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Cells
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Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis
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Cellular and Molecular Mechanisms of Cancer Invasion and 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 (15 September 2024) | Viewed by 15633

Special Issue Editors

Prof. Dr. Wen G. Jiang

E-Mail Website
Guest Editor
Ground Floor, Henry Wellcome Building for Biomedical Research, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK
Interests: cancer invasion; metastasis; angiogenesis; biomarkers; molecular profiling; novel target for metastasis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Qingping Dou

E-Mail Website
Guest Editor
Departments of Oncology, Pharmacology, and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
Interests: molecular targeting; cancer prevention and therapy; drug reposition; ubiquitin–proteasome system; natural products; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

We are calling for manuscripts to this Special Issue on ‘Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis’ for the journal Cells. Invasion and metastasis are key hallmarks in cancer and contribute to the detrimental outcome of the patients with cancer. This Special Issue aims to collect and publish recent discoveries in this area of cancer research. Manuscripts that describe studies on the cellular and molecular mechanisms of invasion and metastasis are welcome. This may include, but is not limited to, metastasis- and invasion-related genes, signalling events underlying metastatic processes, novel markers and new targets, molecular and cellular interventions for metastasis, cell adhesion, cellular communication and junctional regulations of cancer cells, metabolic abnormalities, stromal and the microenvironment. We welcome original contributions and review articles. 

We look forward to receiving your valuable contributions. 

Yours sincerely,
Prof. Dr. Wen G. Jiang
Prof. Dr. Qingping Dou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer invasion
  • cancer metastasis
  • metastasis-related genes
  • metastasis biomarkers
  • novel targets
  • microenvironment
  • stromal factors

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Published Papers (7 papers)

