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Tumour immunology and immunotherapy It metashasis the pivotal Inhibiging of these factors in disease progression and therapeutic strategies. This review covers cancer Cander migration, invasion, and colonization Herbal appetite control distant organs, emphasizing the Inhibiting cancer cell metastasis of cell adhesion and the intricate metastasis process. Inhibition approaches targeting adhesion molecules, such as integrins and cadherins, are discussed. Overall, this review contributes significantly to advancing cancer research and developing targeted therapies, holding promise for improving patient outcomes worldwide. Exploring different inhibition strategies revealed promising therapeutic targets to alleviate adhesion and metastasis of cancer cells.Inhibiting cancer cell metastasis -
The inhibitors prevent the uncontrolled proliferation of cancer cells. This prevents metastasis. The cancer cell inhibitors bind to specific receptors, kinases or signaling pathways. These inhibitors can be used as monotherapy or in combination. The type of cancer is a crucial factor in determining treatment and inhibition methods.
There are many different cancer types. These include breast cancer, prostate cancer, lung cancer, and many more. This comprehensive review encompassing 79 relevant studies demonstrated a consistent effect of adhesion molecule inhibitors in reducing cancer cell metastasis across various cancer types.
These treatments with inhibitors may be particularly effective in late-stage cancer patients. Additionally, stratification by treatment duration revealed that prolonged exposure to integrin inhibitors resulted in substantial reductions in metastasis [ 16 ]. This finding highlights the importance of prolonged treatment regimens when targeting adhesion molecules to inhibit metastasis effectively.
These comprehensive and in-depth results provide valuable insights into the intricate mechanisms governing cancer cell adhesion, metastasis, and their inhibition [ 10 ]. The data elucidate potential therapeutic strategies targeting these processes and reveal critical molecular regulators that could serve as promising targets for developing personalized and effective cancer treatments [ 17 ].
The cancer cells have an increased adhesion strength to the ECM than the normal cells [ 18 ]. Cancer cells showed a mean adhesion force of pN compared to normal cells of 60 pN [ 19 ].
This enhanced adhesion property contributed to the formation of stable focal adhesions, enabling cancer cells to withstand mechanical stresses and promote their survival and proliferation on the ECM [ 7 ]. Further examination of adhesion molecules revealed a complex network of interactions [ 20 ].
The expression of Integrin β1 was 3. Metastatic cells tend to migrate and invade surrounding tissue more aggressively compared to normal cells [ 23 ].
Metastatic cells have a higher speed of migration [ 24 ]. The characteristics described can be observed in various types of cancer. These include in breast cancer, lung cancer, and many others. In addition, metastatic cells exhibited greater directional persistence and chemotactic responses to ECM gradients, indicating their enhanced ability to navigate tissues and invade surrounding environments.
More metalloproteinase 9 MMP9 are in metastatic tumor cells [ 25 , 26 ]. Likewise, more twist-related protein 1 TWIST1 can be found in the metastatic tumor cells [ 25 , 26 ] Fig. The invasion of cancer cells marks the beginning of the metastasis period. The tumor cells either individually or collectively breach the basement membrane and invade the surrounding tissue.
Invasive tumor cells enter the blood vessel, access the bloodstream, and spread. Eventually, secondary tumor cells form. The effectiveness of different inhibition strategies on the behavior of cancer cells was checked by functional tests in vitro [ 27 ].
The therapeutic potential of small-molecule inhibitors was also evaluated [ 30 ]. Protein-protein interaction analysis identified critical regulatory nodes in the adhesion and metastasis pathways [ 33 ]. FAK and Src were identified as central nodes in the adhesion pathway, while β-catenin and SMAD4 played pivotal roles in the EMT pathway [ 34 ].
There is different phosphorylation in metastatic tumor cells. Phosphorylation of FAK and paxillin was significantly elevated in metastatic cells, enhancing focal adhesion turnover and promoting cytoskeletal rearrangement [ 35 ]. Open-access databases and platforms that facilitate data exchange can promote the integration of diverse datasets and support the identification of novel therapeutic targets.
As personalized medicine gains traction, it is crucial to address ethical considerations related to data privacy, informed consent, and equitable access to advanced treatments [ 36 ]. The use of advanced three-dimensional culture systems and patient-derived xenografts is critical in studying the tumor microenvironment and evaluating the efficacy of potential therapies in a more physiologically relevant context [ 37 ].
The efficacy of targeted therapies require validation through clinical trials [ 38 ]. The discovery of predictive biomarkers to identify patients and treatment responses will be critical to the successful implementation of personalized medicine approaches [ 39 ].
Personalized medicine is becoming more important [ 40 ]. Therefore, compliance with data protection, obtaining informed consent and equal access to advanced treatments are critically important safeguards.
Access to personalized therapies aims to reduce the gap in healthcare inequality and empower all patients [ 41 ].
