Inhibited Tumor Cell Migration Research Articles

Effects of Vitamins E and D on Mechanical Properties of Breast Cancerous Cells

Background: Several investigations have demonstrated that vitamins can treat or prevent cancer by altering actin filaments and inhibiting cell migration and proliferation. Vitamins D and E are fat-soluble. This research aims to determine the short-term impact of vitamin D and E on the mechanical properties of breast cancer cells before comparing them with normal breast cells. Methods: Atomic force microscopy (AFM) was used to examine the deformation of MCF-10 normal breast cells, MCF-7 breast cancer cells, and MCF-7 breast cancer cells treated with 0.03 μM vitamin D and 16 μM vitamin E solutions. Young's modulus was calculated employing the Hertz model to determine cell stiffness. Results: The Young's modulus of vitamin D-treated cancer cells (585.8 Pa) was substantially similar to that of normal cells (455.6 Pa). Nevertheless, vitamin E treatment did not affect Young's modulus of cancer cells, which remained remarkably similar to that of untreated cancer cells (216.6 and 203.4 Pa, respectively). Conclusion: Unlike vitamin E, vitamin D enhances the stiffness of tumor cells and makes their mechanical properties similar to normal cells by interfering with actin filaments and cell skeletons, which may inhibit tumor cell migration. Based on these findings, vitamin D appears to be an effective drug for cancer treatment.

Multifunctional Biomimetic Liposomes with Improved Tumor-Targeting for TNBC Treatment by Combination of Chemotherapy, Antiangiogenesis and Immunotherapy.

Triple negative breast cancer (TNBC) featuring high relapses and metastasis shows limited clinical therapeutic efficiency with chemotherapy for the extremely complex tumor microenvironment, especially angiogenesis and immunosuppression. Combination of antiangiogenesis and immunotherapy holds promise for effective inhibition of tumor proliferation and invasion, while it remains challenging for specific targeting drug delivery to tumors and metastatic lesions. Here, a multifunctional biomimetic liposome loading Gambogic acid (G/R-MLP) is developed using Ginsenoside Rg3 (Rg3) to substitute cholesterol and cancer cell membrane coating, which is designed to increase long-circulating action by a low immunogenicity and specifically deliver gambogic acid (GA) to tumor site and metastatic lesions by homologous targeting and glucose transporter targeting. After G/R-MLP accumulates in the primary tumors and metastatic nodules, it synergistically enhances the antitumor efficacy of GA, effectively suppressing the tumor growth and lung metastasis by killing tumor cells, inhibiting tumor cell migration and invasion, achieving antiangiogenesis and improving the antitumor immunity. All in all, the strategy combining chemotherapy, antiangiogenesis, and immunotherapy improves therapeutic efficiency and prolonged survival, providing a new perspective for the clinical treatment of TNBC.

Polyphenolic dendrimers as carriers of anticancer siRNA

Dendrimers have emerged as an important group of nanoparticles to transport drugs, DNA, or RNA into target cells in cancer and other diseases. Various functional modifications can be imposed on dendrimers to increase the efficacy and specificity in delivering their cargo to the target cells and decrease their toxicity. In the present work, we evaluated the potential of carbosilane polyphenolic dendrimers modified with caffeic acid (CA) and polyethylene glycol (PEG) to deliver proapoptotic Mcl-1 and Bcl-2 siRNAs to A549 cancer cells. Dendrimers formed stable complexes with siRNAs as assessed by transmission electron microscopy and gel electrophoresis. Modification of dendrimers with PEG reduced the size and the zeta potential of dendrimer/siRNA complexes. The presence of PEG caused a red shift of the CD spectrum, and this effect was the more pronounced, the higher the dendrimer/siRNA ratio was. The nanocomplexes were internalized by A549. All studied dendrimer/siRNA formulations inhibited tumor cell migration and adhesion and caused an increase in the population of early apoptotic cells. Among four tested dendrimers, the polyphenolic compound containing two caffeic acid moieties complexed with siRNA demonstrated the lowest polydispersity index and showed an excellent transfection profile. In conclusion, this dendrimer are a promising candidate for the delivery of siRNA into cancer cells in further in vivo studies.