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Research

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17 pages, 2778 KiB  
Article
The EphA2 Receptor Regulates Invasiveness and Drug Sensitivity in Canine and Human Osteosarcoma Cells
by Evelyn D. Harris, Jessica C. Sharpe, Timothy Strozen, Shabnam Abdi, Maya Kliewer, Malkon G. Sanchez, Natacha S. Hogan, Valerie MacDonald-Dickinson, Franco J. Vizeacoumar and Behzad M. Toosi
Cells 2024, 13(14), 1201; https://doi.org/10.3390/cells13141201 - 16 Jul 2024
Viewed by 1368
Abstract
Osteosarcoma is an aggressive bone cancer affecting both humans and dogs, often leading to pulmonary metastasis. Despite surgery and chemotherapy being the primary treatment modalities, survival rates remain low in both species, underscoring the urgent need for more efficacious therapeutic options. Accumulating evidence [...] Read more.
Osteosarcoma is an aggressive bone cancer affecting both humans and dogs, often leading to pulmonary metastasis. Despite surgery and chemotherapy being the primary treatment modalities, survival rates remain low in both species, underscoring the urgent need for more efficacious therapeutic options. Accumulating evidence indicates numerous biological and clinical similarities between human and canine osteosarcoma, making it an ideal choice for comparative oncological research that should benefit both species. The EphA2 receptor has been implicated in controlling invasive responses across different human malignancies, and its expression is associated with poor prognosis. In this study, we utilized a comparative approach to match EphA2 functions in human and canine osteosarcoma models. Our objectives were to assess EphA2 levels and its pro-malignant action in osteosarcoma cells of both species. We found that EphA2 is overexpressed in most of both canine and human osteosarcoma cell lines, while its silencing significantly reduced cell viability, migration, and invasion. Moreover, EphA2 silencing enhanced the sensitivity of osteosarcoma cells to cisplatin, a drug commonly used for treating this cancer. Furthermore, inhibition of EphA2 expression led to a significant reduction in tumor development capability of canine osteosarcoma cells. Our data suggest that these EphA2 effects are likely mediated through various signaling mechanisms, including the SRC, AKT, and ERK–MAPK pathways. Collectively, our findings indicate that EphA2 promotes malignant behaviors in both human and canine osteosarcoma and that targeting EphA2, either alone or in combination with chemotherapy, could offer potential benefits to osteosarcoma patients. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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24 pages, 5770 KiB  
Article
Elucidating the Role of MicroRNA-18a in Propelling a Hybrid Epithelial–Mesenchymal Phenotype and Driving Malignant Progression in ER-Negative Breast Cancer
by Madhumathy G. Nair, Apoorva D. Mavatkar, Chandrakala M. Naidu, Snijesh V. P., Anupama C. E., Savitha Rajarajan, Sarthak Sahoo, Gayathri Mohan, Vishnu Sunil Jaikumar, Rakesh S. Ramesh, Srinath B. S., Mohit Kumar Jolly, Tessy Thomas Maliekal and Jyothi S. Prabhu
Cells 2024, 13(10), 821; https://doi.org/10.3390/cells13100821 - 10 May 2024
Viewed by 1684
Abstract
Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial–mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state [...] Read more.
Epigenetic alterations that lead to differential expression of microRNAs (miRNAs/miR) are known to regulate tumour cell states, epithelial–mesenchymal transition (EMT) and the progression to metastasis in breast cancer. This study explores the key contribution of miRNA-18a in mediating a hybrid E/M cell state that is pivotal to the malignant transformation and tumour progression in the aggressive ER-negative subtype of breast cancer. The expression status and associated effects of miR-18a were evaluated in patient-derived breast tumour samples in combination with gene expression data from public datasets, and further validated in in vitro and in vivo breast cancer model systems. The clinical relevance of the study findings was corroborated against human breast tumour specimens (n = 446 patients). The down-regulated expression of miR-18a observed in ER-negative tumours was found to drive the enrichment of hybrid epithelial/mesenchymal (E/M) cells with luminal attributes, enhanced traits of migration, stemness, drug-resistance and immunosuppression. Further analysis of the miR-18a targets highlighted possible hypoxia-inducible factor 1-alpha (HIF-1α)-mediated signalling in these tumours. This is a foremost report that validates the dual role of miR-18a in breast cancer that is subtype-specific based on hormone receptor expression. The study also features a novel association of low miR-18a levels and subsequent enrichment of hybrid E/M cells, increased migration and stemness in a subgroup of ER-negative tumours that may be attributed to HIF-1α mediated signalling. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing miRNA signatures. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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21 pages, 6335 KiB  
Article
Mutant p53 Gain-of-Function Induces Migration and Invasion through Overexpression of miR-182-5p in Cancer Cells
by Tzitzijanik Madrigal, Daniel Ortega-Bernal, Luis A. Herrera, Claudia Haydée González-De la Rosa, Guadalupe Domínguez-Gómez, Elena Aréchaga-Ocampo and José Díaz-Chávez
Cells 2023, 12(20), 2506; https://doi.org/10.3390/cells12202506 - 23 Oct 2023
Cited by 1 | Viewed by 1799
Abstract
The master-key TP53 gene is a tumor suppressor that is mutated in more than 50% of human cancers. Some p53 mutants lose their tumor suppressor activity and acquire new oncogenic functions, known as a gain of function (GOF). Recent studies have shown that [...] Read more.
The master-key TP53 gene is a tumor suppressor that is mutated in more than 50% of human cancers. Some p53 mutants lose their tumor suppressor activity and acquire new oncogenic functions, known as a gain of function (GOF). Recent studies have shown that p53 mutants can exert oncogenic effects through specific miRNAs. We identified the differentially expressed miRNA profiles of the three most frequent p53 mutants (p53R273C, p53R248Q, and p53R175H) after their transfection into the Saos-2 cell line (null p53) as compared with p53WT transfected cells. The associations between these miRNAs and the signaling pathways in which they might participate were identified with miRPath Software V3.0. QRT-PCR was employed to validate the miRNA profiles. We observed that p53 mutants have an overall negative effect on miRNA expression. In the global expression profile of the human miRNome regulated by the p53R273C mutant, 72 miRNAs were underexpressed and 35 overexpressed; in the p53R175H miRNAs profile, our results showed the downregulation of 93 and upregulation of 10 miRNAs; and in the miRNAs expression profile regulated by the p53R248Q mutant, we found 167 decreased and 6 increased miRNAs compared with p53WT. However, we found overexpression of some miRNAs, like miR-182-5p, in association with processes such as cell migration and invasion. In addition, we explored whether the induction of cell migration and invasion by the p53R48Q mutant was dependent on miR-182-5p because we found overexpression of miR-182-5p, which is associated with processes such as cell migration and invasion. Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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19 pages, 7781 KiB  
