Movement Of Cancer Cells Research Articles

Targeting cancer stress-associated hyperinsulinemia and abnormal behavior mitigates lung carcinoma in postmenopausal mouse: Intervention function of peimine

Obesity stress and its associated metabolic disruption increase the likelihood and advancement of several forms of malignancies, such as postmenopausal lung cancer in humans. Also, the mechanism of lung cancer stress-related cognitive impairment and rhythm change are still unknown. Peimine (PE), an alkaloid derived from the Fritillaria genus, has the ability to mitigate the metabolic dysfunctions induced by obesity and inhibit tumor growth. The objective of this study was to investigate the regulatory impact of PE on obese mice with postmenopausal lung cancer generated by a high fat diet. Our initial findings indicate that PE can significantly reduce the metabolic dysfunction caused by a high-fat diet in mice. This is demonstrated by better glucose tolerance and insulin resistance, reduced accumulation of lipids in the liver, and improved histological alterations in the mammary fat pad. Subsequently, the treatment of PE suppressed the formation of lung tumors caused by a high-fat diet in mice models placed in their original location. In addition, PE effectively inhibited the formation of pre-existing lung tumors in a mouse model of postmenopausal women who were fed a high-fat diet. This treatment also reduced the severity of metabolic problems. Notably, laboratory studies demonstrated that insulin exposure increased the growth and movement of lung cancer cells, but this effect was significantly reduced when the cells were co-cultured with PE. Meanwhile, PE intervention can significantly alleviate cancer stress-related cognitive impairment and disturbed circadian rhythm changes and associated gene expression abnormalities in model animals. Analysis using bioinformatics and molecular biology techniques revealed that PE has the ability to decrease the expression levels of signal transducer and activator of transcription 3 (STAT3) in the liver, mammary fat pad, and tumor tissues of postmenopausal mice with obesity generated by a high-fat diet. The inhibitory effects of PE on the growth and movement of lung cancer cells induced by insulin were completely eliminated when STAT3 expression was removed. This suggests that the suppression of STAT3 expression is crucial for PE to exert its anti-cancer effects against lung cancer in the presence of high insulin levels. The findings of our study indicate that consuming PE is highly effective in preventing and treating lung cancer that is connected with obesity. This is achieved via regulating the signaling pathway of STAT3.

Decoding Metastasis: From Cell Death to Fusion in Cancer Progression.

Metastasis is one of the key concepts in modern oncology, which connects the movement of cancer cells in the body with changes in their characteristics and functions. The review examines the main aspects of metastasis, including theories, facts and discoveries that help to better understand this phenomenon and develop new approaches to its treatment. In this article, we also proposed the theory of cell fusion with the formation of hybrid cells as one of the factors of metastasis. We believe that the fusion of tumor cells with other types of motile cells (leukocytes and bone marrow progenitor cells) may represent an additional mechanism of tumor spread. Cells of bone marrow origin, including cells of the myeloid and macrophage lineages, are the best candidates for heterotypic fusion in regenerative conditions. Events such as cell fusion may play a role in tumor dedifferentiation and progression. We presented a number of arguments and data from our own research that speak in favor of the proposed theory. It should be noted that if the fusion of a normal cell with a tumor cell is one of the possible triggers of tumorigenesis and cancer spread, the mechanisms underlying this process may provide possible new targets for treatment. Therefore, their analysis will expand our arsenal of therapeutic tools by adding completely new targets - cell signaling molecules - and will provide the impetus for reconsidering the tumor microenvironment from a different angle.