Synergistic effects of photodynamic therapy and chemotherapy: Activating the intrinsic/extrinsic apoptotic pathway of anoikis for triple-negative breast cancer treatment

Triple-negative breast cancer (TNBC) is a highly invasive and metastatic subtype of breast cancer that often recurs after surgery. Herein, we developed a cyclodextrin-based tumor-targeted nano delivery system that incorporated the photosensitizer chlorin e6 (Ce6) and the chemotherapeutic agent lonidamine (LND) to form the R6RGD-CMβCD-se-se-Ce6/LND nanoparticles (RCC/LND NPS). This nanosystem could target cancer cells, avoid lysosomal degradation and further localize within the mitochondria. The RCC/LND NPS had pH and redox-responsive to control the release of Ce6 and LND. Consequently, the nanosystem had a synergistic effect by effectively alleviating hypoxia, enhancing the production of cytotoxic reactive oxygen species (ROS) and amplifying the efficacy of photodynamic therapy (PDT). Furthermore, the RCC/LND NPS + light weakened anoikis resistance, disrupted extracellular matrix (ECM), activated both the intrinsic apoptotic pathway (mitochondrial pathway) and extrinsic apoptotic pathway (receptor death pathway) of anoikis. In addition, the nanosystem showed significant anti-TNBC efficacy in vivo. These findings collectively demonstrated that RCC/LND NPS + light enhanced the anticancer effects, induced anoikis and inhibited tumor cell migration and invasion through a synergistic effect of chemotherapy and PDT. Overall, this study highlighted the promising potential of the RCC/LND NPS + light for the treatment of TNBC.

Abstract 2732: NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor microenvironment

Abstract The carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is detected on leukocytes, epithelia and endothelia, and involved in cell adhesion through homophilic or heterophilic binding. In various gastrointestinal cancers, NSCLC (non-small cell lung cancer), and melanoma, CEACAM1 is highly expressed on tumor cells and tumor stroma, with its levels increasing as the disease progresses. Notably, CEACAM1 has been found to dampen T and NK cell functions while promoting tumor angiogenesis and metastasis. In this study, we present NB203, a novel CEACAM1/VEGF bispecific antibody developed using Neologics CEACAM-plus, a bifunctional molecule engineering platform designed to target and modulate the tumor microenvironment (TME). NB203 effectively accumulated in the TME and hindered the homophilic or heterophilic interactions of CEACAM1. It demonstrated a significant enhancement in T cell activities and NK cell-mediated killing of CEACAM1-expressing tumor cells, and the inhibition of tumor cell migration and polyploidy through macrophages. More importantly, NB203 was specifically designed to impede tumor angiogenesis. It exhibited an increased binding capacity to both CEACAM1 and VEGF in pro-angiogenic TME, and undermined intratumoral vessel maturation by blocking VEGF and negatively regulating myeloid cell-dependent tumor angiogenesis. In summary, our preclinical data indicate that NB203 exhibits effective anti-tumor activity by mediating NK and cytotoxic T cell activities, improving the immune-suppressive TME, and suppressing tumor angiogenesis. The use of NB203 holds promise in overcoming resistance to anti-VEGF therapy and substantially improving the safety of therapeutic targeting of angiogenesis in cancer treatment. Citation Format: Jinyu Dong, Binbin Wang, Dong Wang, Jie Ni, Tingting Bu, Haojie Wang, Bishnu Nayak, Baiyang Wang, Xin Dong, Yu Zhang. NB203: A Novel therapeutic bispecific antibody targeting CEACAM1/VEGF for tumor immunity and angiogenesis modulation in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2732.

