Metastatic Pathways Research Articles

Prognostic and immunological role of Asporin across cancers and exploration in bladder cancer

BackgroundAsporin (ASPN) has been identified as a player in tumorigenesis, but its precise roles and modulatory function are largely unknown. Methods: In the present study, ASPN expression was first explored, followed by a prognostic evaluation of ASPN and a comprehensive investigation of the connections between ASPN and immunomodulation, immune cell infiltration and potential compounds on a pancancer level. Finally, ASPN expression was validated in bladder urothelial carcinoma (BLCA) tissues, and the potential function of ASPN, including its effects on migration and invasion capabilities, was investigated in tumor cells. Results: The expression of ASPN exhibited significant variation across cancers and was found to be associated with patient prognosis. In addition, the expression level of APSN was markedly correlated with the abundances of infiltrating immune cells and cancer-associated fibroblasts and the expression levels of immunomodulatory genes based on the results of pancancer analysis. Metastasis and immune-associated signaling pathways were identified in enrichment analysis based on ASPN expression. Finally, we confirmed that ASPN expression increased with the degree of malignancy in BLCA tissues and cell lines and that low expression of ASPN hindered the migration and invasion of cells. Conclusions: ASPN has the potential to be a biomarker of cancer prognosis and a therapeutic target, and it also has predictive capability for the progression of BLCA.

Tumour associated endothelial cells: origin, characteristics and role in metastasis and anti-angiogenic resistance.

Tumour progression and metastasis remain the leading causes of cancer-related death worldwide. Tumour angiogenesis is essential for tumour progression. The vasculature surrounding tumours is not only a transport channel for nutrients, oxygen, and metabolites, but also a pathway for metastasis. There is a close interaction between tumour cells and endothelial cells in the tumour microenvironment. Recent studies have shown that tumour-associated endothelial cells have different characteristics from normal vascular endothelial cells, play an important role in tumour progression and metastasis, and are expected to be a key target for cancer therapy. This article reviews the tissue and cellular origin of tumour-associated endothelial cells and analyses the characteristics of tumour-associated endothelial cells. Finally, it summarises the role of tumour-associated endothelial cells in tumour progression and metastasis and the prospects for their use in clinical anti-angiogenic therapy.

DIPG-52. EXTRAPONTINE PROGRESSION WITH STABLE PONTINE DISEASE POST-RADIOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ON A CONNECT TRIAL: IMPLICATIONS FOR RADIATION TREATMENT VOLUMES

Abstract Radiotherapy remains the only treatment modality proven to prolong survival and alleviate symptom burden for patients with DIPG. Upfront focal photon radiation to 54 Gy with 1-1.5cm margins is standard. Subventricular, leptomeningeal, and/or spinal dissemination is observed in up to 50% of cases at autopsy, with activation of metastasis-related pathways (eg, epithelial-mesenchymal transition) in a subset of tumors. Given potential for metastatic spread and critical implications for radiation field volumes, we analyzed the frequency of extrapontine disease progression with pontine tumor stability within a prospective cohort with standardized longitudinal imaging. In a CONNECT consortium-sponsored phase Ib trial with a radiosensitizing agent administered concurrently with focal radiation and adjuvantly, among 10 patients with DIPG who experienced progressive disease with available serial imaging, four (40%) had evidence of disease extension and/or non-contiguous dissemination with stable pontine tumor size at a median of 9 months (range: 5-15 months) from diagnosis. Specifically, extrapontine progression was observed in the spinal cord (n=3), cerebellum (n=2), basal ganglia (n=1), temporal lobe (n=1) and/or leptomeninges and ependymal surfaces (n=1), without radiographic pontine disease progression. Five of the remaining six patients (who came off treatment due to pontine progression) subsequently had radiographic evidence of extrapontine extension (cerebellar, spinal, thalamic, supratentorial). Comprehensive molecular profiling is underway on biopsy or autopsy specimens for three patients, focusing on metastasis pathways. In summary, within a small prospective cohort with longitudinal imaging, we observed extrapontine progression despite local pontine disease control following focal radiotherapy in 40% of patients with DIPG at a median of 9 months after diagnosis. Further research will be essential to identify biological predictors of dissemination and corroborate findings in a larger cohort, but results suggest at least a subset of patients with DIPG may benefit from larger radiation volume expansion into contiguous structures and white matter tracts.