This review was able to highlight the importance of advanced stage-specific responses, the importance of treatment duration, the adhesion properties and metastatic potential of cancer cells, and the effectiveness of inhibition strategies Fig. Inhibition Strategies : Integrin β1-blocking antibodies resulted in a remarkable reduction in cancer cell adhesion to the basement membrane, and E-cadherin upregulators effectively reversed the mesenchymal phenotype in metastatic cells.
Focal adhesion kinase inhibitor significantly disrupted focal adhesion dynamic. The profound increase in cancer cell adhesion to the ECM underscores the significance of this process in cancer progression [ 42 ].
Adhesion to the ECM promotes cell survival and facilitates intravasation during metastasis [ 7 ]. The interplay of integrins and cadherins in mediating interactions has a crucial role between cancer cells and ECM. This interaction is critical for activating downstream signaling pathways that regulate cell motility and invasion [ 43 ].
The crosstalk between adhesion molecules and downstream effectors can provide insights into possible combinatorial therapies [ 44 ].
Cancer cells can modulate the microenvironment to evade immune surveillance, enabling them to survive and thrive during metastasis [ 44 ] Fig. Focal adhesion kinase and SRC have been identified as central nodes in the adhesion pathway.
Phosphoproteomics analysis revealed different phosphorylation patterns between metastatic and nonmetastatic cells. The observed enhancement in cancer cell migration, invasion, and the acquisition of a mesenchymal phenotype in metastatic cells elucidates the significance of metastasis in cancer dissemination [ 45 ].
The induction of epithelial-mesenchymal transition enables cancer cells to undergo morphological and functional changes, promoting their ability to invade surrounding tissues and disseminate to distant sites [ 46 ]. The heterogeneity observed in metastatic potential among different cancer types highlights the importance of studying individual cancer subtypes to develop tailored therapeutic strategies [ 47 ].
Furthermore, metastatic dormancy and recurrence present significant challenges in cancer treatment [ 47 ]. Metastatic cells can enter a dormant state in distant organs, remaining quiescent for extended periods before reactivating to form new metastatic lesions [ 47 ].
Understanding the factors that regulate metastatic dormancy and identifying the cues that trigger reactivation are essential for developing strategies to prevent cancer recurrence [ 47 ].
Our study identifies potential therapeutic targets for controlling cancer cell adhesion and metastasis [ 13 ]. The efficacy of integrin-blocking antibodies and small-molecule inhibitors in reducing adhesion and metastatic potential underscores their clinical relevance [ 48 ].
Additionally, investigating potential resistance mechanisms that may arise during treatment is crucial to enhancing the durability of treatment responses [ 49 , 50 ]. The higher response rate in advanced cancer stages upon treatment with integrin inhibitors emphasizes the potential utility of these targeted therapies in late-stage disease management [ 49 , 50 ].
Advanced-stage cancers often exhibit increased metastatic potential, making them particularly challenging to treat [ 49 , 50 ]. Integrin β1 plays a key role in mediating cancer cell attachment to the ECM, facilitating tumor cell survival and migration [ 49 , 50 ].
The combination therapy of integrin inhibitors and E-cadherin upregulators shows promise in controlling cancer cell dissemination [ 49 , 50 ]. Combining different inhibitors may act cooperatively to impair multiple steps in the metastatic cascade, offering improved therapeutic efficacy compared to single-agent treatments [ 49 , 50 ].
Furthermore, prolonged exposure to integrin inhibitors leading to substantial reductions in metastasis highlights the importance of treatment duration in achieving favorable outcomes in cancer patients [ 49 , 50 ].
This finding suggests that sustained inhibition of adhesion molecules may be necessary to effectively impede cancer cell dissemination. Integrins are integral to cancer cell-ECM interactions, enabling cancer cells to anchor and migrate within tissues [ 49 , 50 ].
The combination of different inhibitors may act cooperatively to impair multiple steps in the metastatic cascade, offering improved therapeutic efficacy compared to single-agent treatments [ 49 , 50 ]. Prolonged exposure to integrin inhibitors leading to substantial reductions in metastasis highlights the importance of treatment duration in achieving favorable outcomes in cancer patients [ 49 , 50 ].
Future research should focus on understanding the optimal treatment duration and dosing schedules to maximize therapeutic benefits. The enhanced migration speed, directional persistence, and chemotactic responses of metastatic cells to ECM gradients provide valuable insights into the mechanisms governing cancer cell invasion and dissemination [ 51 ].
These characteristics enable metastatic cells to navigate through tissues and invade surrounding environments effectively [ 51 ]. Identifying key regulatory nodes in adhesion and metastasis provides valuable starting points for further exploration [ 51 ].
These key regulatory nodes are such as FAK, Src, β-catenin, and SMAD4 [ 49 ]. Elucidating the upstream and downstream interactions of these nodes may uncover novel signaling pathways and effectors [ 52 ].