Abstract 5955: In vivo precision therapy for glioblastoma using a nanodrug targeting microRNA-10b

Abstract Glioblastoma multiforme (GBM) is the most common and aggressive primary brain malignancy, which accounts for about half of all brain tumors. Notably, GBM has been shown to express high levels of microRNA-10b (miR-10b) compared to normal brain tissue, which expresses virtually no miR-10b. Importantly, the mounting body of evidence suggests that suppressing miR-10b in glioblastoma cells disrupts various pathways involved in tumor formation, ultimately leading to the suppression of tumor growth and an increase in apoptosis. We have recently reported that our experimental nanodrug targeting miR-10b (MN-anti-miR10b) effectively suppresses miR-10b expression, inhibits tumor cell migration and invasion, and decreases GBM cell viability in vitro. MN-anti-miR10b consists of an iron oxide core with cross-linked dextran, which acts as the delivery vehicle, and is further conjugated with Cy5.5 fluorophores and therapeutic anti-miR-10b locked-nucleic acid antagomirs. The iron oxide core provides MR imaging contrast while Cy5.5 enables optical imaging modalities in vivo. In this study, U251, human GBM cells, were orthotopically implanted in nude, athymic mice and injected via tail vein with PBS, scrambled antagomir vehicle control (MN-Scr), or MN-anti-miR10b (10 and 20 mg Fe/kg), beginning on day 7 post-implantation. Mice were injected with respective treatments once a week for 6 weeks before assessing changes in survival and expression of miR-10b. In one trial, we assessed the differences in survival between treatment groups after completion of the injection regimen and found that MN-anti-miR10b can increase survival compared to control groups. In another trial, mice were euthanized one week after the last injection and GBM tissues were assessed for miR-10b expression by qRT-PCR. RNA samples extracted from this trial have been submitted for RNA sequencing and differential gene expression analysis will be performed. Here, we demonstrated in vivo that MN-anti-miR10b can efficiently decrease miR-10b expression (57%) and increase median survival (MN-anti-miR10b: 54.5 days vs MN-Scr: 44 days vs PBS: 44 days) compared to PBS and MN-Scr treatment groups. These studies suggest the use of MN-anti-miR10b can be effective in the treatment of GBM in vivo. Citation Format: Bryan Doyun Kim, Elizabeth Kenyon, Ming Chen, Sujan Mondal, Ana de Carvalho, Anna Moore. In vivo precision therapy for glioblastoma using a nanodrug targeting microRNA-10b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5955.

Synthesis, characterization, and efficacy evaluation of a PH-responsive Fe-MOF@GO composite drug delivery system for the treating colorectal cancer

Luteolin is a potent anti-colorectal cancer chemical. However, its effectiveness is hindered by its poor solubility in water and fat, and it is easy to degrade by gastrointestinal enzymes. In this study, a nano-composite carrier, NH2-MIL-101(Fe)@GO (MG), based on aminated MIL-101(Fe) and graphene oxide (GO) was developed and evaluated. This carrier co-delivered luteolin and matrine, while marine was used to balance the pH for the nano-preparation. The loading capacities for luteolin and matrine were approximately 9.8% and 14.1%, respectively. Luteolin's release at pH = 5 was significantly higher than at pH = 7.4, indicating it had an acidic pH response release characteristic. Compared to MOF and GO alone, MG and NH2-MIL-101(Fe)@GO@Drugs (MGD) enhanced anti-cancer activity by inhibiting tumor cell migration, increasing ROS generation, and upregulating the expression of Caspase-3 and Caspase-9. In conclusion, this study contributes new ideas and methods to the treatment strategy of multi-component anti-colorectal cancer therapy. It also advances drug delivery systems and supports the development of more effective and targeted treatment approaches for colorectal cancer.

Construction of an Anoikis-Related Gene Prognostic Signature and Identification of ANGPTL4 as a Key Oncogene in Lung Adenocarcinoma.