High USP4 mRNA is associated with an HPV-positive status in head and neck squamous cell carcinoma patients

IntroductionHead and neck squamous cell carcinoma (HNSCC) is among the most common cancers in the world with a low survival rate and common diagnosis at late stages. Deubiquitination of proteins is involved in tumor growth, metastasis, apoptosis, and immunosuppressive pathways. The impact of the ubiquitin-specific protease (USP4) on survival was only scarcely investigated so far. The goal of our research was to analyze the association of USP4 expression with prognosis and clinicopathological features in HNSCC.MethodsUSP4 mRNA levels were derived from The Cancer Genome Atlas (TCGA) for a cohort of 510 patients. Protein expression of USP4 was analyzed by immunohistochemistry in a second cohort of 113 patients. Associations between USP4 levels and overall survival, disease-free survival and clinicopathological data were analyzed.ResultsHigh levels of USP4 mRNA were associated with prolonged overall survival in univariable analysis. There was no more association with survival after correction for the confounders HPV, stage and smoker status. High USP4 mRNA levels were linked to a lower T-stage, the patient’s age at diagnosis, and a positive HPV status. USP4 protein levels were not associated with prognosis or other features.ConclusionSince high USP4 mRNA was not an independent prognostic marker, we assume that the association is a result of the correlation of high USP4 mRNA with an HPV-positive status. Therefore, further investigation of USP4 mRNA and its association with the HPV status of HNSCC patients is warranted.

Assessment of Immunomorphological Patterns in Metastatic and Non-Metastatic Lymph Nodes of Oral Squamous Cell Carcinoma Patients

Introduction: Metastasis in oral epidermoid carcinoma oral squamous cell carcinoma (OSCC) can occur differently. Lymph nodes and lymphatics which drain the tumour site, serve as the most common pathway for metastasis. Lymph nodes serve as a marker of the immune status of the patient, which in response to a metastatic event, may facilitate or resist the homing of tumour cells. This host immune response is identified by examining various immunoreactive patterns in the lymph node. Materials and Methods: A total of 100 cases of OSCC underwent radical neck dissection and were assessed for grading of tumour histology, immunomorphological patterns (IMPs) in metastatic and non-metastatic lymph nodes as well as the pattern of tumour involvement in positive lymph nodes. All the lymph nodes were histologically evaluated and were grouped as metastatic and non-metastatic lymph nodes, showing four different patterns lymphocyte predominance (LP) pattern, germinal centre predominance (GCP) pattern, sinus histiocytosis (SH) pattern and lymphocyte depleted pattern. Metastatic positive nodes were further evaluated for the pattern of tumour cell invasion within the lymph node. Results: A total number of 1167 lymph nodes were histologically evaluated. Out of all, 239 lymph nodes were positive for metastasis and 928 were non-metastatic nodes. The most frequently encountered lymph node pattern was of LP (854 nodes), followed by GCP (157 nodes), SH (120 nodes) and lymphocyte depleted (36 nodes), respectively. Out of 1167, 239 nodes were positive for metastasis, indicating that as the stage advances, the GCP type predominates (the predominant IMP shifts from LP to GCP), so that facilitating or favouring metastasis. Moreover, the most common pattern seen in metastatic deposits observed was islands/sheets followed by strands/cords. Conclusion: IMPs of regional lymph nodes of OSCCs seem to be an essential factor in serving as a prognostic indicator. Whereas the cell-mediated immune response represented by LP and SH resist the metastasis process, the humoral reflected by GCP favours metastasis.