Enhydrin suppresses the malignant phenotype of GBM via Jun/Smad7/TGF-β1 signaling pathway

GBM is the most threatening form of brain tumor. The advancement of GBM is propelled by the growth, infiltration, and movement of cancer cells. Understanding the underlying mechanisms and identifying new therapeutic agents are crucial for effective GBM treatment.Our research focused on examining the withhold influence of Enhydrin on the destructive activity of GBM cells, both in laboratory settings and within living organisms. By employing network pharmacology and bioinformatics analysis, we have determined that Jun serves as the gene of interest, and EMT as the critical signaling pathway. Mechanistically, Enhydrin inhibits the activity of the target gene Jun to increase the expression of Smad7, which is infinitively regulated by the transcription factor Jun, and as the inhibitory transcription factor, Smad7 can down-regulate TGF-β1 and the subsequent Smad2/3 signaling pathway. Consequently, this whole process greatly hinders the EMT mechanism of GBM, leading to the notable decline in cell proliferation, invasion, and migration. In summary, our research shows that Enhydrin hinders EMT by focusing on the Jun/Smad7/TGF-β1 signaling pathway, presenting a promising target for treating GBM. Moreover, Enhydrin demonstrates encouraging prospects as a new medication for GBM treatment.

Circular RNA HSDL2 promotes breast cancer progression via miR-7978 ZNF704 axis and regulating hippo signaling pathway

Circular RNAs (circRNAs) are a new group of endogenous RNAs recently found to be involved in the development of various diseases, including their confirmed involvement in the progression of several types of cancers. Unluckily, the abnormal expression and functions of circRNAs in breast cancer shall be further investigated. This work aims to elucidate the action and molecular mechanism of circHSDL2 in the malignant progression of breast cancer. Differential expression profiles of circRNAs in breast cancer tissues relative to normal breast tissues and in the exosomes of breast cancer patients compared to healthy women were analyzed from databases to identify potentially functional circRNAs. CircHSDL2 was selected for further investigation. Cell proliferation, migration and invasion assays were done to assess the effect of circHSDL2 overexpression on breast cancer cells. Bioinformatics test and dual-luciferase reporter experiments were done to explore the interaction between circHSDL2 and miRNA. Downstream target genes were further investigated through proteomics analysis and Western blotting. The influence of circHSDL2 on breast cancer in vivo was evaluated through xenograft experiments in nude mice. Functional analysis demonstrated circHSDL2 overexpression promoted the division, movement, and invasion of breast cancer cells both in vivo and in vitro. Mechanistically, circHSDL2 acted as a sponge for miR-7978 to affect ZNF704 expression and thereby regulate the Hippo pathway in breast cancer cells. In conclusion, circHSDL2 regulates the Hippo pathway through the miR-7978/ZNF704 axis to facilitate the malignancy of breast cancer. This may be a potential biomarker and treatment target.

Comprehending the cuproptosis and cancer-immunity cycle network: delving into the immune landscape and its predictive role in breast cancer immunotherapy responses and clinical endpoints.

The role of cuproptosis, a phenomenon associated with tumor metabolism and immunological identification, remains underexplored, particularly in relation to the cancer-immunity cycle (CIC) network. This study aims to rigorously examine the impact of the cuproptosis-CIC nexus on immune reactions and prognostic outcomes in patients with breast cancer (BC), striving to establish a comprehensive prognostic model. In the study, we segregated data obtained from TCGA, GEO, and ICGC using CICs retrieved from the TIP database. We constructed a genetic prognostic framework using the LASSO-Cox model, followed by its validation through Cox proportional hazards regression. This framework's validity was further confirmed with data from ICGC and GEO. Explorations of the tumor microenvironment were carried out through the application of ESTIMATE and CIBERSORT algorithms, as well as machine learning techniques, to identify potential treatment strategies. Single-cell sequencing methods were utilized to delineate the spatial distribution of key genes within the various cell types in the tumor milieu. To explore the critical role of the identified CICs, experiments were conducted focusing on cell survival and migration abilities. In our research, we identified a set of 4 crucial cuproptosis-CICs that have a profound impact on patient longevity and their response to immunotherapy. By leveraging these identified CICs, we constructed a predictive model that efficiently estimates patient prognoses. Detailed analyses at the single-cell level showed that the significance of CICs. Experimental approaches, including CCK-8, Transwell, and wound healing assays, revealed that the protein HSPA9 restricts the growth and movement of breast cancer cells. Furthermore, our studies using immunofluorescence techniques demonstrated that suppressing HSPA9 leads to a notable increase in ceramide levels. This research outlines a network of cuproptosis-CICs and constructs a predictive nomogram. Our model holds great promise for healthcare professionals to personalize treatment approaches for individuals with breast cancer. The work provides insights into the complex relationship between the cuproptosis-CIC network and the cancer immune microenvironment, setting the stage for novel approaches to cancer immunotherapy. By focusing on the essential gene HSPA9 within the cancer-immunity cycle, this strategy has the potential to significantly improve the efficacy of treatments against breast cancer.