Anoikis plays an important role in cancer invasion and metastasis. However, the role of anoikis-related genes, AnRGs, in lung adenocarcinoma (LUAD) is not clear. First, anoikis-related genes (AnRGs) were obtained from the Genecard database. Second, the prognostic risk model of AnRGs was established by univariate Cox analysis, the Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox analysis. Finally, in vitro cell experiments were carried out to determine the expression and function of the key gene AnRGs. Three AnRGs (angiopoietin-like 4, ANGPTL4; Cyclin-Dependent Kinase Inhibitor 3, CDKN3; Solute Carrier Organic Anion Transporter Family Member 1B3, SLCO1B3) were screened for the construction of risk prediction model. Additionally, ANGPTL4 was significantly highly expressed in tumor cells, and the knockdown of ANGPTL4 expression on tumor cells could inhibit tumor cell migration and apoptosis. Constructing a risk model based on anoikis-related genes can effectively differentiate the prognosis of LUAD. ANGPTL4 can be used as a potential new target for LUAD treatment.

Combined Photosensitive Gene Therapy Effective Against Triple-Negative Breast Cancer in Mice Model.

Tumor hypoxia and invasion present significant challenges for the efficacy of photodynamic therapy (PDT) in triple-negative breast cancer (TNBC). This study developed a mitochondrial targeting strategy that combined PDT and gene therapy to promote each other and address the challenges. The positively charged amphiphilic material triphenylphosphine-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and the photosensitizer chloride e6 (Ce6) formed TPS@Ce6 nanoparticles (NPs) by hydrophobic interaction. They electrostatically condensed microRNA-34a (miR-34a) to form stable TPS@Ce6/miRNA NPs. Firstly, Ce6 disrupted the lysosomal membrane, followed by successful delivery of miR-34a by TPS@Ce6/miRNA NPs. Meanwhile, miR-34a reduced ROS depletion and further enhanced the effectiveness of PDT. Consequently, the mutual promotion between PDT and gene therapy led to enhanced anti-tumor effects. Furthermore, the TPS@Ce6/miRNA NPs promoted apoptosis by down-regulating Caspase-3 and inhibited tumor cell migration and invasion by down-regulating N-Cadherin. In addition, in vitro and in vivo experiments demonstrated that the TPS@Ce6/miRNA NPs achieved excellent anti-tumor effects. These findings highlighted the enhanced anticancer effects and reduced migration of tumor cells through the synergistic effects of PDT and gene therapy. Taken together, the targeted co-delivery of Ce6 and miR-34a will facilitate the application of photodynamic and genic nanomedicine in the treatment of aggressive tumors, particularly TNBC.

STK214947, a novel indole alkaloids, inhibits HeLa and SK-HEP-1 cells survival and EMT process by blocking the Notch3 and Akt signals.

Apoptosis and epithelial-to-mesenchymal transition (EMT) are closely associated with tumor survival and metastasis. These are the basic events in tumor occurrence and progression. STK214947 is an indole alkaloid with a skeleton that is similar to that of indirubin. Indole alkaloids have attracted considerable attention because of their antitumor activity. However, the relationship between STK214947 and these basic events remains unknown. In this study, the effects of STK214947 on inducing apoptosis and reversing the EMT process in tumor cells were confirmed. Mild concentrations of STK214947 inhibited tumor cell migration by reversing EMT and significantly regulated the expression of EMT-related proteins, including Notch3, E-cadherin, N-cadherin and vimentin. In addition, STK214947 in high concentration could induce apoptosis by down-regulating Notch3, p-Akt/Akt, and NF-κB, and upregulating Caspase 3. These findings support the further development of STK214947 as a potential antitumor small molecule that targets Notch3 and Akt signal transduction in cancer.

Investigating the Cell Origin and Liver Metastasis Factors of Colorectal Cancer by Single-Cell Transcriptome Analysis.

Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases. Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro. Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion. This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.

