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Cells
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Cellular and Molecular Mechanisms of Cancer Metastasis
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Cellular and Molecular Mechanisms of Cancer Metastasis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 25907

Special Issue Editor

Prof. Dr. Ira-Ida Skvortsova

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Guest Editor
Department of Therapeutic Radiology and Oncology, Tyrolean Cancer Research Institute, Medical University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria
Interests: cancer metastasis; cancer stem cells; therapy resistance; molecular mechanisms; cancer microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

One of the hallmarks of malignant tumors is an ability to metastasize. Unfortunately, metastatic spread is responsible for cancer-related deaths in a majority of patients. Although cancer researchers have uncovered a variety of molecular features associated with the metastatic capabilities of tumor cells, further investigations of the intratumoral processes resulting in metastasis formation are needed. It is currently known that cancer cell dissemination can be regulated by specific cellular properties (enhanced invasive and migratory abilities, increased expression of the molecules associated with metastatic spread, metabolic alterations resulting in the enhancement of cancer cell aggressiveness, etc.) and a number of microenvironmental factors (crosstalk between malignant and nonmalignant cells comprising tumors, cytokine and growth factor release by the cells, proinflammatory stimuli, etc.).

It is proposed that the following aspects of the subject area be highlighted in the Special Issue:

- The role of dormancy in metastasis development;

- Cancer stem cells as a root for metastasis formation;

- The molecular properties of tumor cells with enhanced metastatic capacities;

- The molecular mechanisms of organ-specific metastasis;

- Circulating tumor cells;

- Therapy-induced metastasis;

- Tumor metabolism and metastatic spread;

- The role of the microenvironment (tumor stroma and immune system) in metastatic progression;

- Exosomes in disease progression;

- Cytokines contributing to metastatic spread;

- Metabolic hallmarks of metastasis formation;

- Diagnostic tools for metastasis detection;

- Therapeutic approaches to combating metastatic progression.

We look forward to your contributions.

Prof. Dr. Ira-Ida Skvortsova
Guest Editor

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Related Special Issue

Published Papers (8 papers)

