistance, and the metastatic process, the use of preclinical in vitro models that faithfully summarize the properties of the tumor in patients is still a necessity. The tumor is represented by a diverse group of cell clones, and in recent years, to reproduce in vitro preclinical tumor models, monolayer cell cultures have been supplanted by patient-derived xenograft (PDX) models and cultured organoids derived from the patient (PDO). These models have proved indispensable for the study of the tumor microenvironment (TME) and its interaction with tumor cells. Prostate cancer (PCa) is the most common neoplasia in men in the world. It is characterized by genomic instability and resistance to conventional therapies. Despite recent advances in diagnosis and treatment, PCa remains a leading cause of cancer death. Here, we review the studies of the last 10 years as the number of papers is growing very fast in the field. We also discuss the discovered limitations and the new challenges in using the organoid culture system and in using PDXs in studying the prostate cancer phenotype, performing drug testing, and developing anticancer molecular therapies.

Combined Biomarker System Predicts Prognosis in Patients with Metastatic Oral Squamous Cell Carcinoma.

Metastatic oral squamous cell carcinoma (OSCC) is associated with poor patient prognosis. Metastasis is a complex process involving various proteins, tumor cell alterations, including changes attributable to the epithelial-to-mesenchymal transition (EMT) process, and interactions with the tumor microenvironment (TME). In this study, we investigate a combined protein marker system consisting of connexin 43 (Cx43), EMMPRIN (CD147), E-cadherin, and vimentin, with a focus on their roles in the invasive metastatic progression of OSCC and their potential utility in predicting prognosis. We conducted an immunohistochemical analysis to assess the protein expression profiles of Cx43, EMMPRIN, E-cadherin, and vimentin using tissue samples obtained from 24 OSCC patients. The metastatic process was mapped through different regions of interest (ROIs), including adjacent healthy oral mucosa (OM), center of primary OSCC, invasive front (IF), and local cervical lymph node metastases (LNM). The primary clinical endpoints were disease-free survival (DFS) and overall survival (OS). Substantial changes in the expression profiles of the different marker proteins were observed among the different ROIs, with all p-values < 0.05, signifying statistical significance. Multivariable Cox regression analysis results showed a significant effect of increased EMMPRIN expression toward the IF on DFS (p = 0.019) and OS (p = 0.023). Furthermore, the combined predictive analysis showed a significant predictive value of the marker system for DFS (p = 0.0017) and OS (p = 0.00044). The combined marker system exhibited a significant ability to predict patient prognosis. An increase in EMMPRIN expression toward the IF showed the strongest effect and could be an interesting new antimetastatic therapy approach.

Matrix Metalloproteinase-2 (MMP-2): As an Essential Factor in Cancer Progression.

The development of cancer has been a multistep process involving mutation, proliferation, survival, invasion, and metastasis. Of all the characteristics of cancer, metastasis is believed to be the hallmark as it is responsible for the highest number of cancer-related deaths. In connection with this, Matrix metalloproteinases (MMPs), that has a role in metastasis, are one of the novel therapeutic targets. MMPs belong to the family of zinc-dependent endopeptidases and are capable of degrading the components of the extracellular matrix (ECM). The role of MMPs in ECM remodeling includes tissue morphogenesis, uterine cycling, growth, tissue repair, and angiogenesis. During pathological conditions, MMPs play a critical role in the excessive degradation of ECM which includes arthritis, tumour invasion, tumour metastasis, and several other autoimmune disorders. Moreover, they are believed to be involved in many physiological aspects of the cell, such as proliferation, migration, differentiation, angiogenesis, and apoptosis. It is reported that dysregulation of MMP in a variety of cancer subtypes have a dual role in tumour growth and metastasis processes. Further, multiple studies suggest the therapeutic potential of targeting MMP in invading cancer. The expression of MMP-2 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-2 may be a potential treatment strategy for different diseases, including cancers. Hence, the present review discusses the therapeutic potential of targeting MMP in various types of cancers and their recent patents.

FRI358 A Rare Cause Of SIADH: Leptomeningeal Deposits Metastatic From T-cell Proliferative Disorder