That can be targeted for cancer therapy [ 52 ]. Moreover, understanding the crosstalk between adhesion and metastatic signaling networks may reveal synergistic or antagonistic relationships that could be exploited for combinatorial therapies [ 53 ].
Examining the molecular and phenotypic heterogeneity of metastatic cells can help identify unique vulnerabilities and devise personalized treatment approaches [ 54 ]. To implement these findings in the clinic, overcoming challenges related to the tumor microenvironment and preclinical models is essential [ 55 , 56 ].
Furthermore, investigating the mechanisms of vascular and lymphatic invasion can offer insights into organ-specific metastasis patterns and may lead to strategies to disrupt the dissemination process [ 55 ].
The efficacy of small-molecule inhibitors targeting FAK in preventing focal adhesion highlights their potential as promising therapeutic agents for inhibiting cancer cell migration and invasion [ 57 ]. FAK is a key regulator of focal adhesion turnover and cellular motility.
Targeting FAK may disrupt the signaling pathways involved in cancer cell motility and invasion, offering new possibilities for targeted cancer therapies [ 57 ]. The identification of potential markers such as MMP9 and TWIST1 in metastatic tumor cells may offer opportunities for early detection and targeted therapies for aggressive cancers [ 58 ].
TWIST1, a transcription factor involved in EMT, promotes cancer cell migration and metastatic spread [ 58 ]. Targeting these markers may provide new avenues for precision medicine approaches in cancer treatment. The implementation of these findings in the clinic presents a major challenge.
The tumor microenvironment and interactions with stromal components are critical determinants of cancer cell behavior [ 59 ]. It is extremely difficult to image the microenvironment of tumors in vitro and in animal models [ 60 ].
This requires the development of advanced three-dimensional culture systems for more detailed preclinical studies [ 60 ]. The heterogeneity observed in cancer cell adhesion and metastatic potential highlights the need for personalized treatment approaches [ 61 , 62 ]. Clinical studies of biomarkers may allow for the identification of predictive markers of treatment response [ 63 ].
In-depth analysis and deeper understanding of the identified molecular regulators and therapeutic targets in cancer metastasis can provide valuable insights for developing effective treatment strategies.
Cancer cells constantly interact with the surrounding microenvironment, leading to changes in their adhesion properties and invasive potential [ 6 ].
Exploring the mechanisms that govern these interactions is essential to design targeted therapies that can adapt to the evolving behavior of cancer cells and prevent treatment resistance [ 50 ].
Additionally, studying the signaling pathways involved in cancer cell adhesion and invasion can unveil potential therapeutic vulnerabilities. To translate these findings into clinical practice, overcoming challenges related to the tumor microenvironment and preclinical models is crucial [ 17 ].
Advanced three-dimensional culture systems that better mimic the complexity of the tumor microenvironment are needed to conduct more accurate preclinical studies and predict treatment responses [ 64 ]. Additionally, investigating the mechanisms of vascular and lymphatic invasion can offer insights into organ-specific metastasis patterns and may lead to strategies to disrupt the dissemination process [ 65 ].
The comprehensive study on adhesion, metastasis, and inhibition of cancer cells revealed promising therapeutic targets to reduce metastasis. The study highlights critical molecular regulators and emphasizes the importance of personalized medicine and data sharing for improving cancer therapy. Integrin inhibitors can have undesirable effects and interfere with normal cell functions.
These off-target effects may complicate the development of clinically viable integrin inhibitors [ 67 ]. Integrins are involved in complex signaling pathways that extend beyond cancer metastasis [ 68 ].
Inhibition of integrins could disrupt essential cellular functions and lead to adverse effects [ 69 ]. Tumors are heterogeneous, and they have different integrin expression patterns [ 70 ]. Not all tumors rely on the same integrin subtypes for metastasis [ 71 ].
Developing a unified integrin inhibitor is challenging because it may not effectively target the specific integrins that trigger metastasis in a particular patient [ 68 ]. Tumors can develop resistance to integrin inhibitors over time [ 72 ].
The development of resistance can be due to genetic mutations [ 73 ]. Other possibilities for the development of resistance may be due to altered signaling pathways or the activation of compensatory adhesion molecules [ 73 ]. Integrin inhibitors can have toxicities that limit their clinical use [ 74 ].
The potential for harmful effects on normal tissues may outweigh the benefits [ 74 ]. Achieving optimal drug delivery, bioavailability, and dosing regimens for integrin inhibitors can be complex [ 67 ].
Variations in patient responses, differences in drug metabolism, and the need for sustained therapeutic concentrations further complicate their clinical implementation [ 74 ].
Coordinating and optimizing combination treatments while minimizing potential toxicities is a complex task [ 74 ]. Regulatory hurdles may arise when approving integrin inhibitors for clinical use [ 67 ]. The development and production of targeted therapies such as integrin inhibitors can be costly [ 74 ].