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Research

21 pages, 6288 KiB  
Article
Spastin Promotes the Migration and Invasion Capability of T98G Glioblastoma Cells by Interacting with Pin1 through Its Microtubule-Binding Domain
by Benan Temizci, Seren Kucukvardar and Arzu Karabay
Cells 2023, 12(3), 427; https://doi.org/10.3390/cells12030427 - 27 Jan 2023
Cited by 2 | Viewed by 2401
Abstract
Microtubule-severing protein Spastin has been shown to co-localize with actin in migratory glioblastoma cells and is linked to glioblastomas’ migration and invasion capacity. However, the effectiveness of Spastin in glioblastoma migration and the molecular mechanism underpinning the orientation of Spastin towards actin filaments [...] Read more.
Microtubule-severing protein Spastin has been shown to co-localize with actin in migratory glioblastoma cells and is linked to glioblastomas’ migration and invasion capacity. However, the effectiveness of Spastin in glioblastoma migration and the molecular mechanism underpinning the orientation of Spastin towards actin filaments remain unknown. Here, we demonstrated that Spastin plays an active role in glioblastoma migration by showing a reduced migratory potential of T98G glioblastoma cells using real-time cell analysis (RTCA) in Spastin-depleted cells. Pull-down assays revealed that a cis–trans isomerase Pin1 interacts with Spastin through binding to the phosphorylated Pin1 recognition motifs in the microtubule-binding domain (MBD), and immunocytochemistry analysis showed that interaction with Pin1 directs Spastin to actin filaments in extended cell regions. Consequently, by utilizing RTCA, we proved that the migration and invasion capacity of T98G glioblastoma cells significantly increased with the overexpression of Spastin, of which the Pin1 recognition motifs in MBD are constitutively phosphorylated, while the overexpression of phospho-mutant form did not have a significant effect on migration and invasion of T98G glioblastoma cells. These findings demonstrate that Pin1 is a novel interaction partner of Spastin, and their interaction drives Spastin to actin filaments, allowing Spastin to contribute to the glioblastomas’ migration and invasion abilities. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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15 pages, 4487 KiB  
Article
Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration
by Attila Varga, Minh Tu Nguyen, Kinga Pénzes, Bence Bátai, Pál Gyulavári, Bianka Gurbi, József Murányi, Péter Csermely, Miklós Csala, Tibor Vántus and Csaba Sőti
Cells 2023, 12(2), 212; https://doi.org/10.3390/cells12020212 - 4 Jan 2023
Cited by 3 | Viewed by 2253
Abstract
Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using [...] Read more.
Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype. Here, using different prostate cancer cell lines, we report that Hsp90 ensures PKD3 conformational stability and function to promote cancer cell migration. We found that pharmacological inhibition of either PKDs or Hsp90 dose-dependently abrogated the migration of DU145 and PC3 metastatic prostate cancer cells. Hsp90 inhibition by ganetespib caused a dose-dependent depletion of PKD2, PKD3, and Akt, which are all involved in metastasis formation. Proximity ligation assay and immunoprecipitation experiments demonstrated a physical interaction between Hsp90 and PKD3. Inhibition of the chaperone–client interaction induced misfolding and proteasomal degradation of PKD3. PKD3 siRNA combined with ganetespib treatment demonstrated a specific involvement of PKD3 in DU145 and PC3 cell migration, which was entirely dependent on Hsp90. Finally, ectopic expression of PKD3 enhanced migration of non-metastatic LNCaP cells in an Hsp90-dependent manner. Altogether, our findings identify PKD3 as an Hsp90 client and uncover a potential mechanism of Hsp90 in prostate cancer metastasis. The molecular interaction revealed here may regulate other biological and pathological functions. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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15 pages, 2111 KiB  
Article
miR-18a Mediates Immune Evasion in ER-Positive Breast Cancer through Wnt Signaling
by Madhumathy G. Nair, Apoorva D, Chandrakala M, Snijesh VP, Sharada Patil, Anupama CE, Geetashree Mukherjee, Rekha V. Kumar, Jyothi S. Prabhu and Sridhar TS
Cells 2022, 11(10), 1672; https://doi.org/10.3390/cells11101672 - 18 May 2022
Cited by 7 | Viewed by 3446
Abstract
ER-positive (ER+) breast cancer is considered immunologically ‘silent’ with fewer tumor-infiltrating immune cells. We have previously demonstrated the role of miR-18a in mediating invasion and poor prognosis in ER+ breast cancer by activation of the Wnt signaling pathway. Here, we explored the immune-modulatory [...] Read more.
ER-positive (ER+) breast cancer is considered immunologically ‘silent’ with fewer tumor-infiltrating immune cells. We have previously demonstrated the role of miR-18a in mediating invasion and poor prognosis in ER+ breast cancer by activation of the Wnt signaling pathway. Here, we explored the immune-modulatory functions of high levels of miR-18a in these tumors. A microarray-based gene expression analysis performed in miR-18a over-expressed ER+ breast cancer cell lines demonstrated dysregulation and suppression of immune-related pathways. Stratification of the ER+ tumor samples by miR-18a levels in the TCGA and METABRIC cohort and immune cell identification performed using CIBERSORT and Immune CellAI algorithms revealed a higher proportion of T-regulatory cells (p < 0.001) and a higher CD4/CD8 ratio (p < 0.01). miR-18a over-expressed MCF7 co-cultured with THP-1 showed decreased antigen presentation abilities and increased invasiveness and survival. They also promoted the differentiation of pro-tumorigenic M2 macrophages. Inhibition of the Wnt pathway in miR-18a over-expressed cells brought about the restoration of TAP-1, a protein critical for antigen presentation. Examination of tumor specimens from our case series showed that miR-18a high ER+ tumors had a dense lymphocyte infiltrate when compared to miR-18a low tumors but expressed a higher CD4/CD8 ratio and the M2 macrophage marker CD206, along with the invasive marker MMP9. We report for the first time an association between miR-18a-mediated Wnt signaling and stromal immune modulation in ER+ tumors. Our results highlight the possibility of formulating specific Wnt pathway inhibitors that may be used in combination with immune checkpoint blockers (ICB) for sensitizing ‘immune-cold’ ER+ tumors to immunotherapy. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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8 pages, 1945 KiB  