Abstract 43: Heme Oxygenase 1 Counteracts Pro-Stemness and Pro-Invasive Effect Triggered by Communication With Bone Progenitors in Prostate Cancer Cells

Abstract Purpose: Mortality in prostate cancer (PCa) patients is mostly associated with bone metastasis and aggressive phenotypes promoted by prostate cancer stem cells (PCSCs). We have previously described that heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme catabolism with antioxidant and antiinflammatory properties, presents an antitumoral role in PCa. In this work, we assessed the role of HO-1 as a modulator of stemness and metastasis associated genes in PCa cells conditioned by bone progenitor cells. Methods: An indirect transwell co-culture system of PC3 cells, a PCa cell line, with MC3T3 cells, an osteoblast precursor cell line, was developed as an in vitro model of PCa bone metastasis. Additionally, PC3 cells were pre-treated with hemin, a pharmacological HO-1 inductor. An RNA-seq was performed to analyze the transcriptome of PC3 cells. The expression of a curated list of 87 genes associated with stemness, metastasis and the STAT3 pathway, including PCSC and classic pluripotency markers, together with a gene signature previously described by our group (ADAM15, BCL2L1, LTBR, MBNL2, SPINT1), was assessed. Results were complemented with survival data of PCa patients (TCGA-PRAD, n=565). Results: Our results showed that PC3 cells co-cultured with MC3T3 cells displayed an upregulation of PCSC markers CD44, ALDH1A3 and ALDH1L2, pluripotency markers OCT4 and SOX2, and BCL2L1 and LTBR, two genes included in our signature, compared with non-co-cultured PC3 cells. Further, when comparing co-cultured PC3 cells vs. co-cultured PC3 cells pre-treated with hemin, in the latter group the expression of 71/87 genes associated with stemness, metastasis and STAT3 pathway decreased, including CD44, ALDH1A3, ALDH1L2, OCT4, MBNL2 and ADAM15. Moreover, when evaluating patients’ disease progression free survival, those with high expression of OCT4 showed a lower risk of the event. Conclusion: HO-1 expression modulates stemness and metastasis related genes in PCa, promoting a more differentiated state, counteracting the pro-stemness effect of communication with bone progenitors. This further supports the antitumoral role of HO-1 in PCa pointing out to its potential as a therapeutic target for the disease. Citation Format: Ines Achinelli, Agustina Sabater, Pablo Sanchis, Nicolás Anselmino, Sofía Lage-Vickers, Gaston Pascual, Rocio Seniuk, Pamela Freiria, Javier Cotignola, Elba Vazquez, María Sol Ruiz, Geraldine Gueron, Ayelen Toro. Heme Oxygenase 1 Counteracts Pro-Stemness and Pro-Invasive Effect Triggered by Communication With Bone Progenitors in Prostate Cancer Cells [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 43.

An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation-Mediated Combination Tumor Therapy.

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP-1 peptide is reported. The resulting generation 5 (G5) dendrimer-based nanodevice, known as G5-PEG-LyP-1-CuS-DMXAA NPs (GLCD NPs), possess good colloidal stability, pH-sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP-1-targeted killing effect on breast tumors by combining CuS-mediated photothermal therapy (PTT) and DMXAA-induced vascular disruption, while also triggering antitumor immune responses through PTT-induced immunogenic cell death and DMXAA-mediated immune regulation via M1 polarization of tumor-associated macrophages and dendritic cell maturation. In addition, with the LyP-1-mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two-pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation-mediated combination tumor therapy with potential for clinical translations.

Poly-G for tumor matched samples chronicles the evolution of human colorectal cancer

Objective: To analyze poly-guanine (poly-G) genotypes and construct the phylogenetic tree of colorectal cancer (CRC) and provide an efficient and convenient method for the study of intra-tumor heterogeneity and tumor metastasis pathway. Methods: The clinicopathological information of patients with primary colorectal cancer resection with regional lymph node metastases were retrospectively collected in the Department of General Surgery, General Hospital of Tianjin Medical University from January 2017 to December 2017. The paraffin sections of the paired tumor samples were performed consecutively, and multi-region microdissection was performed after histogene staining. The phenol-chloroform extraction and ethanol precipitation scheme was used to obtain DNA, and Poly-G multiplex PCR amplification and capillary electrophoresis detection were performed. The correlation between Poly-G mutation frequency and clinicopathological parameters was analyzed. Based on the difference of Poly-G genotypes between paired samples, the distance matrix was calculated, and the phylogenetic tree was constructed to clarify the tumor metastasis pathway. Results: A total of 237 paired samples were collected from 20 patients including 134 primary lesions, 66 lymph node metastases, 37 normal tissues, and Poly-G mutation was detected in 20 patients (100%). The mutation frequency of Poly-G in low and undifferentiated patients was (74.10±23.11)%, higher than that in high and medium differentiated patients [(31.36±12.04)%, P<0.001]. In microsatellite instability patients, the mutation frequency of Poly-G was (68.19±24.80)%, which was higher than that in microsatellite stable patients [(32.40±14.90)%, P=0.003]. The Poly-G mutation frequency was not correlated with age, gender, and pathological staging (all P>0.05). Based on Poly-G genotype difference of the paired samples, the phylogenetic trees of 20 patients were constructed, showing the evolution process of the tumor, especially the subclonal origins of lymph node metastasis. Conclusion: Poly-G mutations accumulate in the occurrence and development of CRC, and can be used as genetic markers to generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.

