The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target

Background. c-MET is a receptor tyrosine kinase receptor (RTK) for the hepatocyte growth factor (HGF). The binding of HGF to c-MET regulates several cellular functions: differentiation, proliferation, epithelial cell motility, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, it is known to be involved in carcinogenesis. Comprehension of HGF-c-MET signaling pathway might have important clinical consequences allowing to predict prognosis, response to treatment, and survival rates based on its expression and dysregulation. Discussion. c-MET represents a useful molecular target for novel engineered drugs. Several clinical trials are underway for various solid tumors and the development of new specific monoclonal antibodies depends on the recent knowledge about the definite c-MET role in each different malignance. Recent clinical trials based on c-MET molecular targets result in good safety profile and represent a promising therapeutic strategy for solid cancers, in monotherapy or in combination with other target drugs. Conclusion. The list of cell surface receptors crosslinking with the c-MET signaling is constantly growing, highlighting the importance of this pathway for personalized target therapy. Research on the combination of c-MET inhibitors with other drugs will hopefully lead to discovery of new effective treatment options.

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Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

Cancers ◽

10.3390/cancers11050714 ◽

2019 ◽

Vol 11 (5) ◽

pp. 714 ◽

Cited By ~ 17

Author(s):

Rama Soundararajan ◽

Jared Fradette ◽

Jessica Konen ◽

Stacy Moulder ◽

Xiang Zhang ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Checkpoint Inhibitors ◽

Cytotoxic T Cells ◽

Treatment Options ◽

Survival Rates ◽

Treatment Strategies ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Cancer Types

Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.

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The Role of microRNAs in Cholangiocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22147627 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7627

Author(s):

Tingting Shi ◽

Asahiro Morishita ◽

Hideki Kobara ◽

Tsutomu Masaki

Keyword(s):

Cell Cycle Progression ◽

Target Genes ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Mesenchymal Transition ◽

Diagnosis And Prognosis ◽

Related Risk

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.

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Analysis of DIP2C as a novel regulator for epithelial-mesenchymal transition of rheumatoid arthritis synovium and a potential therapeutic target

Impact ◽

10.21820/23987073.2021.8.28 ◽

2021 ◽

Vol 2021 (8) ◽

pp. 28-30

Author(s):

Masao Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Therapeutic Target ◽

Epithelial Mesenchymal Transition ◽

Poor Response ◽

Associate Professor ◽

Therapeutic Interventions ◽

Response To Treatment ◽

Potential Therapeutic Target ◽

Mesenchymal Transition ◽

Long Time

Rheumatoid arthritis (RA) is an autoimmune disease that can cause damage to the joints, cartilage and bone. There is no cure but early diagnosis can help mitigate damage. Sometimes RA is particularly difficult to treat, for example when the disease took a long time to be diagnosed. Associate Professor Masao Tanaka, Graduate School of Medicine, Kyoto University, Japan, leads a team of researchers working to improve understanding of the causes of poor response to treatment in RA with a long morbidity. The goal is to restore patients' therapeutic responsiveness, thereby improving outcomes. A previous focus for Tanaka was on a protein called FSTL1. He is now exploring DIP2 as a binding molecule for FSTL1. Other important mechanisms Tanaka is exploring are DNA methylation and the mechanisms of carnitine, which has been found to decrease a variety of activation signalling by inhibiting ceramide production in T cells. He and the team are exploring the involvement of these mechanisms in DIP2. In his most recent investigations, Tanaka is exploring DIP2C as a novel regulator for epithelial-mesenchymal transition of RA synovium and a potential therapeutic target. He is focusing on molecules that are expressed in the cells in joints, making the work directly applicable to RA. The team is carrying out a cohort study called KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) that involves around 2,000 outpatients with RA. Ultimately, Tanaka hopes to identify a reproducible combination of patient conditions and therapeutic interventions that achieve better treatment results for RA patients.

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Epithelial–Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Medicina ◽

10.3390/medicina55040083 ◽

2019 ◽

Vol 55 (4) ◽

pp. 83 ◽

Cited By ~ 23

Author(s):

Francesco Salton ◽

Maria Volpe ◽

Marco Confalonieri

Keyword(s):

Epithelial Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Treatment Options ◽

Alveolar Epithelium ◽

Alveolar Epithelial Cells ◽

Mesenchymal Transition ◽

Alveolar Epithelial ◽

Serious Disease

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial–mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

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Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma

Cancers ◽

10.3390/cancers12102761 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2761

Author(s):

Fabiana Mallone ◽

Marta Sacchetti ◽

Alessandro Lambiase ◽

Antonietta Moramarco

Keyword(s):

Clinical Trials ◽

Uveal Melanoma ◽

Treatment Options ◽

Survival Rates ◽

Metastatic Tumor ◽

Clinical Use ◽

Future Perspectives ◽

Diagnosis And Prognosis ◽

Novel Treatment ◽

Combinational Therapies

Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use.