Development of an SPRi Test for the Quantitative Detection of Cadherin 12 in Human Plasma and Peritoneal Fluid

A new method for the determination of cadherin 12 (CDH12)—an adhesive protein that has a significant impact on the development, growth, and movement of cancer cells—was developed and validated. The method is based on a biosensor using surface plasmon resonance imaging (SPRi) detection. A quartz crystal microbalance was used to analyze the characteristics of the formation of successive layers of the biosensor, from the linker monolayer to the final capture of CDH12 from solution. The association equilibrium constant (KA = 1.66 × 1011 dm3 mol−1) and the dissociation equilibrium constant (KD = 7.52 × 10−12 mol dm−3) of the anti-CDH12 antibody–CDH12 protein complex were determined. The determined analytical parameters, namely the values determining the accuracy, precision, and repeatability of the method, do not exceed the permissible 20% deviations specified by the aforementioned institutions. The proposed method is also selective with respect to possible potential interferents, occurring in up to 100-fold excess concentration relative to the CDH12 concentration. The determined Limit of Quantification (LOQ = 4.92 pg mL−1) indicates the possibility of performing quantitative analysis in human plasma or peritoneal fluid without the need to concentrate the samples; however, particular attention should be paid to their storage conditions, as the analyte does not exhibit high stability. The Passing–Bablok regression model revealed good agreement between the reference method and the SPRi biosensor, with ρSpearman values of 0.961 and 0.925.

Abstract 3612: KAT8/SIRT7-medicated fascin-K41 acetylation/deacetylation regulates tumor metastasis

Abstract Background: Although it is not expressed in the normal differentiated epithelial tissue of adult animals, fascin is highly expressed in a variety of cancers, including esophageal cancer, working as an important oncogenic protein. fascin promotes migration and invasion of cancer cells by binding F-actin to promote the formation of filopodia and invadopodia. However, it is not clear how exactly the function of fascin is systematically regulated in cancer cells. There are three regions on the surface of fascin protein that are significantly rich in positively charged lysine and arginine. These regions are now thought to be potential F-actin binding sites. We hypothesize that cancer cells may regulate the function of fascin by post-translational modifications of key amino acids in these three regions, especially by acetylation. Based on this, this study aims to identify acetyltransferases that regulate the acetylation of fascin in esophageal cancer cells and reveal the effect of acetylation on the function of fascin. Results: 1) Co-IP, pull-down, and immunofluorescence results showed that KAT8 interact with fascin and co-localize in esophageal cancer cells. 2) Mass spectrometry identification of the products of acetylation in vitro revealed that KAT8 acetylates fascin at K41 and K241. By means of Ack41-fascin specific antibodies, further analysis proved that KAT8 acetylated fascin K41. 3) Co-IP and immunofluorescence results showed that SIRT7 interact with fascin and co-localize in esophageal cancer cells, moreover, treatment of cells with SIRT7-specific inhibitor significantly increased the level of AcK41-fascin, and however, overexpressing SIRT7 reduces the level of AcK41-fascin. 4) Immunohistochemical results showed that the level of AcK41-fascin was lower in esophageal cancer tissues of patients with lymph node metastasis; Analysis of overall survival and tumor-free survival curves showed that patients with high levels of AcK41-fascin had a better prognosis. 5) Cell wound healing and transwell assay showed that fascin K41 residue mimics acetylation inhibit the movement and invasion of esophageal cancer cells. 6) Furthermore, in vitro F-actin binding assays showed that mutations mimicing acetylation of K41 inhibited the activity of fascin bunding F-actin. 7) Immunofluorescence assay showed that fascin K41 residue mimics acetylation inhibited fascin's ability to promote filopodia and invadopodia formation in esophageal cancer cells. Conclusions: 1) KAT8 is an acetyltransferase that catalyzes fascin K41 acetylation in esophageal cancer cells, while SIRT7 decides to catalyze AcK41-fascin deacetylation. 2) SIRT7-mediated deacetylation of AcK41-fascin promotes the formation of filopodia and invadopodia, which promotes the invasion and metastasis of esophageal cancer cells. (This work was supported by grants from the National Natural Science Foundation of China (No.81872372 and 81902469)) Citation Format: Da-Jia Li, Yin-Wei Cheng, Li-Yan Xu, En-Min Li. KAT8/SIRT7-medicated fascin-K41 acetylation/deacetylation regulates tumor metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3612.