The relationship between the Hippo signaling pathway and bone metastasis of breast cancer.

Bone is the most common site of metastasis from breast cancer, which is the most prevalent cancer affecting women globally. Bone metastasis from breast cancer severely affects the quality of life of patients and increases mortality. The molecular mechanisms of metastasis, colonization, and proliferation of breast cancer cells in bone are complex and involve the interaction between breast cancer cells and the bone microenvironment. However, the precise mechanism is not clear at present. In recent years, the Hippo signaling pathway has attracted much attention due to its important role in regulating the expression of major effector molecules during tumor development. In particular, studies have found that the mutation and aberrant expression of the core components of the Hippo signaling pathway affect breast cancer cell migration and invasion, indicating that this pathway plays a role in bone metastasis, although the molecular mechanism of this pathway in breast cancer metastasis has not been fully elucidated. In this review, we discuss the function of the Hippo signaling pathway, introducing its role in breast cancer metastasis, especially bone metastasis of breast cancer, so as to lay a solid theoretical foundation for further research and for the development of effective targeted therapeutic agents.

Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy.

Cancer metastasis is a significant challenge in cancer treatment, and most existing drugs are designed to inhibit tumor growth but are often ineffective in treating metastatic cancer, which is the leading cause of cancer-related deaths. Resveratrol, a polyphenol found in grapes, berries, and peanuts, has shown potential in preclinical studies as an anticancer agent to suppress metastasis. However, despite positive results in preclinical studies, little progress has been made in clinical trials. To develop resveratrol as an effective anticancer agent, it is crucial to understand its cellular processes and signaling pathways in tumor metastasis. This review article evaluates the current state and future development strategies of resveratrol to enhance its potency against cancer metastasis within its therapeutic dose. In addition, we critically evaluate the animal models used in preclinical studies for cancer metastasis and discuss novel techniques to accelerate the translation of resveratrol from bench to bedside. The appropriate selection of animal models is vital in determining whether resveratrol can be further developed as an antimetastatic drug in cancer therapy.

Exosome-mediated miR-200a delivery into TGF-β-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression

Exosomes are small extracellular vesicles that can be derived from human cells such as mesenchymal stem cells (MSCs). The size of exosomes is at nano-scale range and owing to their biocompatibility and other characteristics, they have been promising candidates for delivery of bioactive compounds and genetic materials in disease therapy, especially cancer therapy. Gastric cancer (GC) is a leading cause of death among patients and this malignant disease affects gastrointestinal tract that its invasiveness and abnormal migration mediate poor prognosis of patients. Metastasis is an increasing challenge in GC and microRNAs (miRNAs) are potential regulators of metastasis and related molecular pathways, especially epithelial-to-mesenchymal transition (EMT). In the present study, our aim was to explore role of exosomes in miR-200a delivery for suppressing EMT-mediated GC metastasis. Exosomes were isolated from MSCs via size exclusion chromatography. The synthetic miR-200a mimics were transfected into exosomes via electroporation. AGS cell line exposed to TGF-β for EMT induction and then, these cells cultured with miR-200a-loaded exosomes. The transwell assays performed to evaluate GC migration and expression levels of ZEB1, Snail1 and vimentin measured. Exosomes demonstrated loading efficiency of 5.92 ± 4.6%. The TGF-β treatment transformed AGS cells into fibroblast-like cells expressing two stemness markers, CD44 (45.28%) and CD133 (50.79%) and stimulated EMT. Exosomes induced a 14.89-fold increase in miR-200a expression in AGS cells. Mechanistically, miR-200a enhances E-cadherin levels (P < 0.01), while it decreases expression levels of β-catenin (P < 0.05), vimentin (P < 0.01), ZEB1 (P < 0.0001) and Snail1 (P < 0.01), leading to EMT inhibition in GC cells. This pre-clinical experiment introduces a new strategy for miR-200a delivery that is of importance for preventing migration and invasion of GC cells.