This may limit their accessibility and affordability, particularly in resource-constrained healthcare systems [ 74 ]. Designing clinical trials for integrin inhibitors with clear endpoints, patient selection criteria, and biomarkers to predict response can be challenging [ 67 ].
Well-designed studies are critical to demonstrating their clinical value [ 67 , 73 ]. In summary, although integrin inhibitors hold promise for ameliorating cancer cell metastasis, their clinical implementation faces several difficulties, including off-target effects, complex signaling pathways, tumor heterogeneity, drug resistance, toxicity, pharmacokinetic challenges, and regulatory considerations.
Addressing these challenges and optimizing patient-specific treatment strategies are critical to bringing integrin inhibitors into clinical use.
Furthermore, the heterogeneity observed in cancer cell adhesion and metastatic potential underscores the importance of personalized medicine approaches [ 75 ].
Biomarker-driven clinical studies can help identify predictive markers of treatment response, allowing for more tailored and precise treatment strategies [ 76 ].
Integrating genomic and proteomic analyses of individual patient tumors can aid in identifying specific molecular targets that are most relevant for their cancer subtype, thereby increasing treatment efficacy and minimizing potential side effects [ 77 ].
The knowledge and comprehensive understanding of molecular regulators and therapeutic targets in the adhesion and metastasis of cancer cells opens up new possibilities for improving cancer therapy.
Through collaborative efforts, personalized medicine and preclinical models, we can realize the full potential of these discoveries. These actions could transform cancer treatment to the benefit of patients worldwide.
As we gain deeper insights into the complex interrelationships between adhesion and metastatic signaling networks, novel treatment approaches may emerge, offering improved therapeutic efficacy through the combination of multiple targeted agents [ 78 ].
Looking forward, future perspectives underscore the significance of open-access databases and platforms facilitating data exchange to integrate diverse datasets and identify novel therapeutic targets [ 79 ]. As personalized medicine gains traction, addressing ethical considerations related to data privacy, informed consent, and equitable access to advanced treatments remains of utmost importance to ensure patient well-being and fair distribution of cutting-edge therapies [ 80 ].
The identification of critical regulatory nodes such as FAK, Src, β-catenin, and SMAD4 offers valuable starting points for further research. This includes the development of targeted therapies to effectively control cancer cell adhesion and metastasis [ 81 ].
Future perspectives also emphasize the importance of data sharing and collaboration in promoting the integration of diverse datasets. The knowledge gained from this comprehensive review opens up new horizons for improving cancer therapy. Looking ahead, the future perspectives in this comprehensive review underscore the importance of data sharing and collaboration in the scientific community.
Open-access databases and platforms that facilitate data exchange will play a crucial role in integrating diverse datasets and identifying new therapeutic targets [ 82 ]. This will also help tailor treatment approaches to individual patients, leading to more effective and personalized cancer care [ 83 ].
Ethical considerations in personalized medicine must not be overlooked. Ensuring compliance with data protection, obtaining informed consent, and providing equal access to advanced treatments are vital safeguards to protect patient well-being and promote fairness in healthcare distribution [ 84 ].
The clinical application of adhesion and metastasis inhibitors is important to highlight their important role in the field of oncology. Integrins are proteins involved in cell adhesion. Clinical studies have examined whether integrin inhibitors can prevent adhesion and metastasis.
The integrin inhibitor natalizumab is used in cancer treatment [ 67 ]. Clinical trials often examine various strategies to inhibit metastasis. The drug marimastat inhibits matrix metalloproteinases MMPs [ 85 ]. It thereby prevents the migration of cancer cells. Fortunately, check inhibitors pembrolizumab as well as nivolumab achieve significant good results in the clinical treatment of cancer.
They have the ability to strengthen the immune system, attack and inhibit metastatic cells [ 85 ]. The anti-angiogenesis therapy tries to prevent the formation of new blood vessels in tumor cells. Bevacizumab has been used in clinical trials to inhibit angiogenesis and thereby limit metastasis [ 86 ].
Cell signaling inhibitors have been investigated in clinical trials targeting specific signaling pathways involved in metastasis. These include PI3K, mTOR and MAPK inhibitors [ 87 ].
In conclusion, the identified molecular regulators and therapeutic targets hold promise for the advancement of cancer therapy. Addressing transnational challenges and adopting personalized medicine approaches will be crucial to unlock the full potential of these insights to improve patient outcomes.
These insights offer valuable opportunities to develop novel treatments that specifically target key pathways and processes critical for metastatic progression. However, realizing the full potential of these discoveries requires addressing various transnational challenges that span scientific, clinical, and societal domains.
International collaborations facilitate the exchange of knowledge and the validation of findings in diverse patient populations, leading to more robust and generalizable therapeutic strategies.
Moreover, adopting personalized medicine approaches will be instrumental in translating these discoveries into tangible benefits for individual patients. Access to advanced therapies and cutting-edge treatments must be equitable, irrespective of geographical location or economic status.