SLFN5 promotes reversible epithelial and mesenchymal transformation in ovarian cancer

Ovarian cancer is a disease with increasing incidence worldwide, and there is an urgent need for chemotherapy and biological targeted therapy. Epithelial-mesenchymal transformation (EMT) is an important initiation stage for tumor cells to acquire the ability to invade and metastasize. A growing number of findings suggest that human Schlafen family member 5(SLFN5) plays a key role in malignancy. However, the role of SLFN5 in ovarian cancer cells has not been fully elucidated. Samples were collected from patients with ovarian cancer diagnosed in Hangzhou First People's Hospital, and the expression of SLFN5 was detected by fluorescence quantitative PCR. The relationship between SLFN5 expression and the progression and malignancy of ovarian cancer was analyzed by using the expression profile data from the Cancer Genome Atlas (TCGA) database. The mRNA expression levels of SLFN5 related upstream and downstream signaling pathways were studied by fluorescence quantitative PCR. Silencing SLFN5 was performed by siRNA transfection. The expression of SLFN5 and transfer-related proteins was examined by Western blot. Transwell and wound healing experiments investigated the migration and invasion ability of ovarian cancer cells. TCGA database analysis results showed that in the population with high SLFN5 expression, compared with the group with low SLFN5 expression, OS was worse (P = 0.011). SLFN5 silencing had a significant inhibitory effect on EMT and invasion movement of ovarian cancer cells. RT-PCR method was used to detect the mRNA changes of SLFN5 in ovarian cancer tissue and adjacent tissue. It was found that the expression of SLFN5 in ovarian cancer tissue was increased, with a significant difference (P < 0.05). Together, these results suggest that SLFN5 may play a synergistic role in tumorigenesis and development of ovarian cancer cells, providing a potential target for future drug development for the treatment of ovarian cancer.

Surface activity of cancer cells: The fusion of two cell aggregates

A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body. Although how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been comprehensively formulated, the impact of physical interactions on cell spreading remains less understood. Cumulative effects of physical interactions exist as the interplay between various physical parameters such as (1) tissue surface tension, (2) viscoelasticity caused by collective cell migration, and (3) solid stress accumulated in the cell aggregate core region. This review aims to point out the role of these physical parameters in cancer cell spreading by considering and comparing the rearrangement of various mono-cultured cancer and epithelial model systems such as the fusion of two cell aggregates. While epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension, which directs cell movement from the surface to the core region of two-aggregate systems, cancer cells rather perform surface cell rearrangement. Cancer cells migrate toward the surface of the two-aggregate system driven by the solid stress while the surface tension is significantly reduced. The solid stress, accumulated in the core region of the two-aggregate system, is capable of suppressing the movement of epithelial cells that can undergo the jamming state transition; however, this stress enhances the movement of cancer cells. We have focused here on the multi-scale rheological modeling approaches that aimed at reproducing and understanding these biological systems.

A cancer model with nonlocal free boundary dynamics.