NDRG1 facilitates self-renewal of liver cancer stem cells by preventing EpCAM ubiquitination.

Portal vein tumour thrombus (PVTT) is the main pathway of HCC intrahepatic metastasis and is responsible for the poor prognosis of patients with HCC. However, the molecular mechanisms underlying PVTT vascular metastases have not been fully elucidated. NDRG1 expression was assessed by immunohistochemistry and immunoblotting in clinical specimens obtained from curative surgery. The functional relevance of NDRG1 was evaluated using sphere formation and animal models of tumorigenicity and metastasis. The relationship between NDRG1 and EpCAM was explored using molecular biological techniques. NDRG1 protein was upregulated in HCC samples compared to non-tumorous tissues. Furthermore, NDRG1 expression was enhanced in the PVTT samples. Our functional study showed that NDRG1 was required for the self-renewal of tumour-initiating/cancer stem cells (CSCs). In addition, NDRG1 knockdown inhibited the proliferation and migration of PVTT-1 cells in vitro and in vivo. NDRG1 was found to stabilise the functional tumour-initiating cell marker EpCAM through protein-protein interactions and inhibition of EpCAM ubiquitination. Our findings suggest that NDRG1 enhances CSCs expansion, PVTT formation and growth capability through the regulation of EpCAM stability. NDRG1 may be a promising target for the treatment of patients with HCC and PVTT.

Instrumental and transcriptome analysis reveals the chemotherapeutic effects of doxorubicin-loaded black phosphate nanosheets on abiraterone-resistant prostate cancer

Prostate cancer is the second most common cause of cancer-related deaths in men and is common in most developed countries. Androgen deprivation therapy (ADT) that uses abiraterone acetate (AA) is an effective second-line treatment for prostate cancer. However, approximately 20–40% of patients develop primary resistance to abiraterone post-treatment. In this study, we aimed to understand the molecular mechanisms underlying the development of abiraterone resistance in prostate cancer cells and the potential use of black phosphorus nanosheets (BPNS) for treating abiraterone-resistant prostate cancer. We first established abiraterone-resistant prostate cancer PC-3 cells and found that these cells have higher migration ability than normal prostate cancer cells. Using comparative transcriptomic and bioinformatics analyses between abiraterone-sensitive PC-3 and abiraterone-resistant PC-3 cells, we highlighted the differentially expressed genes (DEGs) involved in the biological processes related to prostate gland morphogenesis, drug response, immune response, angiogenesis. We further studied the therapeutic effects of BPNS. Our results show that BPNS reduced the proliferation and migration of abiraterone-resistant PC-3 cells. Bioinformatics analysis, including gene ontology, Kyoto encyclopedia of genes and genomes enrichment analysis, and ingenuity pathway analysis (IPA) of the DEGs, suggested that BPNS treatment controlled cancer cell proliferation, metastasis, and oncogenic signaling pathways. Furthermore, the IPA gene network highlighted the involvement of the MMP family, ATF, and notch families in the anti-prostate cancer function of BPNS. Our findings suggest that BPNS may have a chemotherapeutic function in treating abiraterone-resistant prostate cancer.