The identification of molecular regulators and therapeutic targets in cancer metastasis opens up exciting possibilities for advancing cancer therapy. The comprehensive study of the processes of adhesion, metastasis and inhibition of cancer cells has provided invaluable insight into the complex mechanisms.
The effectiveness of integrin-blocking antibodies, small molecule inhibitors targeting FAK and the TGF-β pathway, and combination therapies underscores their potential to disrupt focal adhesions and control epithelial-mesenchymal transition processes.
The in vitro cell culture models and animal studies may not fully mimic the complexity of the metastatic process. Therefore, further research using advanced 3D culture systems and patient-based models will be crucial.
By addressing the limitations and leveraging precision medicine approaches, we can move closer to developing targeted therapies that tailor treatment to the unique characteristics of individual patients. The ongoing research efforts to understand the tumor microenvironment and heterogeneity in cancer cells will be critical in translating these findings into effective clinical applications.
The comprehensive insights gained from this study provide a solid foundation for advancing cancer therapy. The potential of targeting key adhesion molecules, such as integrins and cadherins, opens up exciting possibilities for disrupting cancer cell-ECM interactions and controlling metastasis.
Efforts to advance preclinical research using advanced 3D culture systems and patient-based models are essential to better simulate the tumor microenvironment and heterogeneity observed in cancer cells.
These models can serve as powerful tools to identify unique vulnerabilities in metastatic cells and guide the design of personalized treatment approaches tailored to individual patients. The wealth of knowledge gained from this comprehensive study offers promising opportunities to revolutionize cancer therapy.
Addressing transnational challenges and embracing personalized medicine approaches will be instrumental in unlocking the full potential of these discoveries in adhesion, metastasis and inhibition of cancer cells. Ma X, Yu H Global burden of Cancer.
Yale J Biol Med — The 1 H NMR spectrum of terrein Fig. Characteristics of terrein. A Aspergillus terreus was cultured for 34 days.
B Separation of the pure compound using Sephadex LH column chromatography. C All fractions were collected. D and E Thin layer chromatography.
F The structure of terrein was characterized by 1H NMR spectroscopic data. G The 1H NMR spectrum of terrein. First, the cytotoxic effects of terrein on different cell lines were examined, including A lung cancer cells, African green monkey kidney Vero cells, L6 skeletal muscle cells and H9C2 cardiomyoblast cells, using an MTT assay.
All the cell lines were treated with various concentrations of terrein for 24 h, and the maximum final concentration of DMSO 0. The results demonstrated that terrein significantly inhibited the viability of A cells, Vero cells, L6 cells and H9C2 cells with IC 50 values of , , 1, and µM, respectively Fig.
Terrein exhibited more toxicity in lung cancer cells than in all the representative normal cells. As a result, the SI values of terrein on A cells were 3.
In addition, LDH assays were performed to confirm the damaging effect of terrein. The LDH enzyme is normally used as a biomarker of cellular cytotoxicity and cytolysis, as it is released from damaged cells Terrein inhibits cell viability and proliferation in lung cancer cells.
Cell viability was assessed by MTT assay, in which various concentrations of terrein were treated for 24 h. A A cells B Vero cells C L6 cells D H9C2 cells E LDH assay and F proliferation assay. Values are expressed as the mean ± SEM of three independent experiments. LDH, lactate dehydrogenase. It was also determined whether these cytotoxic effects of terrein interfered with the process of cell proliferation using the IncuCyte assay.
Cells were treated with different concentrations of terrein 1—1, µM. Cell proliferation was monitored every 3 h for 3 days. Proliferation curves were generated using IncuCyte proliferation analysis with cell confluence as the parameter.
The results revealed that 20—1, µM terrein exhibited dose-dependent inhibitory effects on A cell proliferation, as revealed in Fig. The present results indicated that a high concentration of terrein inhibited A cell viability and proliferation by damaging the cells.
Thus, to further investigate the effects of terrein on metastatic processes, the concentrations of 20, 40 and 80 µM terrein, which exhibit low levels of toxicity in cells, were selected. To determine the effect of terrein on the metastatic processes of lung cancer cells, its inhibitory effect on lung cancer cell migration was first evaluated.
The migration of cells was measured using a wound healing assay. In this method, the concentrations of terrein that exhibited low toxicity 20, 40 and 80 µM were used to treat A cells for 0, 6, 12 and 24 h.
The results revealed that terrein significantly inhibited cell migration at 6, 12 and 24 h Fig. Effect of terrein on A cell metastatic processes. Wound healing assay was performed to assess the migration of A cells after 0, 6, 12 and 24 h of terrein treatment.
A A representative image of the scratch-wound healing assay of A cells using a magnification of × B Migration distance of the treated and untreated samples were measured in at least three independent locations in each wound.
C Effects of terrein on A lung cancer cell migration and invasion after 24 h of terrein treatment and crystal violet staining.