Cancer cells at the tumor boundary move in the direction of the oxygen gradient, while cancer cells far within the tumor are in a necrotic state. This paper introduces a simple mathematical model that accounts for these facts. The model consists of cancer cells, cytotoxic T cells, and oxygen satisfying a system of partial differential equations. Some of the model parameters represent the effect of anti-cancer drugs. The tumor boundary is a free boundary whose dynamics is determined by the movement of cancer cells at the boundary. The model is simulated for radially symmetric and axially symmetric tumors, and it is shown that the tumor may increase or decrease in size, depending on the "strength" of the drugs. Existence theorems are proved, global in-time in the radially symmetric case, and local in-time for any shape of tumor. In the radially symmetric case, it is proved, under different conditions, that the tumor may shrink monotonically, or expand monotonically.

Celastrus orbiculatus Thunb. extract inhibits EMT and metastasis of gastric cancer by regulating actin cytoskeleton remodeling

Ethnopharmacological relevanceThe traditional Chinese medicine herb Celastrus orbiculatus Thunb. is an important folk medicinal plant in China that has been used as an anti-inflammatory, antitumor, and analgesic in various diseases. Recent years, many studies have reported the significant effects of Celastrus orbiculatus Thunb. extract (COE) on gastric cancer. However, the specific mechanism by which COE regulates gastric cancer cytoskeleton remodeling and thus inhibits EMT has not yet been reported. Aim of studyTo study the effect and mechanism of COE in inhibiting the epithelial-mesenchymal transition (EMT) and metastasis of gastric cancer cells, laying an experimental foundation for the clinical application and further development of COE. MethodsThe high-content cell dynamic tracking system was used to continuously track the trajectory of cell movement in real time. Through the high-content data, the average movement distance and movement speed of the cells are calculated. Additionally, the dynamic images of the cell movement in the high-content imaging system are derived to analyze the impact of COE on the movement of gastric cancer cells. Cytoskeleton staining experiment was performed to detect the effect of COE on the assembly of gastric cancer cell cytoskeleton proteins. Western blot was employed to detect the changes of EMT and metastasis-related proteins in the gastric cancer cells treated by COE. The effect of COE on the key regulatory protein Cofilin-1 (CFL1) of cell movement was examined by Western blot and protein degradation experiment. The effect of COE on EMT and metastasis of the gastric cancer cells lacking CFL1 was assessed by a transwell assay. The in vivo inhibitory effect of COE on EMT and metastasis of gastric cancer was determined by the animal living image system. IHC assays were used to detect the levels of EMT-related proteins in COE reversal in vivo. ResultThe results showed that the movement distance and average movement speed of gastric cancer cells after COE treatment were significantly lower than those of the control group. Cytoskeleton staining experiments revealed that COE can significantly change the distribution of skeletal proteins in gastric cancer cells. Additionally, COE treatment significantly reduced the expression of Matrix metalloproteinases (MMP-2, MMP-9) and other proteins. Furthermore, COE can significantly accelerate the degradation of CFL1 protein, and both COE treatment and CFL1 deletion can significantly inhibit EMT and metastasis of gastric cancer cells. Lastly, the number of peritoneal metastases of gastric cancer cells was significantly reduced in animals after COE treatment. COE can reverse the levels of EMT-related proteins while reducing the expression levels of CFL1 protein in vivo. ConclusionCOE can significantly inhibit EMT and metastasis of gastric cancer cells in vivo and in vitro. This effect may be achieved by reducing the stability of CFL1 and inhibiting the assembly of actin in gastric cancer cells.

The Role of Perineural Invasion in Prostate Cancer and Its Prognostic Significance.

Simple SummaryProstate cancer is one of the most frequently diagnosed cancers in men worldwide. Perineural invasion (PNI), the movement of cancer cells along nerves, is a commonly observed approach to tumor spread and is important in both research and clinical practice of prostate cancer. However, despite many studies reporting on molecules and pathways involved in PNI, understanding its clinical relevance remains insufficient. In this review, we aim to summarize the current knowledge of mechanisms and prognostic significance of PNI in prostate cancer, which may provide new perspectives for future studies and improved treatment.Perineural invasion (PNI) is a common indication of tumor metastasis that can be detected in multiple malignancies, including prostate cancer. In the development of PNI, tumor cells closely interact with the nerve components in the tumor microenvironment and create the perineural niche, which provides a supportive surrounding for their survival and invasion and benefits the nerve cells. Various transcription factors, cytokines, chemokines, and their related signaling pathways have been reported to be important in the progress of PNI. Nevertheless, the current understanding of the molecular mechanism of PNI is still very limited. Clinically, PNI is commonly associated with adverse clinicopathological parameters and poor outcomes for prostate cancer patients. However, whether PNI could act as an independent prognostic predictor remains controversial among studies due to inconsistent research aim and endpoint, sample type, statistical methods, and, most importantly, the definition and inclusion criteria. In this review, we provide a summary and comparison of the prognostic significance of PNI in prostate cancer based on existing literature and propose that a more standardized description of PNI would be helpful for a better understanding of its clinical relevance.

EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation.

EWI2 is a transmembrane immunoglobulin superfamily (IgSF) protein that physically associates with tetraspanins and integrins. It inhibits cancer cells by influencing the interactions among membrane molecules including the tetraspanins and integrins. The present study revealed that, upon EWI2 silencing or ablation, the elevated movement and proliferation of cancer cells in vitro and increased cancer metastatic potential and malignancy in vivo are associated with (i) increases in clustering, endocytosis, and then activation of EGFR and (ii) enhancement of Erk MAP kinase signaling. These changes in signaling make cancer cells (i) undergo partial epithelial-to-mesenchymal (EMT) for more tumor progression and (ii) proliferate faster for better tumor formation. Inhibition of EGFR or Erk kinase can abrogate the cancer cell phenotypes resulting from EWI2 removal. Thus, to inhibit cancer cells, EWI2 prevents EGFR from clustering and endocytosis to restrain its activation and signaling.

The role of selected molecular factors in ovarian cancer metastasis.

The main reason for treatment failure in ovarian cancer is chemoresistance and the presence of metastasis. Ascites, whichallows the physical movement of cancer cells, the lymphovascular pathway, and several molecular factors and signalling axes, are involved in metastasis. Ascites, with the involvement of cytokines and chemokines, MAPK/STAT1 and NOTCH as well as CXCL12/CXCR4 signaling pathways and circulating anoikis induces cancer dissemination, in particular to the peritoneum and omentum. The spread of lymphatic and bloodstream cancer cells is a multi-stage process. Tumour infiltration of the stroma and lymphovascular space (LVSI) produces biologically active cancer-associated fibroblasts and macrophages (CAFs, TAMs) that secrete numerous cytokines, chemokines and growth factors, inhibit NK function, induce epithelial-mesenchymal transition (EMT), resulting in an increase of the metastatic potential of cancer cells and the formation of cancer stem cells (CSCs). Overexpression of some genes, and microRNAs, in LVSI-(LMGS) associated with metastasis has been identified. The role of extracellular vesicles (EVs) transporting metastasis-associated factors has been described as has the role of cancer stem cells (CSCs) in chemotherapy resistance and metastasis. Sirtuins, enzymes involved in metastasis formation, have also been detected. Certain types of microRNAs (miR-509-3p, microRNA-506-3p) and melatonin have been shown to inhibit metastasis.

The p53-Driven Anticancer Effect of Ribes fasciculatum Extract on AGS Gastric Cancer Cells.

Cancer metastasis is directly related to the survival rate of cancer patients. Although cancer metastasis proceeds by the movement of cancer cells, it is fundamentally caused by its resistance to anoikis, a mechanism of apoptosis caused by the loss of adhesion of cancer cells. Therefore, it was found that inhibiting cancer migration and reducing anoikis resistance are important for cancer suppression, and natural compounds can effectively control it. Among them, Ribes fasciculatum, which has been used as a medicinal plant, was confirmed to have anticancer potential, and experiments were conducted to prove various anticancer effects by extracting Ribes fasciculatum (RFE). Through various experiments, it was observed that RFE induces apoptosis of AGS gastric cancer cells, arrests the cell cycle, induces oxidative stress, and reduces mobility. It was also demonstrated that anoikis resistance was attenuated through the downregulation of proteins, such as epidermal growth factor receptor (EGFR). Moreover, the anticancer effect of RFE depends upon the increase in p53 expression, suggesting that RFE is suitable for the development of p53-targeted anticancer materials. Moreover, through xenotransplantation, it was found that the anticancer effect of RFE confirmed in vitro was continued in vivo.