Article
Assessment of BPV-1 Mediated Matrix Metalloproteinase Genes Deregulation in the In Vivo and In Vitro Models Designed to Explore Molecular Nature of Equine Sarcoids
by Przemysław Podstawski, Katarzyna Ropka-Molik, Ewelina Semik-Gurgul, Marcin Samiec, Maria Skrzyszowska, Zenon Podstawski, Tomasz Szmatoła, Maciej Witkowski and Klaudia Pawlina-Tyszko
Cells 2022, 11(8), 1268; https://doi.org/10.3390/cells11081268 - 8 Apr 2022
Cited by 5 | Viewed by 2166
Abstract
Matrix metalloproteinases (MMPs) represent a family of enzymes capable of biocatalytically breaking down the structural and functional proteins responsible for extracellular matrix (ECM) integrity. This capability is widely used in physiological processes; however, imbalanced MMP activity can trigger the onset and [...] Read more.
Matrix metalloproteinases (MMPs) represent a family of enzymes capable of biocatalytically breaking down the structural and functional proteins responsible for extracellular matrix (ECM) integrity. This capability is widely used in physiological processes; however, imbalanced MMP activity can trigger the onset and progression of various pathological changes, including the neoplasmic transformation of different cell types. We sought to uncover molecular mechanisms underlying alterations in transcriptional profiles of genes coding for MMPs, which were comprehensively identified in equine adult dermal tissue bioptates, sarcoid-derived explants, and ex vivo expanded adult cutaneous fibroblast cell (ACFC) lines subjected to inducible oncogenic transformation into sarcoid-like cells. The results strongly support the hypothesis that the transcriptional activity of MMP genes correlates with molecular modifications arising in equine dermal cells during their conversion into sarcoid cells. The alterations in MMP transcription signatures occurs in both sarcoid tissues and experimentally transformed equine ACFC lines expressing BPV1-E4^E1 transgene, which were characterized by gene up- and down-regulation patterns. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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17 pages, 3054 KiB  
Article
S100A4 Is a Strong Negative Prognostic Marker and Potential Therapeutic Target in Adenocarcinoma of the Stomach and Esophagus
by Christoph Treese, Kimberly Hartl, Michelle Pötzsch, Matthias Dahlmann, Moritz von Winterfeld, Erika Berg, Michael Hummel, Lena Timm, Beate Rau, Wolfgang Walther, Severin Daum, Dennis Kobelt and Ulrike Stein
Cells 2022, 11(6), 1056; https://doi.org/10.3390/cells11061056 - 21 Mar 2022
Cited by 6 | Viewed by 3222
Abstract
Deregulated Wnt-signaling is a key mechanism driving metastasis in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S). The oncogene S100A4 was identified as a Wnt-signaling target gene and is known to promote metastasis. In this project, we illuminate the role of S100A4 for [...] Read more.
Deregulated Wnt-signaling is a key mechanism driving metastasis in adenocarcinoma of the gastroesophageal junction and stomach (AGE/S). The oncogene S100A4 was identified as a Wnt-signaling target gene and is known to promote metastasis. In this project, we illuminate the role of S100A4 for metastases development and disease prognosis of AGE/S. Five gastric cancer cell lines were assessed for S100A4 expression. Two cell lines with endogenous high S100A4 expression were used for functional phenotyping including analysis of proliferation and migration after stable S100A4 knock-down. The prognostic value of S100A4 was evaluated by analyzing the S100A4 expression of tissue microarrays with samples of 277 patients with AGE/S. S100A4 knock-down induced lower migration in FLO1 and NCI-N87 cells. Treatment with niclosamide in these cells led to partial inhibition of S100A4 and to reduced migration. Patients with high S100A4 expression showed lower 5-year overall and disease-specific survival. In addition, a larger share of patients in the S100A4 high expressing group suffered from metachronous metastasis. This study identifies S100A4 as a negative prognostic marker for patients with AGE/S. The strong correlation between S100A4 expression, metastases development and patient survival might open opportunities to use S100A4 to improve the prognosis of these patients and as a therapeutic target for intervention in this tumor entity. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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18 pages, 13626 KiB  
Article
CRISPR/Cas9 Mediated Knockout of Cyclooxygenase-2 Gene Inhibits Invasiveness in A2058 Melanoma Cells
by Cathleen Haase-Kohn, Markus Laube, Cornelius K. Donat, Birgit Belter and Jens Pietzsch
Cells 2022, 11(4), 749; https://doi.org/10.3390/cells11040749 - 21 Feb 2022
Cited by 9 | Viewed by 3223
Abstract
The inducible isoenzyme cyclooxygenase-2 (COX-2) is an important hub in cellular signaling, which contributes to tumor progression by modulating and enhancing a pro-inflammatory tumor microenvironment, tumor growth, apoptosis resistance, angiogenesis and metastasis. In order to understand the role of COX-2 expression in melanoma, [...] Read more.
