Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer

Cells ◽

10.3390/cells9061481 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1481

Author(s):

Chenghui Zhou ◽

Ningbo Fan ◽

Fanyu Liu ◽

Nan Fang ◽

Patrick S. Plum ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanism ◽

Therapy Resistance ◽

Metabolic Reprogramming ◽

Current Evidence ◽

Mesenchymal Transition ◽

Therapeutic Implications

Esophageal cancer (EC) is an aggressive form of cancer, including squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) as two predominant histological subtypes. Accumulating evidence supports the existence of cancer stem cells (CSCs) able to initiate and maintain EAC or ESCC. In this review, we aim to collect the current evidence on CSCs in esophageal cancer, including the biomarkers/characterization strategies of CSCs, heterogeneity of CSCs, and the key signaling pathways (Wnt/β-catenin, Notch, Hedgehog, YAP, JAK/STAT3) in modulating CSCs during esophageal cancer progression. Exploring the molecular mechanisms of therapy resistance in EC highlights DNA damage response (DDR), metabolic reprogramming, epithelial mesenchymal transition (EMT), and the role of the crosstalk of CSCs and their niche in the tumor progression. According to these molecular findings, potential therapeutic implications of targeting esophageal CSCs may provide novel strategies for the clinical management of esophageal cancer.

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Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

Journal of Clinical Medicine ◽

10.3390/jcm8101542 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1542 ◽

Cited By ~ 36

Author(s):

Mohit Kumar Jolly ◽

Toni Celià-Terrassa

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Relevant Literature ◽

Phenotypic Heterogeneity ◽

State Transitions ◽

Strong Impact ◽

Mesenchymal Transition ◽

Cancer Aggressiveness

Genetic and phenotypic heterogeneity contribute to the generation of diverse tumor cell populations, thus enhancing cancer aggressiveness and therapy resistance. Compared to genetic heterogeneity, a consequence of mutational events, phenotypic heterogeneity arises from dynamic, reversible cell state transitions in response to varying intracellular/extracellular signals. Such phenotypic plasticity enables rapid adaptive responses to various stressful conditions and can have a strong impact on cancer progression. Herein, we have reviewed relevant literature on mechanisms associated with dynamic phenotypic changes and cellular plasticity, such as epithelial–mesenchymal transition (EMT) and cancer stemness, which have been reported to facilitate cancer metastasis. We also discuss how non-cell-autonomous mechanisms such as cell–cell communication can lead to an emergent population-level response in tumors. The molecular mechanisms underlying the complexity of tumor systems are crucial for comprehending cancer progression, and may provide new avenues for designing therapeutic strategies.

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MiR-205 Dysregulations in Breast Cancer: The Complexity and Opportunities

Non-Coding RNA ◽

10.3390/ncrna5040053 ◽

2019 ◽

Vol 5 (4) ◽

pp. 53 ◽

Cited By ~ 9

Author(s):

Xiao ◽

Humphries ◽

Yang ◽

Wang

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Target Gene ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Therapy Resistance ◽

Cancer Cell Proliferation ◽

Mesenchymal Transition

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that downregulate target gene expression by imperfect base-pairing with the 3′ untranslated regions (3′UTRs) of target gene mRNAs. MiRNAs play important roles in regulating cancer cell proliferation, stemness maintenance, tumorigenesis, cancer metastasis, and cancer therapeutic resistance. While studies have shown that dysregulation of miRNA-205-5p (miR-205) expression is controversial in different types of human cancers, it is generally observed that miR-205-5p expression level is downregulated in breast cancer and that miR-205-5p exhibits a tumor suppressive function in breast cancer. This review focuses on the role of miR-205-5p dysregulation in different subtypes of breast cancer, with discussions on the effects of miR-205-5p on breast cancer cell proliferation, epithelial–mesenchymal transition (EMT), metastasis, stemness and therapy-resistance, as well as genetic and epigenetic mechanisms that regulate miR-205-5p expression in breast cancer. In addition, the potential diagnostic and therapeutic value of miR-205-5p in breast cancer is also discussed. A comprehensive list of validated miR-205-5p direct targets is presented. It is concluded that miR-205-5p is an important tumor suppressive miRNA capable of inhibiting the growth and metastasis of human breast cancer, especially triple negative breast cancer. MiR-205-5p might be both a potential diagnostic biomarker and a therapeutic target for metastatic breast cancer.

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Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

Journal of Oncology ◽

10.1155/2011/591427 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 30

Author(s):

Tetsu Hayashida ◽

Hiromitsu Jinno ◽

Yuko Kitagawa ◽

Masaki Kitajima

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Breast Cancer Metastasis ◽

Cell Junctions ◽

Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

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Exploring Hyperoxia Effects in Cancer—From Perioperative Clinical Data to Potential Molecular Mechanisms

Biomedicines ◽

10.3390/biomedicines9091213 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1213

Author(s):

Anca Irina Ristescu ◽

Crina Elena Tiron ◽

Adrian Tiron ◽

Ioana Grigoras

Keyword(s):

Cancer Patients ◽

Cancer Progression ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Experimental Studies ◽

Perioperative Period ◽

Postoperative Recovery ◽

Mesenchymal Transition ◽

Oncological Treatment

Increased inspiratory oxygen concentration is constantly used during the perioperative period of cancer patients to prevent the potential development of hypoxemia and to provide an adequate oxygen transport to the organs, tissues and cells. Although the primary tumours are surgically removed, the effects of perioperative hyperoxia exposure on distal micro-metastases and on circulating cancer cells can potentially play a role in cancer progression or recurrence. In clinical trials, hyperoxia seems to increase the rate of postoperative complications and, by delaying postoperative recovery, it can alter the return to intended oncological treatment. The effects of supplemental oxygen on the long-term mortality of surgical cancer patients offer, at this point, conflicting results. In experimental studies, hyperoxia effects on cancer biology were explored following multiple pathways. In cancer cell cultures and animal models, hyperoxia increases the production of reactive oxygen species (ROS) and increases the oxidative stress. These can be followed by the induction of the expression of Brain-derived neurotrophic factor (BDNF) and other molecules involved in angiogenesis and by the promotion of various degrees of epithelial mesenchymal transition (EMT).