Resveratrol-derived inhibitors of the E3 ubiquitin ligase PELI1 inhibit the metastasis of triple-negative breast cancer

Triple-negative breast cancer (TNBC), as the most challenging subtype of breast cancer, exerts highly invasive ability and metastatic nature to the lymph nodes, which is correlated with poor survival rates among patients. Pellino-1 (PELI1) is an E3 ubiquitin ligase involved in tumor invasion and metastasis, and has the potential to be developed as a novel therapeutic target for TNBC. In this study, we identified a potent inhibitor of PELI1, namely compound 3d, on the basis of natural stilbene framework through medicinal chemistry approaches. This novel PELI1 inhibitor 3d showed potent binding affinity to PELI1 (Kd 8.2 μM) in fluorescence quenching assay, and markedly interrupted the interaction of PELI1 and SNAIL/SLUG confirmed by co-immunoprecipitation. Moreover, 3d exhibited potent antitumor activity in inhibiting tumor cell migration in scratch wound healing assay without affecting cell proliferation in vitro, and down-regulated the downstream EMT-effectors of PELI1 as assessed by western blotting. In the experimental lung metastasis model, 3d showed anti-TNBC metastasis efficacy without observable toxicity in vivo.

A Cu-Based Metal-Organic Framework Cu-Cip with Cuproptosis for Cancer Therapy and Inhibition of Cancer Cell Migration.

Microflora within cancer cells plays a pivotal role in promoting metastasis of cancer. However, contemporary anticancer research often overlooks the potential benefits of combining anticancer and antibacterial agents. Consequently, a metal-organic framework Cu-Cip with cuproptosis and antibacterial properties was synthesized for cancer therapy. To enhance the anticancer effect of the material, Mn2+ was loaded into Cu-Cip, yielding Mn@Cu-Cip. The fabricated material was characterized using single-crystal X-ray diffraction, PXRD, and FT-IR. By interacting with overexpressed H2O2 to produce ROS and accumulating Cu ions in cancer cells, MOFs exhibited excellent anticancer performance. Moreover, the material displayed the function of damaging Staphylococcus aureus and Escherichia coli, revealing the admirable antibacterial properties of the material. In addition, the antibacterial ability could inhibit tumor cell migration. The Cu-based MOF revealed promising applications in the field of tumor treatment.

Label-Free Single-Cell SERS Detection and Fluorescence Imaging of Molecular Responses to Endoplasmic Reticulum Stress under Electrical Stimulation.

The endoplasmic reticulum (ER) is one of the most important organelles in eukaryotic cells, in which most proteins and lipids are synthesized to regulate complex cellular processes. Generally, the excessive accumulation of unfolded or misfolded proteins can disturb ER homeostasis and induce endoplasmic reticulum stress (ERS). Howbeit, the molecular stress responses within ERS and metastatic behaviors of tumor cells during electrical stimulation (ES) are still poorly investigated and remain a challenge. In this study, by the combined use of fluorescence imaging, ER-targeting plasmonic nanoprobes were developed to trace molecular stress response profiling within the ER during a constant-voltage ES process at ∼1 V based on label-free surface-enhanced Raman spectroscopy (SERS). The excess accumulation of β-misfolded proteins was found after the ES, leading to breaking of the ER homeostasis and further inducing mitochondrial dysfunction. Notably, the excessive stress of ER under ES can destroy the calcium ion balance and induce significant upregulation of calreticulin expression. Importantly, the content ratio of two kinds of cadherin between E-cadherin and N-cadherin was gradually improved with the voltages boosted. Meanwhile, the epithelial adhesion factor expression was ascended with voltages amplified, leading to inhibiting tumor cell migration at low voltages or death under higher voltages (∼1 V). This study provides cellular insights into the ES approach for tumor therapy and also provides a simple and effective method for detecting molecular stress responses in endoplasmic reticulum stress.

