scholarly journals Regulators at Every Step—How microRNAs Drive Tumor Cell Invasiveness and Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3709
Author(s):  
Tomasz M. Grzywa ◽  
Klaudia Klicka ◽  
Paweł K. Włodarski
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Level ◽  
Invasion And Metastasis ◽  
Metastatic Niche ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Cell Invasiveness

Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial–mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.

scholarly journals The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

2020 ◽  
Vol 21 (3) ◽  
pp. 765 ◽  
Author(s):  
Antonio Villalobo ◽  
Martin W. Berchtold
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Small Gtpases ◽  
Vast Number ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Iq Motif ◽  
Metastasis Development ◽  
Cell Invasiveness

Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

scholarly journals Tumor Cell-Secreted ISG15 Promotes Tumor Cell Migration and Immune Suppression by Inducing the Macrophage M2-Like Phenotype

2020 ◽  
Vol 11 ◽  
Author(s):  
Ren-Hui Chen ◽  
Zhi-Wen Xiao ◽  
Xiao-Qing Yan ◽  
Ping Han ◽  
Fa-Ya Liang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Stage ◽  
Advanced Tumor Stage ◽  
Tumor Cell Migration ◽  
Advanced Tumor ◽  
Interferon Stimulated Gene 15 ◽  
Small Molecular Inhibitors

Interferon-stimulated gene 15 (ISG15) is known to be involved in tumor progression. We previously reported that ISG15 expressed on nasopharyngeal carcinoma (NPC) cells and related to poor prognosis of patients with NPC. We further observed that ISG15 can be secreted by NPC cell and expressed on the macrophages in situ. However, the role of ISG15 in tumor-associated macrophages (TAMs) remains poorly understood. In the present study, we found that ISG15 treatment induces macrophages with M2-like phenotype, and the enhancement of NPC cell migration and tumorigenicity. Mechanically, ISG15-induced M2-like phenotype is dependent on the interaction with its receptor, LFA-1, and engagement of SRC family kinase (SFK) signal, and the subsequent secretion of CCL18. Blocking LFA-1, or SRC signal with small molecular inhibitors, or neutralizing with anti-CCL18 antibody can impede the activation of LFA-1-SFK-CCL18 axis in ISG15-treated macrophages. Clinically, ISG15+ CD163+ TAMs related to impaired survival of patients and advanced tumor stage of NPC. Furthermore, we found ISG15+ CD163+ macrophages inhibited antitumor CD8+ cells responses in NPC. Together, our findings suggested tumor cell-secreted ISG15, which acted as a tumor microenvironmental factor, induces M2-like phenotype, promoting tumor progression and suppression of cytotoxic T lymphocyte response.

scholarly journals LAIR-1 overexpression inhibits osteosarcoma epithelial-mesenchymal transition via GLUT1-related energy metabolism

2020 ◽  
Author(s):  
Jinxue Zhang ◽  
Yuan Zhang ◽  
Yongming Liu ◽  
Xin Yi ◽  
Shiyang Cheng ◽  
...  
Keyword(s):  
Cell Migration ◽  
Energy Metabolism ◽  
Quantitative Pcr ◽  
Western Blotting ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Immunoglobulin Superfamily ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration

Abstract Background: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor belonging to the immunoglobulin superfamily. Although prior studies have evaluated the biological role of LAIR in solid tumors, the precise mechanisms underlying LAIR-1 functions as a regulator of tumor biological functions remains unclear. Methods: LAIR-1 expression was evaluated using an osteosarcoma (OS) tissue microarray by immunohistochemical analysis. Wound healing and Transwell assays were performed to evaluate tumor cell migration. Quantitative PCR and western blotting were conducted to detect the expression of epithelial-mesenchymal transition (EMT)-related molecules. RNA-sequencing (RNA-seq) was conducted to evaluate the mRNA expression profiles after overexpressing LAIR-1 in OS cells. Glucose uptake and glucose transporter (Glut) 1 expression in OS cells in vitro were evaluated by flow cytometry and western blotting. Results: LAIR-1 expression significantly differed between the T1 and T2 stages of OS tumors, and LAIR-1 overexpression inhibited OS cell migration. LAIR-1 expression was inversely correlated with the expression of EMT-associated transcription factors via the Forkhead box O1/Twist1 signal transduction pathway. Furthermore, RNA-seq and quantitative PCR demonstrated that EMT energy metabolism-related molecules were significantly reduced after LAIR-1 overexpression. Conclusions: Notably, overexpression of LAIR-1 in OS cells decreased Glut1 expression. These findings provide insight into the molecular mechanism underlying OS progression.

scholarly journals TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis

2021 ◽  
Vol 5 (2) ◽  
pp. e202101261
Author(s):  
Simon Grelet ◽  
Cécile Fréreux ◽  
Clémence Obellianne ◽  
Ken Noguchi ◽  
Breege V Howley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Primary Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Elevated Expression

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial–mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.

scholarly journals Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

2015 ◽  
Vol 23 (2) ◽  
pp. R85-R111 ◽  
Author(s):  
Annu Makker ◽  
Madhu Mati Goel
Keyword(s):  
High Risk ◽  
Tumor Progression ◽  
Endometrial Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Early Stage ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Endometrioid Endometrial Carcinoma

Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70–80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial–mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis – the most fatal consequence of endometrial carcinogenesis.

scholarly journals Podoplanin Associates with CD44 to Promote Directional Cell Migration

2010 ◽  
Vol 21 (24) ◽  
pp. 4387-4399 ◽  
Author(s):  
Ester Martín-Villar ◽  
Beatriz Fernández-Muñoz ◽  
Maddy Parsons ◽  
Maria M. Yurrita ◽  
Diego Megías ◽  
...  
Keyword(s):  
Cell Migration ◽  
Epithelial Mesenchymal Transition ◽  
Resonance Energy Transfer ◽  
Mouse Skin ◽  
Resonance Energy ◽  
Fluorescence Lifetime Imaging ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Podoplanin Expression

Podoplanin is a transmembrane glycoprotein up-regulated in different human tumors, especially those derived from squamous stratified epithelia (SCCs). Its expression in tumor cells is linked to increased cell migration and invasiveness; however, the mechanisms underlying this process remain poorly understood. Here we report that CD44, the major hyaluronan (HA) receptor, is a novel partner for podoplanin. Expression of the CD44 standard isoform (CD44s) is coordinately up-regulated together with that of podoplanin during progression to highly aggressive SCCs in a mouse skin model of carcinogenesis, and during epithelial-mesenchymal transition (EMT). In carcinoma cells, CD44 and podoplanin colocalize at cell surface protrusions. Moreover, CD44 recruitment promoted by HA-coated beads or cross-linking with a specific CD44 antibody induced corecruitment of podoplanin. Podoplanin–CD44s interaction was demonstrated both by coimmunoprecipitation experiments and, in vivo, by fluorescence resonance energy transfer/fluorescence lifetime imaging microscopy (FRET/FLIM), the later confirming its association on the plasma membrane of cells with a migratory phenotype. Importantly, we also show that podoplanin promotes directional persistence of motility in epithelial cells, a feature that requires CD44, and that both molecules cooperate to promote directional migration in SCC cells. Our results support a role for CD44-podoplanin interaction in driving tumor cell migration during malignancy.

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