Inhibition of the Sonic Hedgehog Pathway using Small Molecule Inhibitors: Targeting Colon Cancer Stem Cells

&lt;p&gt;Background: The Hedgehog (HH) pathway is a key regulator of many important processes in vertebrate embryonic development, including stem cell maintenance, cell differentiation, tissue polarity and cell proliferation. During pathway activation, Ptch no longer inhibits Smo and the full length Gli translocates to the nucleus resulting in the transcription of oncogenes. When constitutively activated, this leads to tumorigenesis in several human cancers. Cyclopamine acts as an antagonist of the HH signalling pathway by directly binding to the Smo heptahelical domain. The involvement of this pathway in metastasis, and its presence in cancer stem cells (CSCs), makes it a valid option for developing a targeted therapeutic against it. &lt;p&gt; Methods: CSC were isolated from DLD1 and HT29 cell lines using magnetic cell separation labelling the CD133 receptor. The growth patterns of isolated CSCs (CD133 positive) in comparison to non-stem cells (CD133 negative) were analysed using real-time cell impedance assays (RTCA). Thereafter, adhesion, invasion and migration assays were performed with the application of small molecule inhibitors. The expression levels of CD133 and SHH were evaluated using confocal microscopy following treatment with cyclopamine. &lt;p&gt; Results and Discussion: Growth of CSCs appeared to be slower than non-CSCs. Adhesion, invasion and cell migration were inhibited when CSCs were pharmacologically treated either with cyclopamine or SANT-2 (a synthetic analogue of cyclopamine), small molecule inhibitors of the HH pathway. Using confocal microscopy the cell surface expression of Sonic Hedgehog (SHH) was significantly decreased following treatment with cyclopamine, while the expression of CD133 remained unaffected. &lt;p&gt; Conclusion: Considering these in vitro results, small molecule inhibitors targeting the SHH pathway appear to be promising therapeutic tools for the treatment of metastatic colon CSCs.&lt;/p&gt;

Metastasis prevention: How to catch metastatic seeds.

Despite considerable advances in the evolution of anticancer therapies, metastasis still remains the main cause of cancer mortality. Therefore, current strategies for cancer cure should be redirected towards prevention of metastasis. Targeting metastatic pathways represents a promising therapeutic opportunity aimed at obstructing tumor cell dissemination and metastatic colonization. In this review, we focus on preclinical studies and clinical trials over the last five years that showed high efficacy in suppressing metastasis through targeting lymph node dissemination, tumor cell extravasation, reactive oxygen species, pre-metastatic niche, exosome machinery, and dormancy.

Dynamacophore model for breast cancer estrogen receptor alpha as an effective lead generation screening technique

Regardless to overwhelming quantum of cancer research worldwide, there are few drugs on the market to treat disease conditions. This is owing to multiple process inferences of drug targets in integrated pathways for invasion, growth, and metastasis. Over the past years, the death rate due to breast cancer has been increasing, that set the stage for improved better treatment. Therefore, there is a persistent and vital demand for innovative development of drugs to treat breast cancer. Many studies have reported that more than 60% of breast cancers are Estrogen receptor-α (ERα)-positive tumours and a key transcription factor, Estrogen receptor-α (ERα) was believed to promote proliferation of breast cancer cells. In this study, 150 ns of molecular dynamics was performed for protein-ligand complex to retrieve the potential stable conformations. The most populated dynamics cluster of 4-Hydroxytamoxifen intact with active site amino acid was selected to generate dynamacophore model (dynamic pharmacophore). Further, internal model validation with AU-ROC values ∼0.93 indicate the best model to screen library. The refined hits are funnelled in pharmacokinetics/dynamics, CDOCKER molecular docking, MM-GBSA and density functional theory to identify the promising ERα ligand candidates. Communicated by Ramaswamy H. Sarma

New method of modified chemoradiotherapy for cancer of the upper and middle ampullary rectum