Abstract Disclosure: S. Bendaram: None. R. Zielinski: None. V. Kantorovich: None. Introduction: Atypical causes of SIADH, though rare, are important to identify and diagnose in order to optimize timely treatment. Case: Patient is a 51-year-old male with history of obesity and pre-diabetes who presented to the ED with symptoms of generalized weakness and severe fatigue with no antecedent events such as nausea, vomiting, diarrhea, fever or recent illness. He denied lightheadedness or a syncopal episode. History was significant for the use of prednisone for a skin rash in the recent past. Labs were significant for mild hyponatremia with sodium level of 130 mmol/L [136-141] with a low serum osmolality at 273 mOsm/kg and a urine osmolality of 287 mOsm/kg. Further evaluation revealed a low cortisol level of 1.9 ug/dL [6.2 - 19.4]. Repeat cortisol was also low at 1.1 ug/dl. Cosyntropin stimulation test resulted in insufficient response, and iatrogenic adrenal insufficiency was suspected due to prior steroid use. Steroid replacement therapy was initiated with Hydrocortisone. The patient’s ACTH was found to be inappropriately normal at 17pg/ml (6-50). For further evaluation, he underwent MRI Pituitary which revealed leptomeningeal lesions concerning for an infectious, inflammatory, or malignant metastatic process. At this time, he was still hyponatremic with sodium of 130 mmol/L and continued to complain of weakness and not feeling well overall, however denied any neurological symptoms. Repeat labs for hyponatremia showed serum osmolality of 283 mOsm/kg and urine osmolality of 573 mOsm/kg while urine sodium was 100 mmol/L, concerning for mild SIADH. This was managed with fluid restriction initially and then with addition of salt tablets. He underwent lumbar puncture with Cerebrospinal fluid analysis, which did not reveal an infectious etiology. A rheumatological work up for inflammatory cause was negative. Imaging of his chest and abdomen in a search for primary malignancy revealed soft tissue lesions in the abdominal subcutaneous fat. Biopsy of the soft tissue lesions were concerning for a T-cell lymphoproliferative disorder with the absence of typical histological features. Repeat biopsy, flow cytometry and cytogenetic studies were inconclusive, which was suspected to be secondary to the patient receiving steroids prior to the biopsy. Conclusion: This case represents SIADH likely caused by a T-cell lymphoproliferative disorder. Although the biopsies have been inclusive, if the patient has Non-Hodgkin’s T cell lymphoma (NHL), leptomeningeal spread is a known complication of this disorder. The underlying mechanism that we propose behind SIADH in our patient is the leptomeningeal lesion located near the hypothalamus enhancing ADH release. Presentation: Friday, June 16, 2023

IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas

Introduction: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. Materials and Methods: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. Results: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. Conclusions: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

LINC00922 decoys SIRT3 to facilitate the metastasis of colorectal cancer through up-regulation the H3K27 crotonylation of ETS1 promoter

BackgroundLysine crotonylation (Kcr) is up-regulation in colorectal cancer (CRC) tissues, while its specific contribution remains uncertain. This study aimed to elucidate the role and mechanism of crotonylation on Lys27 of histone H3 (H3K27cr) in facilitating CRC metastasis.MethodsImmunohistochemistry was employed to investigate the correlation between H3K27cr and CRC metastasis. Both in vitro and in vivo assays employing loss function or gain function approaches were conducted to elucidate the role of LINC00922 in promoting CRC metastasis. ScRNA-seq analysis and immunoprecipitation analyses were employed to explore the underlying mechanism by which LINC00922 facilitates CRC metastasis through H3K27cr.ResultsClinically, H3K27cr was upregulated in metastatic CRC tissues and positively correlated with advanced clinical stages. Functionally, knockdown of LINC00922 inhibited migration of CRC cells both in vitro and in vivo. Furthermore, the supplementation of NaCr restored the migration and invasion levels of LINC00922 stable knockdown cells by restoring the H3K27cr level. Mechanistically, LINC00922 promoted invasion and migration through H3K27cr mediated cell adhesion molecules (CAMs) in epithelial cells. Notably, LINC00922 interacted with the protein sirtuin 3 (SIRT3) and obstructed its binding to the promoter region of ETS1, leading to an elevation in the level of H3K27cr in this promoter region and the subsequent activation of ETS1 transcription.ConclusionsOur findings uncovered a novel regulatory function of H3K27cr, regulated by LINC00922, in facilitating CRC metastasis. This discovery contributed to a deeper comprehension of the involvement of histone crotonylation in the metastatic process of CRC.

Engineering subarachnoid trabeculae with electrospun poly(caprolactone) (PCL) scaffolds to study leptomeningeal metastasis in medulloblastoma

Leptomeningeal metastasis (LM) occurs when cancer cells infiltrate the subarachnoid space (SAS) and metastasize to the fibrous structures that surround the brain and spinal cord. These structures include the leptomeninges (i.e., the pia mater and arachnoid mater), as well as subarachnoid trabeculae, which are collagen-rich fibers that provide mechanical structure for the SAS, support resident cells, and mediate flow of cerebrospinal fluid (CSF). Although there is a strong expectation that the presence of fibers within the SAS influences LM to be a major driver of tumor progression and lethality, exactly how trabecular architecture relates to the process of metastasis in cancer is poorly understood. This lack of understanding is likely due in part to the difficulty of accessing and manipulating this tissue compartment in vivo. Here, we utilized electrospun polycaprolactone (PCL) to produce structures bearing remarkable morphological similarity to native SAS fiber architecture. First, we profiled the native architecture of leptomeningeal and trabecular fibers collected from rhesus macaque monkeys, evaluating both qualitative and quantitative differences in fiber ultrastructure for various regions of the CNS. We then varied electrospinning parameters to produce a small library of PCL scaffolds possessing distinct architectures mimicking the range of fiber properties observed in vivo. For proof of concept, we studied the metastasis-related behaviors of human pediatric medulloblastoma cells cultured in different fiber microenvironments. These studies demonstrated that a more open, porous fiber structure facilitates DAOY cell spread across and infiltration into the meningeal mimic. Our results present a new tissue engineered model of the subarachnoid space and affirm the expectation that fiber architecture plays an important role in mediating metastasis-related behaviors in an in vitro model of pediatric medulloblastoma.