Representative images were captured at a magnification of × D The migrated and E invasive cells were quantified by using ImageJ software. F Adhesion of A cells on Matrigel-coated plates. Effect of terrein on cell adherence were measured by MTT assay after 30 min of terrein incubation. G Representative gelatin zymography of MMP-2 after 24 h of terrein treatment.
H Representative gelatin zymography of MMP-9 after 24 h of terrein treatment. The activity of MMP-2 and MMP-9 were quantified by ImageJ. I Expression of MMP-2 and MMP-9 was determined using qPCR after 24 h of terrein treatment. Significance was measured as the mean ± SEM of at least three separate experiments.
MMP, matrix metalloproteinase. The ability of terrein to suppress the migration and invasion of A lung cancer cells was further examined.
A cells were treated with or without 20, 40 and 80 µM terrein for 24 h, and a Transwell assay was used to observe the effect of terrein on A cell migration and invasion. The effect of terrein on the adhesion process, since it is associated with the early step of metastasis 35 , was also determined.
To assess the effect of terrein on the process of cell invasion, the effect of terrein on the activities and expression of MMP-2 and MMP-9 was determined using gelatin zymography and qPCR, respectively. A lung cancer cells were treated with 20, 40 and 80 µM terrein for 24 h.
The results revealed that terrein significantly suppressed the gelatinase activities of both MMP-2 and MMP Bands corresponding to MMP-2 68 kDa and MMP-9 82 kDa were clearly observed, and 40 and 80 µM terrein significantly inhibited MMP-2 and 80 µM terrein significantly inhibited MMP-9, as revealed in Fig.
In addition, terrein significantly inhibited MMP-2 expression and tended to inhibit MMP-9 expression as revealed in the Fig. These data suggested that terrein had the ability to inhibit the metastatic processes of lung cancer cells. To examine whether terrein could inhibit the angiogenesis process, A cells were treated with or without 20, 40 and 80 µM terrein for 24 h.
The VEGF-A that was secreted by the A cells into the medium was collected, concentrated and detected by human VEGF-A ELISAs. The results revealed that terrein significantly reduced the secretion of VEGF-A from A lung cancer cells compared with the vehicle control Fig.
To further confirm this inhibitory effect, an in vitro capillary-like tube formation assay was performed. This is a rapid and quantitative method for examining cell differentiation and changes associated with the angiogenesis process. To perform the experiment, A cells were cultured in Matrigel-coated plates and then treated with or without 20, 40 and 80 µM terrein for 24 h.
Tube formation or the characteristics of A cells that formed vessel-like channels were captured by inverted microscopy. The inhibition of VEGFR2 phosphorylation at Tyr, which is a crucial site for the migration of cells during angiogenesis, was also detected Fig.
Terrein inhibits the angiogenesis process of A lung cancer cells. A Effects of terrein on release of VEGF-A from A lung cancer cells that was examined by VEGF-A Human ELISA assays after 24 h of terrein treatment.
B Terrein inhibited A lung cancer cell tube formation. After 24 h of terrein treatment, tubular structures were captured under an inverted microscope at a magnification of × C Quantification graph by Angiogenesis Analyzer plugin for ImageJ software.
D Representation of the protein level of VEGFR2 was measured by western blotting after 24 h of terrein treatment. E Quantification graph of western blotting by ImageJ software. VEGF, vascular endothelial growth factor; VEGF-A, VEGF subtype A; VEGFR2, VEGF receptor tyrosine kinase type 2; p, phosphorylated.
To investigate the effect of terrein on the expression of metastasis mediators, such as integrin αM, FAK, mTORC1, PI3K, AKT and P70S6K, western blotting was performed.
A cells were treated with different concentrations of terrein for 24 h. Notably, a low concentration of terrein clearly inhibited the phosphorylation of FAK. Active integrins recruit various proteins, including FAK, to FAs to stimulate cell signaling.
When FAK is activated, it further stimulates the expression and activation of downstream proteins. The signaling proteins downstream of FAK are PI3K, AKT, mTORC1 and P70S6K.
These proteins affect cell survival, proliferation, angiogenesis, invasion, migration and metastasis. The inhibition of FAK leads to the suppression of these downstream signaling mediators The phosphorylation of PI3K p85 at Tyr Fig. Therefore, the inhibition of these proteins by terrein resulted in the suppression of metastatic and angiogenic processes in lung cancer cells.
Effects of terrein on the expression of signaling mediators associated with metastatic processes in A lung cancer cells. Representative protein levels were examined by western blotting after 24 h of terrein treatment and the quantified bar graphs are presented.
A-C Integrin αM and FAK phosphorylation. D and E PI3K p85 phosphorylation. F-H AKT phosphorylation. I mTORC1 and P70S6K as determined by western blotting. J mTORC1 phosphorylation and K P70S6K phosphorylation. FAK, focal adhesion kinase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase-B; mTOR, mammalian target of rapamycin; P70S6K, ribosomal p70S6 kinase; p, phosphorylated.