The last decade is characterized by significant progress in the treatment of rectal cancer (reduction in the number of relapses to 5–6 % with the use of prolonged radiation therapy) before surgery. The greatest success has been achieved in the treatment of cancer of the lower ampulla of the rectum, when it is possible to develop a complete clinical response of the rectal tumor to chemoradiotherapy. Nevertheless, the requirement issues to improve the results of treatment of cancer of the upper and middle ampullar rectum with an increase in the survival of patients remain. Which makes it relevant to develop new methods, that increase the effectiveness of the treatment of rectal cancer.The method of modified chemoradiotherapy for cancer of the upper ampulla of the rectum was developed in our study. The method is as follows: at the first stage, one day before the start of radiation therapy, the patient undergoes superselective catheterization of the superior rectal artery through the radial or femoral artery, followed by regional administration of radiomodifying chemotherapy drugs: cisplatin 50 mg and fluorouracil 500 mg. In one day, patients begin to undergo a course of conformal remote large- fraction radiation therapy to the primary focus and metastasis pathways for 5 sessions with a single focal dose of 5 Gy to a total focal dose of 25 Gy using a low-energy linear accelerator. During the entire course of radiation therapy, fluorouracil 500 mg is administered daily intravenously for 30 minutes in 30 minutes before the session. Surgical intervention with the sampling of material for research is carried out 6–8 weeks after the radiation therapy is completed. To assess the effectiveness of the modified chemoradiotherapy, the stage of tumor regression was determined according to the RECIST scale, and the level of therapeutic pathomorphology of the tumor according to Dworak was determined during a morphological study of the rectal tumor removed during the operation.The developed method of modified chemoradiotherapy makes it possible to achieve regression of the rectal tumor in a short time, reduce the time and increase the effectiveness of treatment. The method of modified chemoradiotherapy is intended for patients with cancer of the upper and middle ampullar rectum T3-4N0-2M0, for whom radiation therapy is indicated as the first stage of treatment, after which resection of the rectum is performed in a standard volume.

Network pharmacology-integrated molecular docking analysis of phytocompounds of Caesalpinia pulcherrima (peacock flower) as potential anti-metastatic agents

Caesalpinia pulcherrima, or peacock flower, has been a subject of cancer therapeutics research, showing promising anti-cancer and anti-metastatic properties. The present research aims to investigate the anti-metastatic potential of the flower, through bioinformatics approaches. Metastasis targets numbering 471 were identified through overlap analysis following NCBI gene, Gene Card and OMIM query. Phytocompounds of the flower were retrieved from PubChem and their protein interactions predicted using Super-PRED and TargetNet. The 28 targets that overlapped with the predicted proteins were used to generate STRING >0.7. Enrichment analysis revealed that C. pulcherrima may inhibit metastasis through angiogenesis-related and leukocyte migration-related pathways. HSP90AA1, ESR1, PIK3CA, ERBB2, KDR and MMP9 were identified as potential core targets while and 6 compounds (3-[(4-Hydroxyphenyl)methylidene]-7,8-dimethoxychromen-4-one (163076213), clotrimazole (2812), Isovouacapenol A (636673), [(4aR,5R,6aS,7R,11aS,11bR)-4a-hydroxy-4,4,7,11b-tetramethyl-9-oxo-1,2,3,5,6,6a,7,11a-octahydronaphtho[2,1-f][1]benzofuran-5-yl] benzoate (163104827), Stigmast-5-en-3beta-ol (86821) and 4,2'-dihydroxy-4'-methoxychalcone (592216)) were identified as potential core compounds. Molecular docking analysis and molecular dynamics simulations investigations revealed that ERBB2, HSP90AA1 and KDR, along with the newly discovered 163076213 compound to be the most significant metastasis targets and bioactive compound, respectively. These three core targets demonstrated interactions consistent with angiogenesis and leukocyte migration pathways. Furthermore, potentially novel interactions, such as KDR-MMP9, KDR-PIK3CA, ERBB2-HSP90AA1, ERBB2-ESR1, ERBB2-PIK3CA and ERBB2-MMP9 interactions were identified and may play a role in crosslinking the aforementioned metastatic pathways. Therefore, the present study revealed the main mechanisms behind the anti-metastatic effects of C. pulcherrima, paving the path for further research on these compounds and proteins to accelerate the research of cancer therapeutics and application of C. pulcherrima. Communicated by Ramaswamy H. Sarma

Depriving Tumor Cells of Ways to Metastasize: Ferroptosis Nanotherapy Blocks Both Hematogenous Metastasis and Lymphatic Metastasis.