Mechanism by which Human Papillomavirus 16 Infection Interferes with Progression and Immune Evasion of Cervical Cancer by Acting on Th9 Cytokines

High-risk human papillomavirus types are associated with most of cervical cancer cases. To explore the mechanism by which human papillomavirus 16 infections interferes with the progression and immune evasion of cervical cancer by acting on T helper 9 cells cytokines. Cervical cancer cells were obtained from China Center for Type Culture Collection. Cells were cultured in Roswell Park Memorial Institute Medium-1640. Through wound healing test and transwell analysis, the effect of interleukin-9 on the movement, migration and invasion of cancer cells was evaluated. The expression of epithelial-mesenchymal transition markers and programmed death-ligand 1 and programmed cell death protein 1 messenger ribonucleic acid was detected. Human papillomavirus 16 and interleukin-9 receptor had higher expression in cervical cancer tumor tissue than normal group. The proliferation of cervical cancer cells was inhibited in interleukin-9 transfection group compared with the cervical cancer group. Interleukin-9 transfection group reduced N-cadherin and vimentin expression, and increased E-cadherin expression. Interleukin-9 inhibition group increased N-cadherin and vimentin expression and decreased E-cadherin expression. Interleukin-9 transfection group reduced programmed death-ligand 1 and programmed cell death protein 1 expression, while interleukin-9 inhibition group increased programmed death-ligand 1 and programmed cell death protein 1 expression. These cytokines can limit tumor proliferation, movement, migration and invasion. They induce the up-regulation of E-cadherin expression in cervical cells and inhibit programmed death-ligand 1 and programmed cell death protein 1 expression, thereby expressing tumor antigens.

FC-BBR/IND-induced glucose oxidase nanodrugs for targeted combination therapy

Targeted therapy from cells to mitochondria can improve the bioavailability and therapeutic effects of drugs. Combination therapy by combining two or more therapeutic methods comes to be seen a hopeful strategy to overcome the emergence of resistance. Ferrocene (FC) derivatives of the sandwich structure can not only directly inhibit the proliferation of cancer cells but also catalyze the Fenton reaction to enhance chemodynamic therapy. Berberine (BBR) is a Chinese herbal extract with mitochondria-targeted anticancer activity. In our work, glucose oxidase (GOD) was induced to self-assemble by ferrocene-berberine conjugate (FC-BBR) and indomethacin (IND), which was then encapsulated by hyaluronic acid (HA) and formed nanodrugs (FC-BBR/IND@GOD@HA NPs). Molecular simulation results showed that the drugs could be bound to multiple sites of GOD and induce its self-assembly. The prepared nanoassembly could inhibit the proliferation and induce the apoptosis of HepG2 cells, which might be the result of targeted chemodynamic therapy and starvation therapy. Moreover, the FC-BBR/IND@GOD@HA NPs could also promote the production of reactive oxygen species and the loss of mitochondrial membrane potential and block the cells in S phase. More importantly, it could inhibit the movement and migration of cancer cells, which gave it the potential to prevent tumor metastasis.

Phycocyanin inhibits pancreatic cancer metastasis via suppressing epithelial-mesenchymal transition and targeting Akt/β-catenin pathway.