The inducible isoenzyme cyclooxygenase-2 (COX-2) is an important hub in cellular signaling, which contributes to tumor progression by modulating and enhancing a pro-inflammatory tumor microenvironment, tumor growth, apoptosis resistance, angiogenesis and metastasis. In order to understand the role of COX-2 expression in melanoma, we investigated the functional knockout effect of COX-2 in A2058 human melanoma cells. COX-2 knockout was validated by Western blot and flow cytometry analysis. When comparing COX-2 knockout cells to controls, we observed significantly reduced invasion, colony and spheroid formation potential in cell monolayers and three-dimensional models in vitro, and significantly reduced tumor development in xenograft mouse models in vivo. Moreover, COX-2 knockout alters the metabolic activity of cells under normoxia and experimental hypoxia as demonstrated by using the radiotracers [18F]FDG and [18F]FMISO. Finally, a pilot protein array analysis in COX-2 knockout cells verified significantly altered downstream signaling pathways that can be linked to cellular and molecular mechanisms of cancer metastasis closely related to the enzyme. Given the complexity of the signaling pathways and the multifaceted role of COX-2, targeted suppression of COX-2 in melanoma cells, in combination with modulation of related signaling pathways, appears to be a promising therapeutic approach. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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21 pages, 2847 KiB  
Article
Lipocalin-2 (LCN2) Deficiency Leads to Cellular Changes in Highly Metastatic Human Prostate Cancer Cell Line PC-3
by Sarah K. Schröder, Manuela Pinoé-Schmidt and Ralf Weiskirchen
Cells 2022, 11(2), 260; https://doi.org/10.3390/cells11020260 - 13 Jan 2022
Cited by 12 | Viewed by 3332
Abstract
The transporter protein lipocalin-2 (LCN2) also termed neutrophil-gelatinase-associated lipocalin (NGAL) has pleiotropic effects in tumorigenesis in various cancers. Since the precise role of LCN2 in prostate cancer (PCa) is poorly understood, we aimed to elucidate its functions in PCa in vitro. For this [...] Read more.
The transporter protein lipocalin-2 (LCN2) also termed neutrophil-gelatinase-associated lipocalin (NGAL) has pleiotropic effects in tumorigenesis in various cancers. Since the precise role of LCN2 in prostate cancer (PCa) is poorly understood, we aimed to elucidate its functions in PCa in vitro. For this purpose, LCN2 was transiently suppressed or permanently depleted in human PC-3 cells using siRNA or CRISPR/Cas9-mediated knockout. Effects of LCN2 suppression on expression of different tumorigenic markers were investigated by Western blot analysis and RT-qPCR. LCN2 knockout cells were analyzed for cellular changes and their ability to cope endoplasmic stress compared to parenteral PC-3 cells. Reduced LCN2 was accompanied by decreased expression of IL-1β and Cx43. In PC-3 cells, LCN2 deficiency leads to reduced proliferation, diminished expression of pro-inflammatory cytokines, lower adhesion, and disrupted F-actin distribution. In addition, IL-1β expression strongly correlated with LCN2 levels. LCN2 knockout cells showed enhanced and sustained activation of unfolded protein response proteins when treated with tunicamycin or cultured under glucose deprivation. Interestingly, an inverse correlation between phosphorylation of eukaryotic initiation factor 2 α subunit (p-eIF2α) and LCN2 expression was observed suggesting that LCN2 triggers protein synthesis under stress conditions. The finding that LCN2 depletion leads to significant phenotypic and cellular changes in PC-3 cells adds LCN2 as a valuable target for the treatment of PCa. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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20 pages, 32824 KiB  
Article
Wnt5A and TGFβ1 Converges through YAP1 Activity and Integrin Alpha v Up-Regulation Promoting Epithelial to Mesenchymal Transition in Ovarian Cancer Cells and Mesothelial Cell Activation
by Zeinab Dehghani-Ghobadi, Shahrzad Sheikh Hasani, Ehsan Arefian and Ghamartaj Hossein
Cells 2022, 11(2), 237; https://doi.org/10.3390/cells11020237 - 11 Jan 2022
Cited by 10 | Viewed by 3685
Abstract
In this paper, we investigate whether Wnt5A is associated with the TGF-β1/Smad2/3 and Hippo-YAP1/TAZ-TEAD pathways, implicated in epithelial to mesenchymal transition (EMT) in epithelial ovarian cancer. We used 3D and 2D cultures of human epithelial ovarian cancer cell lines SKOV-3, OVCAR-3, CAOV-4, and [...] Read more.
In this paper, we investigate whether Wnt5A is associated with the TGF-β1/Smad2/3 and Hippo-YAP1/TAZ-TEAD pathways, implicated in epithelial to mesenchymal transition (EMT) in epithelial ovarian cancer. We used 3D and 2D cultures of human epithelial ovarian cancer cell lines SKOV-3, OVCAR-3, CAOV-4, and different subtypes of human serous ovarian cancer compared to normal ovary specimens. Wnt5A showed a positive correlation with TAZ and TGFβ1 in high- and low-grade serous ovarian cancer specimens compared to borderline serous and normal ovaries. Silencing Wnt5A by siRNAs significantly decreased Smad2/3 activation and YAP1 expression and nuclear shuttling in ovarian cancer (OvCa) cells. Furthermore, Wnt5A was required for TGFβ1-induced cell migration and invasion. In addition, inhibition of YAP1 transcriptional activity by Verteporfin (VP) altered OvCa cell migration and invasion through decreased Wnt5A expression and inhibition of Smad2/3 activation, which was reverted in the presence of exogenous Wnt5A. We found that the activation of TGFβ1 and YAP1 nuclear shuttling was promoted by Wnt5A-induced integrin alpha v. Lastly, Wnt5A was implicated in activating human primary omental mesothelial cells and subsequent invasion of ovarian cancer cells. Together, we propose that Wnt5A could be a critical mediator of EMT-associated pathways. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Metastasis)
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