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SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.682773 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lei Lv ◽

Qiyi Yi ◽

Ying Yan ◽

Fengmei Chao ◽

Ming Li

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Migration And Invasion ◽

Akt Inhibitor ◽

Colon Adenoma ◽

Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

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Role of Metabolic Reprogramming in Epithelial–Mesenchymal Transition (EMT)

International Journal of Molecular Sciences ◽

10.3390/ijms20082042 ◽

2019 ◽

Vol 20 (8) ◽

pp. 2042 ◽

Cited By ~ 17

Author(s):

Hyunkoo Kang ◽

Hyunwoo Kim ◽

Sungmin Lee ◽

HyeSook Youn ◽

BuHyun Youn

Keyword(s):

Tumor Progression ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metabolic Reprogramming ◽

Metabolic Enzyme ◽

Diverse Range ◽

Mesenchymal Transition ◽

Altered Glucose

Activation of epithelial–mesenchymal transition (EMT) is thought to be an essential step for cancer metastasis. Tumor cells undergo EMT in response to a diverse range of extra- and intracellular stimulants. Recently, it was reported that metabolic shifts control EMT progression and induce tumor aggressiveness. In this review, we summarize the involvement of altered glucose, lipid, and amino acid metabolic enzyme expression and the underlying molecular mechanisms in EMT induction in tumor cells. Moreover, we propose that metabolic regulation through gene-specific or pharmacological inhibition may suppress EMT and this treatment strategy may be applied to prevent tumor progression and improve anti-tumor therapeutic efficacy. This review presents evidence for the importance of metabolic changes in tumor progression and emphasizes the need for further studies to better understand tumor metabolism.

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NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

Integrative Biology ◽

10.1093/intbio/zyz021 ◽

2019 ◽

Vol 11 (6) ◽

pp. 251-263 ◽

Cited By ~ 28

Author(s):

Federico Bocci ◽

Satyendra C Tripathi ◽

Samuel A Vilchez Mercedes ◽

Jason T George ◽

Julian P Casabar ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Collective Cell Migration ◽

Mesenchymal Transition ◽

Regulatory Circuit ◽

Clinical Records ◽

E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

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Mapping lung cancer epithelial-mesenchymal transition states and trajectories with single-cell resolution

Nature Communications ◽

10.1038/s41467-019-13441-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 19

Author(s):

Loukia G. Karacosta ◽

Benedict Anchang ◽

Nikolaos Ignatiadis ◽

Samuel C. Kimmey ◽

Jalen A. Benson ◽

...

Keyword(s):

Lung Cancer ◽

Single Cell ◽

Cancer Progression ◽

Time Course ◽

Epithelial Mesenchymal Transition ◽

Clinical Samples ◽

Neural Net ◽

Mesenchymal Transition ◽

Phenotypic Profile

AbstractElucidating the spectrum of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in clinical samples promises insights on cancer progression and drug resistance. Using mass cytometry time-course analysis, we resolve lung cancer EMT states through TGFβ-treatment and identify, through TGFβ-withdrawal, a distinct MET state. We demonstrate significant differences between EMT and MET trajectories using a computational tool (TRACER) for reconstructing trajectories between cell states. In addition, we construct a lung cancer reference map of EMT and MET states referred to as the EMT-MET PHENOtypic STAte MaP (PHENOSTAMP). Using a neural net algorithm, we project clinical samples onto the EMT-MET PHENOSTAMP to characterize their phenotypic profile with single-cell resolution in terms of our in vitro EMT-MET analysis. In summary, we provide a framework to phenotypically characterize clinical samples in the context of in vitro EMT-MET findings which could help assess clinical relevance of EMT in cancer in future studies.

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Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment

Acta Naturae ◽

10.32607/actanaturae.11010 ◽

2020 ◽

Vol 12 (3) ◽

pp. 4-23

Author(s):

A. V. Gaponova ◽

S. Rodin ◽

A. A. Mazina ◽

P. V. Volchkov

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

The Body ◽

Epithelial Tissue ◽

Mesenchymal Transition ◽

Tumor Dissemination

About 90% of all malignant tumors are of epithelial nature. The epithelial tissue is characterized by a close interconnection between cells through cellcell interactions, as well as a tight connection with the basement membrane, which is responsible for cell polarity. These interactions strictly determine the location of epithelial cells within the body and are seemingly in conflict with the metastatic potential that many cancers possess (the main criteria for highly malignant tumors). Tumor dissemination into vital organs is one of the primary causes of death in patients with cancer. Tumor dissemination is based on the so-called epithelialmesenchymal transition (EMT), a process when epithelial cells are transformed into mesenchymal cells possessing high mobility and migration potential. More and more studies elucidating the role of the EMT in metastasis and other aspects of tumor progression are published each year, thus forming a promising field of cancer research. In this review, we examine the most recent data on the intracellular and extracellular molecular mechanisms that activate EMT and the role they play in various aspects of tumor progression, such as metastasis, apoptotic resistance, and immune evasion, aspects that have usually been attributed exclusively to cancer stem cells (CSCs). In conclusion, we provide a detailed review of the approved and promising drugs for cancer therapy that target the components of the EMT signaling pathways.

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