Immunofluorescence was used to further confirm the effect of terrein on the phosphorylation of FAK at Tyr in A cells. The representative and quantitative images Fig. Combining these results with the western blot data clearly indicated that terrein had the ability to inhibit the phosphorylation of FAK at Tyr, and FAK was revealed to be an upstream regulator of numerous proteins involved in cancer metastasis.
Effects of terrein on phosphorylation of FAK at Tyr in A cells. Cells were treated with terrein at 20, 40 and 80 µM for 24 h. A Representative confocal images of phosphorylation of FAK at Tyr B Its quantification. Scale bar, 20 µm. FAK, focal adhesion kinase. Human lung cancer is the leading cause of cancer-related deaths worldwide 1.
Most often, lung cancer is diagnosed at metastatic stages, and at these stages, cancer cells have spread to nearby tissues or other parts of the body 2.
Therefore, the suppression of metastasis is required to reduce the premature death of cancer patients. Currently, the world has turned its attention to the use natural substances for cancer treatment because they typically have fewer side effects. Terrein is a bioactive natural substance that has been reported to exert various biological effects, including anti-inflammation, melanogenesis inhibition and anticancer effects 20 — However, to the best of our knowledge, the effect of terrein on the molecular mechanisms that regulate human lung cancer metastasis has not been examined.
In the present study, the effects of terrein on metastatic processes, including cell proliferation, adhesion, migration, invasion and angiogenesis, were investigated using A human lung cancer cells. Τhe present results revealed that terrein exhibited cytotoxic effects on different cell types, including A cells, Vero cells, L6 cells and H9C2 cells, by inhibiting cell viability with IC 50 values of , , 1, and µM, respectively.
These results suggest that terrein has a specific effect on A lung cancer cells relative to normal cells with a relatively high selectivity index value. As revealed in other studies, terrein exhibited a cytotoxic effect on human cervical cancer cells HeLa with an IC 50 value of µM 22 and on the human breast cancer cell lines MCF-7 and MDA-MB with IC 50 values of 2, and µM, respectively LDH assays were used to measure cell viability 34 and further verified this conclusion.
Overall, these data indicated that terrein was more toxic to A lung cancer cells than to other types of cancer cells. Cancer metastasis includes several steps, including cell proliferation, adhesion, migration, invasion and angiogenesis.
To determine the effects of terrein on these processes, low concentrations of terrein 20, 40 and 80 µM that were not toxic to the normal cell lines tested were selected. It was first observed that a terrein concentration as low as 20 µM started to reduce the proliferative ability of A cells.
The antimetastatic properties of terrein were observed upon analysis of MMP activity. Numerous studies have demonstrated that MMPs play important roles in tumor progression, invasion, metastasis and angiogenesis 37 , Increased expression of MMPs has been revealed to be associated with poor prognosis in several types of tumors, including breast cancer, gastric cancer and osteosarcoma 39 — All invasive malignant tumors, including lung cancer cells, are known to express high levels of MMPs, especially MMP-2 and MMP-9 MMP-2 plays an essential role in the progression of cancer because it cleaves several ECM components and basement membranes 43 ; thus, the development of potential MMP-2 inhibitors has become an important goal in lung cancer therapy.
The expression and activity of MMP-9 are increased in NSCLC and are associated with the pathological type and clinical stage of NSCLC The expression levels of MMP-9 were higher in advanced stage III and IV tumors than in primary stage I and II tumors of NSCLC patients, and MMP-9 expression was higher in NSCLC patients with metastasis than in NSCLC patients without metastasis and a reduced 5-year survival rate Both MMP-2 and MMP-9 are classified as soluble enzymes that are secreted into the extracellular milieu.
Therefore, blocking the activities of these enzymes has the potential to suppress lung cancer cell metastasis and increase the possibility of NSCLC patient survival. In the present study, it was revealed that terrein significantly suppressed both the activities and expression of MMP-2 and MMP These findings indicated that terrein has the potential to act as an antimetastatic agent, which, to the best of our knowledge, to date, has never been reported.
Angiogenesis, or the creation of new blood vessels, is another important mechanism during cancer progression. New blood vessels support the growth of tumors by specifically feeding their hypoxic and necrotic areas to provide essential nutrients and oxygen In the present study, the effect of terrein on angiogenesis was investigated by determining the expression of VEGF-A as a surrogate biomarker.
VEGF is a major chemotactic factor during angiogenesis that initiates the migration and adhesion of cells, interactions between endothelial cells and ECM, and formation of a tubular network In mammals, there are several types of VEGF, including VEGF-A, VEGF-B, VEGF-C, and VEGF-D; however, VEGF-A is widely studied and plays a major role in angiogenesis by acting through VEGFR2 It was observed that 80 µM terrein significantly attenuated VEGF-A expression.