Article
Deciphering the Role of p60AmotL2 in Epithelial Extrusion and Cell Detachment
by Weiyingqi Cui, Aravindh Subramani, Pedro Fonseca, Yumeng Zhang, Le Tong, Yuanyuan Zhang, Lars Egevad, Andreas Lundqvist and Lars Holmgren
Cells 2023, 12(17), 2158; https://doi.org/10.3390/cells12172158 - 28 Aug 2023
Cited by 1 | Viewed by 1497
Abstract
Preserving an accurate cell count is crucial for maintaining homeostasis. Apical extrusion, a process in which redundant cells are eliminated by neighboring cells, plays a key role in this regard. Recent studies have revealed that apical extrusion can also be triggered in cells [...] Read more.
Preserving an accurate cell count is crucial for maintaining homeostasis. Apical extrusion, a process in which redundant cells are eliminated by neighboring cells, plays a key role in this regard. Recent studies have revealed that apical extrusion can also be triggered in cells transformed by oncogenes, suggesting it may be a mechanism through which tumor cells escape their microenvironment. In previous work, we demonstrated that p60AmotL2 modulates the E-cadherin function by inhibiting its connection to radial actin filaments. This isoform of AmotL2 is expressed in invasive breast and colon tumors and promotes invasion in vitro and in vivo. Transcriptionally regulated by c-Fos, p60AmotL2 is induced by local stress signals such as severe hypoxia. In this study, we investigated the normal role of p60AmotL2 in epithelial tissues. We found that this isoform is predominantly expressed in the gut, where cells experience rapid turnover. Through time-lapse imaging, we present evidence that cells expressing p60AmotL2 are extruded by their normal neighboring cells. Based on these findings, we hypothesize that tumor cells exploit this pathway to detach from normal epithelia and invade surrounding tissues. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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24 pages, 6717 KiB  
Article
Modulation of E-Cadherin Function through the AmotL2 Isoforms Promotes Ameboid Cell Invasion
by Aravindh Subramani, Weiyingqi Cui, Yuanyuan Zhang, Tomas Friman, Zhihai Zhao, Wenmao Huang, Pedro Fonseca, Weng-Onn Lui, Vani Narayanan, Justyna Bobrowska, Małgorzata Lekka, Jie Yan, Daniel E. Conway and Lars Holmgren
Cells 2023, 12(13), 1682; https://doi.org/10.3390/cells12131682 - 21 Jun 2023
Cited by 2 | Viewed by 2327
Abstract
The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining [...] Read more.
The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining cell–cell contacts. Furthermore, the inactivation of E-cadherin triggers invasion in vitro. However, the role of E-cadherin is complex, as metastasizing cells maintain E-cadherin expression, which appears to have a positive role in the survival of tumor cells. In this report, we present a novel mechanism delineating how E-cadherin function is modulated to promote invasion. We have previously shown that E-cadherin is associated with p100AmotL2, which is required for radial actin formation and the transmission of mechanical force. Here, we present evidence that p60AmotL2, which is expressed in invading tumor cells, binds to the p100AmotL2 isoform and uncouples the mechanical constraint of radial actin filaments. We show for the first time that the coupling of E-cadherin to the actin cytoskeleton via p100AmotL2 is directly connected to the nuclear membrane. The expression of p60AmotL2 inactivates this connection and alters the properties of the nuclear lamina, potentiating the invasion of cells into micropores of the extracellular matrix. In summary, we propose that the balance of the two AmotL2 isoforms is important in the modulation of E-cadherin function and that an imbalance of this axis promotes ameboid cell invasion. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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22 pages, 3803 KiB  
Article
Proteoglycan SPOCK1 as a Poor Prognostic Marker Promotes Malignant Progression of Clear Cell Renal Cell Carcinoma via Triggering the Snail/Slug-MMP-2 Axis-Mediated Epithelial-to-Mesenchymal Transition
by Yung-Wei Lin, Yu-Ching Wen, Chi-Hao Hsiao, Feng-Ru Lai, Shun-Fa Yang, Yi-Chieh Yang, Kuo-Hao Ho, Feng-Koo Hsieh, Michael Hsiao, Wei-Jiunn Lee and Ming-Hsien Chien
Cells 2023, 12(3), 352; https://doi.org/10.3390/cells12030352 - 17 Jan 2023
Cited by 9 | Viewed by 2671
Abstract
Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein [...] Read more.
Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein levels were observed in ccRCC tissues compared to normal tissues and correlated with advanced clinical stages, larger tumor sizes, and lymph node and distal metastases. Knockdown and overexpression of SPOCK1 in ccRCC cells led to decreased and increased cell clonogenic and migratory/invasive abilities in vitro as well as lower and higher tumor growth and invasion in vivo, respectively. Mechanistically, the gene set enrichment analysis (GSEA) database was used to identify the gene set of epithelial-to-mesenchymal transition (EMT) pathways enriched in ccRCC samples with high SPOCK1 expression. Further mechanistic investigations revealed that SPOCK1 triggered the Snail/Slug–matrix metalloproteinase (MMP)-2 axis to promote EMT and cell motility. Clinical ccRCC samples revealed SPOCK1 to be an independent prognostic factor for overall survival (OS), and positive correlations of SPOCK1 with MMP-2 and mesenchymal-related gene expression levels were found. We observed that patients with SPOCK1high/MMP2high tumors had the shortest OS times compared to others. In conclusion, our findings reveal that SPOCK1 can serve as a useful biomarker for predicting ccRCC progression and prognosis, and as a promising target for treating ccRCC. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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Review