Blood and lymph are two main pathways of tumor metastasis; however, hematogenous metastasis and lymphatic metastasis are difficult to inhibit simultaneously. Ferroptosis provides a new breakthrough for metastasis inhibition, but how to effectively trigger ferroptosis in tumor cells remains a major challenge. Metastatic tumor cells are prone to ferroptosis in blood, while they may be protected from ferroptosis in lymph. In this study, a nanoplatform DA/RSL3 was constructed for the intracellular codelivery of the polyunsaturated arachidonic acid (AA) and the GPX4 inhibitor RSL3, which could not only induce ferroptosis but also alleviate ferroptosis resistance. As a result, DA/RSL3 effectively triggered ferroptosis in tumor cells, thereby impairing the ability of tumor cells to metastasize in both blood and lymph. Furthermore, a fucoidan blocking strategy was proposed to maximize the efficacy of DA/RSL3. Fu+DA/RSL3 showed excellent efficacy in 4T1 tumor-bearing mice. This ferroptosis nanotherapy is promising for metastatic cancer treatment.

PD17-11 MOLECULAR PROFILING REVEALS IMMUNOSUPPRESSIVE TUMOR IMMUNE MICROENVIRONMENT IN PRIMARY VERSUS PAIRED ASYNCHRONOUS METASTATIC CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023PD17-11 MOLECULAR PROFILING REVEALS IMMUNOSUPPRESSIVE TUMOR IMMUNE MICROENVIRONMENT IN PRIMARY VERSUS PAIRED ASYNCHRONOUS METASTATIC CLEAR CELL RENAL CELL CARCINOMA Brittney Cotta, Srinivas Nallandhighal, Daniel Triner, Nathan Graham, Rohit Mehra, Marcin Cieslik, Amy Kasputis, Todd Morgan, and Simpa Salami Brittney CottaBrittney Cotta More articles by this author , Srinivas NallandhighalSrinivas Nallandhighal More articles by this author , Daniel TrinerDaniel Triner More articles by this author , Nathan GrahamNathan Graham More articles by this author , Rohit MehraRohit Mehra More articles by this author , Marcin CieslikMarcin Cieslik More articles by this author , Amy KasputisAmy Kasputis More articles by this author , Todd MorganTodd Morgan More articles by this author , and Simpa SalamiSimpa Salami More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is a highly immune infiltrated cancer, but how the tumor immune microenvironment (TIME) evolves during disease progression is unknown. Insights into heterogeneity within primary ccRCC raise questions about potential heterogeneity between primary and paired metastatic tumors. This information may improve understanding of immune evasion leading to metastatic disease and response to immunotherapy. In this study, we characterize and compare the TIME of primary ccRCC with paired asynchronous metastases. METHODS: Analysis of ccRCC patients who developed recurrence post radical nephrectomy and had both primary and metastatic tissue available. Whole-transcriptome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) specimens using the illumina platform. Differential expression gene (DEG) analysis was performed using R package edgeR. Gene set enrichment analyses (GSEA) to identify hallmark pathway enrichment was performed using R package fgsea. TIME deconvolution was quantified using CIBEROSRT, an in silico flow cytometry tool. RESULTS: 42 tumor samples from 19 patients (19 primary tumors with 23 matched metastases) were analyzed. Metastasis sites included lung (n=6), bone (n=6), adrenal (n=4), liver (n=2), lymph node (n= 2), and soft tissue (n=3). Angiogenesis and epithelial to mesenchymal transition (EMT) were the most significantly enriched pathways in metastases compared to primary tumors (FDR < 5%). The primary tumors displayed a more immunosuppressive TIME than their matched metastases when comparing immune cell types. (Figure 1). The higher proportion of T regulatory cells (Tregs) in primary tumors was consistent compared against all metastasis tissue types. Metastasis samples displayed higher proportion of M2 macrophages (p=0.003), with the highest proportion in bone and soft tissue. Bone metastases also appeared to be more immunosuppressive in their TIME when compared to lung metastases, with greater Tregs and a lower immune content score. CONCLUSIONS: We demonstrate higher infiltration of immunosuppressive cells in the TIME of primary ccRCC compared with metastatic sites. Further studies are necessary to determine the prognostic and therapeutic significance of these findings. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e500 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brittney Cotta More articles by this author Srinivas Nallandhighal More articles by this author Daniel Triner More articles by this author Nathan Graham More articles by this author Rohit Mehra More articles by this author Marcin Cieslik More articles by this author Amy Kasputis More articles by this author Todd Morgan More articles by this author Simpa Salami More articles by this author Expand All Advertisement PDF downloadLoading ...