According to our previous research, phycocyanin (PC) could inhibit pancreatic tumor growth obviously. However, little is known about the effects of phycocyanin on pancreatic tumor metastasis. This study was aimed to investigate whether phycocyanin inhibits pancreatic cancer cells' metastasis and the potential underlying mechanisms. Human pancreatic carcinoma cell lines PANC-1 and BxPC3 were treated with phycocyanin (5, 10, 20, and 40 μM) for 48 h or 72 h. BALB/c nude mice were inoculated intravenously with luciferase-PANC-1 cells to establish a tumor metastasis model. BALB/c nude mice were also inoculated subcutaneously with PANC-1 cells to establish a xenograft tumor model. Our results indicated that (1) phycocyanin inhibited migration, invasion, and movement of pancreatic cancer cells in vitro, and tumor metastasis in mouse xenograft tumor model; (2) phycocyanin significantly changed cell morphology and epithelial-mesenchymal transition (EMT) phenotype in pancreatic cancer cells; (3) phycocyanin decreased the phosphorylation level of Akt and the level of nuclear β-catenin. Moreover, administration of Akt activator SC79 counteracted the inhibitory effect of phycocyanin on the migration of pancreatic cancer cells, associated with the reversal of epithelial-mesenchymal transition and Akt/β-catenin signaling pathway. Taken together, our results suggest that phycocyanin inhibits pancreatic cancer metastasis via suppressing epithelial-mesenchymal transition and targeting the Akt/β-catenin pathway.

Abstract 1927: Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases

Abstract Vessel co-option in colorectal cancer liver metastases (CRCLM) has been recognized as one of the mechanistic pathways of resistance against anti-angiogenic therapy. The cancer cells are highly motile in co-opted lesions, which move toward and along the pre-existing sinusoidal vessels and hijack them to gain access to nutrient. The movement of cancer cells is accompanied by displacement of the hepatocytes. However, the molecular mechanisms underlying this displacement are unclear yet. To examine whether apoptosis involved in hepatocytes displacement by cancer cells in co-opted lesions, we performed immunohistochemical staining for pro-apoptotic markers, such as cleaved caspase-3 and cleaved PARP-1. We observed overexpression of pro-apoptotic markers in liver parenchyma of co-opted lesions compared to angiogenic lesions, specifically the hepatocytes that are in close proximity to the cancer cells. In vitro, we found that culturing hepatocytes with either colorectal cancer cells or conditioned media of co-opted CRCLM organoids induces apoptosis. Importantly, our results also suggested proprotein convertase subtilisin/kexin type 9 (PCSK-9 or PC-9) as a potential mediator of cancer cells-driven hepatocytes apoptosis. Altogether, these results confirm that cancer cells exploit apoptosis to establish vessel co-option in CRCLM. Citation Format: Miran Rada, Migmar Tsamchoe, Audrey Kapelanski-Lamoureux, Jessica Bloom, Stephanie Petrillo, Sébastien Tabariès, Diane H. Kim, Peter Younan, Alex Gregorieff, Peter Siegel, Anthoula Lazaris, Peter Metrakos. Cancer cells induce apoptosis in hepatocytes as one of the mechanisms to displace hepatocytes in vessel co-opted colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1927.

Targeting SNARE-Mediated Vesicle Transport to Block Invadopodium-Based Cancer Cell Invasion.

During metastasis, cancer cells can invade extracellular matrix (ECM) through a process mediated by matrix-degrading protrusions of the plasma membrane, termed invadopodia. Formation of invadopodia correlates with cells’ invasive and metastatic potential, and thus presents a potential target for therapeutic approaches to target metastatic progression. Invadopodia formation is dependent on the recruitment of proteins involved in intracellular signaling, actin cytoskeleton remodeling, and proteolytic matrix modification. The latter includes matrix degrading enzymes such as MT1-MMP, MMP2, and MMP9. These essential invadopodium-associated enzymes are required for localized matrix degradation, and their localization at invadopodia is central to invadopodium-based cancer cell invasion. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) facilitate intracellular vesicle traffic, including that involved in the transport of invadopodium-associated proteins, and in so doing promote modification of ECM and modulation of signaling pathways involved in the movement of cancer cells. Specific SNARE complexes have been found to support invadopodia formation, and these complexes are, in turn, regulated by associated proteins that interact specifically with SNAREs. Targeting SNARE regulatory proteins thus provides a possible approach to disrupt SNARE-dependent delivery of invadopodial proteins, including MT1-MMP, to sites of ECM modification. Here, we review recent studies of SNARE regulators that hold potential as targets for the development of anti-metastatic therapies for patients burdened with invadopodia-forming cancer types.