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16 pages, 951 KiB  
Review
MT1-MMP as a Key Regulator of Metastasis
by Noritaka Tanaka and Takeharu Sakamoto
Cells 2023, 12(17), 2187; https://doi.org/10.3390/cells12172187 - 31 Aug 2023
Cited by 9 | Viewed by 2790
Abstract
Membrane type1-matrix metalloproteinase (MT1-MMP) is a member of metalloproteinases that is tethered to the transmembrane. Its major function in cancer progression is to directly degrade the extracellular matrix components, which are mainly type I–III collagen or indirectly type IV collagen through the activation [...] Read more.
Membrane type1-matrix metalloproteinase (MT1-MMP) is a member of metalloproteinases that is tethered to the transmembrane. Its major function in cancer progression is to directly degrade the extracellular matrix components, which are mainly type I–III collagen or indirectly type IV collagen through the activation of MMP-2 with a cooperative function of the tissue inhibitor of metalloproteinase-2 (TIMP-2). MT1-MMP is expressed as an inactive form (zymogen) within the endoplasmic reticulum (ER) and receives truncation processing via furin for its activation. Upon the appropriate trafficking of MT1-MMP from the ER, the Golgi apparatus to the cell surface membrane, MT1-MMP exhibits proteolytic activities to the surrounding molecules such as extracellular matrix components and cell surface molecules. MT1-MMP also retains a non-proteolytic ability to activate hypoxia-inducible factor 1 alpha (HIF-1A) via factors inhibiting the HIF-1 (FIH-1)-Mint3-HIF-1 axis, resulting in the upregulation of glucose metabolism and oxygen-independent ATP production. Through various functions of MT1-MMP, cancer cells gain motility on migration/invasion, thus causing metastasis. Despite the long-time efforts spent on the development of MT1-MMP interventions, none have been accomplished yet due to the side effects caused by off-target effects. Recently, MT1-MMP-specific small molecule inhibitors or an antibody have been reported and these inhibitors could potentially be novel agents for cancer treatment. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Cancer Invasion and Metastasis)
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