Remodeling of intestinal epithelium derived extracellular vesicles by nanoparticles and its bioeffect on tumor cell migration

Extracellular vesicles (EVs) are an effective tool to elucidate the bioeffect of nanomedicines. To clarify the interaction between oral nanomedicines and intestinal epithelial cells, and their bioeffects on downstream cells, polystyrene nanoparticles (PS-NPs) with different sizes were used as the model nanomedicines for EVs induction. Caco-2 monolayers were selected as the model of the intestinal epithelium and DLD-1 cells as the colorectal cancer model proximal to the gastrointestinal tract. It is found that compared with small-sized (25, 50, 100 nm) PS-NPs, the large-sized (200 and 500 nm) exhibited higher co-localization with multivesicular bodies and lysosomes, and more significant reduction of lysosomal acidification in Caco-2 cells. Proteomic and western-blotting analysis showed that the EVs remodeled by large-sized PS-NPs exhibited a higher extent of protein expression changes. The in vitro and in vivo signaling pathway detection in DLD-1 cells and DLD-1 cell xenograft nude mice showed that the remodeled EVs by large-sized PS-NPs inhibited the activation of multiple signaling pathways including Notch3, EGF/EGFR, and PI3K/Akt pathways, which resulted in the inhibition of tumor cell migration. These results primarily clarify the regulation mechanisms of nanomedicines-EVs-receptor cells chain. It provides a new perspective for the rational design and bioeffect evaluation of oral drug nanomaterials and sets up the fundamental knowledge for novel tumor therapeutics in the future.

Design, Synthesis, and Antitumor Activity Evaluation of Proteolysis-Targeting Chimeras as Degraders of Extracellular Signal-Regulated Kinases 1/2.

Inhibition of the extracellular signal-regulated kinases 1/2 (ERK1/2) alone or in combination with other targets has emerged as a promising treatment strategy for a variety of human tumors. In addition to the development of inhibitors, the development of ERK1/2 degraders is an alternative approach to decrease its activity. We synthesized proteolysis-targeting chimeras (PROTACs) as effective ERK1/2 degraders, among which B1-10J showed high degradative activity, with DC50 of 102 nM and cytotoxic IC50 of 2.2 μM against HCT116 cells. Moreover, B1-10J dose-dependently inhibited tumor cell migration. Xenograft experiments in nude mice demonstrated that B1-10J inhibited HCT116 tumor cell growth and achieved significant regression of tumors at a daily dose of 25 mg/kg.

Expression of an oxysterol-metabolizing enzyme in colorectal cancer and its relation to tumor cell behavior and prognosis

Oxysterols and oxysterol-metabolizing enzymes have been implicated in the pathogenesis of various cancers. However, the distinct function of the oxysterol-metabolizing enzyme cytochrome P450 family 39 Subfamily A Member 1 (CYP39A1) in colorectal cancer (CRC) remains unclear. The aims of the current study were to evaluate whether CYP39A1 affects the oncogenic behaviors of CRC cells and to investigate the prognostic value of its expression in CRC. A CYP39A1 small-interfering RNA was used to block CYP39A1 gene expression in DLD1 and SW480 cells. The expression of CYP39A1 in CRC tissues was investigated by immunohistochemistry. Tumor angiogenesis and lymphangiogenesis were assessed by CD34 and D2–40 immunohistochemical staining, respectively. CYP39A1 knockdown inhibited tumor cell migration and invasion in DLD1 and SW480 cells. Angiogenesis was also inhibited through the decreased expression of vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor (HIF)−1α, and angiostatin and endostatin expression increased. In addition, CYP39A1 knockdown inhibited the lymphangiogenesis by decreasing the expression of VEGF-C. CYP39A1 expression was increased in CRC tissues compared with normal colorectal mucosa. CYP39A1 expression was associated with tumor stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The microvessel and lymphatic vessel density values of CYP39A1-positive tumors were significantly higher than those of CYP39A1-negative tumors. These results indicate that CYP39A1 is associated with tumor progression by influencing tumor cell angiogenesis and lymphangiogenesis in CRC.

Transferrin-Decorated PLGA Nanoparticles Loaded with an Organoselenium Compound as an Innovative Approach to Sensitize MDR Tumor Cells: An In Vitro Study Using 2D and 3D Cell Models.