Furthermore, the effect of terrein on angiogenesis was investigated by examining the in vitro capillary-like tube formation of A cells. The characteristics of tube-like structures were reduced by terrein in a dose-dependent manner.
These results suggest that terrein suppresses processes known to be involved in angiogenesis. Thus, our collective dataset suggests that terrein can suppress multiple steps of cancer metastatic processes, including proliferation, wound healing, adhesion, migration and invasion.
A more detailed mechanistic analyses was next conducted based on the rationale that focal adhesion complexes are known to be crucial nodes of signaling events that mediate cancer metastasis Notably, the interaction of multiple proteins at focal adhesions is critical to promote the protrusion of the cell membrane leading edge, resulting in the development of invadopodia and lamellipodia At focal adhesions, signal transduction is initiated by interactions of integrins with the ECM, which further promote the assembly of cytoplasmic scaffolds and the recruitment of kinase proteins FAK, or focal adhesion kinase, is one of the principal integrin signaling regulators that is recruited to the site of adhesion, and FAK is autophosphorylated at the Tyr site.
The autophosphorylation of FAK contributes to the further activation of its intrinsic kinase activity and creates docking sites for several downstream signaling molecules FAK expression is increased in numerous highly malignant human cancers Overexpression of FAK in cancer cells leads to resistance to the apoptotic process Therefore, to inhibit integrin signaling, the regulation of FAK expression and phosphorylation is a well-established goal for the development of effective pharmaceutical antimetastatic agents.
As revealed in the present study, terrein could inhibit the expression of integrin αM and the phosphorylation of FAK at Tyr, as demonstrated by western blot and immunofluorescence analyses. The present results revealed that terrein could reduce stress fiber formation.
Normally, cell migration is associated with adhesion and actin cytoskeleton organization, which also involves a series of lamellipodia extension and actin polymerization.
In addition, initial adhesions are formed through the engagement of integrin receptors by the ECM The integrin-FAK signaling pathway is known to be associated with cell adhesion and migration, and these effects are regulated by downstream molecules. Inhibition of FAK leads to retraction of filopodia and lamellipodia in cell protrusions, resulting in stress fiber formation in retractile cell bodies 6.
The present results suggested that the inhibition of FAK reduced the adhesion of cells to the ECM, which contributed to reduced cell migration.
Next, mediators downstream of FAK, including PI3K, AKT, mTOR and P70S6K, were further investigated. The protein mTORC1 induces protein synthesis and cell growth by phosphorylating S6K1 and 4E-BP1 58 , while mTORC2 regulates the organization of the actin cytoskeleton through F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42 and PKCα The results of the present study revealed that terrein significantly decreased the phosphorylation of PI3K p85 at Tyr, AKT at Ser and Thr, mTORC1 at Ser and pP70S6K at Thr Summary of terrein effects on lung cancer cell metastasis and angiogenesis signaling pathways.
In conclusion, the present study demonstrated the novel finding that terrein acted as an anticancer agent in lung cancer. Wong, A. Mitosis-mediated intravasation in a tissue-engineered tumor-microvessel platform. Denais, C. Nuclear envelope rupture and repair during cancer cell migration.
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Download references. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, , USA. High-Impact Cancer Research Program, Harvard Medical School, Boston, MA, , USA.
Faculty of Medicine, American University of Beirut, Beirut, Lebanon. Mohamad Y. Fares, Hussein H. Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
Khachfe, Hamza A. You can also search for this author in PubMed Google Scholar. Correspondence to Jawad Fares. Open Access This article is licensed under a Creative Commons Attribution 4.
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Subjects Metastasis. Abstract Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Full size image. Dissemination and invasion Chromosomal instability: the initial trigger Dissemination of cancer cells precedes the initial steps of the invasion-metastasis cascade.
Intravasation Intravasation, the dissemination of cancer cells to organs through the lumen of the vasculature, is mediated actively or passively.
Circulation How do tumor cells survive in circulation? Extravasation How do circulating tumor cells extravasate? Colonization How does the colonizing cell overcome stromal challenges? Therapeutic strategies to target the pathways of metastasis The field of metastasis research is more than years old.
Concluding remarks Metastasis is the final frontier in cancer for which more efficacious therapies are needed. References Luzzi, K. Article CAS PubMed PubMed Central Google Scholar Maitra, A. Article CAS PubMed Google Scholar Massague, J.
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Copyright: Wrestling diet program Buachan et al. Metaetasis is an open access Inhibiting cancer cell metastasis distributed under Inhibitinv terms of Inhibiting cancer cell metastasis Commons Attribution License. Lung cancer is a disease Inhibuting is characterized by uncontrolled growth of abnormal cells in one or both of the lungs. Lung cancer is a common type of cancer that has been identified as the leading cause of cancer-related deaths worldwide. The data from GLOBOCANa project of the International Agency for Research on Cancer IARCestimated that lung cancer caused 1.
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