Multidrug resistance (MDR) is the main challenge in cancer treatment. In this sense, we designed transferrin (Tf)-conjugated PLGA nanoparticles (NPs) containing an organoselenium compound as an alternative to enhance the efficacy of cancer therapy and sensitize MDR tumor cells. Cytotoxicity studies were performed on different sensitive tumor cell lines and on an MDR tumor cell line, and the Tf-conjugated NPs presented significantly higher antiproliferative activity than the nontargeted counterparts in all tested cell lines. Due to the promising antitumor activity of the Tf-decorated NPs, further studies were performed using the MDR cells (NCI/ADR-RES cell line) comparatively to one sensitive cell line (HeLa). The cytotoxicity of NPs was evaluated in 3D tumor spheroids and, similarly to the results achieved in the 2D assays, the Tf-conjugated NPs were more effective at reducing the spheroid's growth. The targeted Tf-NPs were also able to inhibit tumor cell migration, presented a higher cell internalization and induced a greater number of apoptotic events in both cell lines. Therefore, these findings evidenced the advantages of Tf-decorated NPs over the nontargeted counterparts, with the Tf-conjugated NPs containing an organoselenium compound representing a promising drug delivery system to overcome MDR and enhance the efficacy of cancer therapy.

Screening a DNA Aptamer Specifically Targeting Integrin β3 and Partially Inhibiting Tumor Cell Migration.

Due to its key roles in malignant tumor progression and reprograming of the tumor microenvironment, integrin β3 has attracted great attention as a new target for tumor therapy. However, the structure-function relationship of integrins β3 remains incompletely understood, leading to the shortage of specific and effective targeting probes. This work uses a purified extracellular domain of integrin β3 and integrin β3-positive cells to screen aptamers, specifically targeting integrin β3 in the native conformation on live cells through the SELEX approach. Following meticulous truncation and characterization of the initial aptamer candidates, the optimized aptamer S10yh2 was produced, exhibiting a low equilibrium dissociation constant (Kd) in the nanomolar range. S10yh2 displays specific recognition of cancer cells with varying levels of integrin β3 expression and demonstrates favorable stability in serum. Subsequent analysis of docking sites revealed that S10yh2 binds to the seven amino acid residues located in the core region of integrin β3. The S10yh2 aptamer can downregulate the level of integrin heterodimer αvβ3 on integrin β3 overexpressed cancer cells and partially inhibit cell migration behavior. In summary, S10yh2 is a promising probe with a small size, simple synthesis, good stability, high binding affinity, and selectivity. It therefore holds great potential for investigating the structure-function relationship of integrins.

Melittin inhibits tumor cell migration and enhances cisplatin sensitivity by suppressing IL-17 signaling pathway gene LCN2 in castration-resistant prostate cancer.

Melittin is a small molecule polypeptide extracted from the abdominal cavity of bees, which is used to treat inflammatory diseases and relieve pain. However, the antitumor effect of melittin and its mechanisms remain unclear, especially in castration-resistant prostate cancer (CRPC). Through CCK-8 assay, colony formation assay, wound healing assay and Transwell migration assay, we explored the effect of melittin on CRPC cell lines. In addition, with microarray analysis, gene ontology analysis and kyoto encyclopedia of genes and genomes analysis, this study identified key genes and signaling pathways that influence the growth of PC-3 cells. Meanwhile, the effect of melittin on CRPC was also verified through subcutaneous tumor formation experiments. Finally, we also tested the relevant indicators of human prostate cancer (PCa) specimens through immunohistochemistry and H＆E stating. Here, melittin was verified to inhibit the cell proliferation and migration of CPRC. Moreover, RNA-sequence analysis demonstrated that Interleukin-17 (IL-17) signaling pathway gene Lipocalin-2 (LCN2) was downregulated by melittin treatment in CRPC. Further investigation revealed that overexpression of LCN2 was able to rescue tumor suppression and cisplatin sensitivity which melittin mediated. Interestingly, the expression of LCN2 is highly related to metastasis in PCa. In brief, our study indicates that LCN2 plays an oncogenic role in CRPC and melittin may be selected as an attractive candidate for CRPC therapy.