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Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

Gastroenterology Research and Practice ◽

10.1155/2019/7698786 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15

Author(s):

Fiona Turkes ◽

Juliet Carmichael ◽

David Cunningham ◽

Naureen Starling

Keyword(s):

Clinical Trials ◽

Biliary Tract ◽

Treatment Options ◽

Prognostic Significance ◽

Response To Treatment ◽

Genomic Profiling ◽

Biliary Tract Cancers ◽

Comprehensive Genomic Profiling ◽

Genomic Aberrations ◽

Oncology Treatment

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

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Carcinosarcomas and Related Cancers: Tumors Caught in the Act of Epithelial-Mesenchymal Transition

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.9523 ◽

2018 ◽

Vol 36 (2) ◽

pp. 210-216 ◽

Cited By ~ 28

Author(s):

Angela Pang ◽

Mariana Carbini ◽

Andre L. Moreira ◽

Robert G. Maki

Keyword(s):

Clinical Trials ◽

Phase Transitions ◽

Epithelial Mesenchymal Transition ◽

Neuroendocrine Differentiation ◽

Anatomic Site ◽

Second Neoplasm ◽

Mesenchymal Transition ◽

Reactive Process ◽

Aggressive Tumors ◽

Organ Site

In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.

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Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

Molecular Medicine Reports ◽

10.3892/mmr.2014.3143 ◽

2014 ◽

Vol 11 (5) ◽

pp. 3539-3546 ◽

Cited By ~ 10

Author(s):

MINGDI ZHANG ◽

WEI GONG ◽

YONG ZHANG ◽

YONG YANG ◽

DI ZHOU ◽

...

Keyword(s):

Gallbladder Cancer ◽

Interleukin 6 ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Mesenchymal Transition

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Slug and Vimentin Downregulation at the Metastatic Site Is Associated With Skip-N2 Metastasis of Lung Adenocarcinoma

10.21203/rs.3.rs-797170/v2 ◽

2022 ◽

Author(s):

Yasemin SAYGIDEGER ◽

Alper AVCI ◽

Emine BAGIR ◽

Burcu SAYGIDEĞER DEMİR ◽

Aycan SEZAN Ms ◽

...

Keyword(s):

Lung Cancer ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Cancer Tissue ◽

Mrna Levels ◽

Bioinformatics Analyses ◽

Tissue Samples ◽

Mesenchymal Transition ◽

Slug Expression ◽

E Cadherin

Abstract Objective: Lung cancer displays heterogeneity both in the tumor itself and in its metastatic regions. One interesting behavior of the tumor is known as Skip N2 metastasis, which N2 lymph nodes contain tumor cells while N1 are clean. In this study, mRNA levels of epithelial mesenchymal transition (EMT) related genes in skip N2 and normal N2 involvements of non-small cell lung cancer tissues were investigated to evaluate the possible molecular background that may contribute to the pathogenesis of Skip N2 metastasis. Materials and Methods: Eighty-three surgically resected and paraffin embedded lymph node samples of lung cancer patients were analyzed in this study, which 40 of them were Skip N2. N2 tissues were sampled from 50% tumor containing areas and total RNA was extracted. mRNA levels for 18S, E-cadherin, Vimentin, ZEB1 and SLUG were analyzed via qPCR and E-cadherin and vimentin protein levels via immunohistochemistry (IHC). Bioinformatic analysis were adopted using online datasets to evaluate significantly co-expressed genes with SLUG in lung cancer tissue samples.Results: Skip-N2 patients who had adenocarcinoma subtype had better survival rates. Comparative analysis of PCR results indicated that Skip N2 tumor tissues had increased E-Cadherin/Vimentin ratio and ZEB1 mRNA expression, and significantly decreased levels of SLUG. E-cadherin IHC staining were higher in Skip N2 and Vimentin were in Non-Skip N2. TP63 had a strong correlation with SLUG expression in the bioinformatics analyses.Conclusion: The results indicate that, at molecular level, Skip N2 pathogenesis has different molecular background and regulation of SLUG expression may orchestrate the process.

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Histone methyltransferase SETD1A participates in lung cancer progression

10.21203/rs.3.rs-66780/v2 ◽

2020 ◽

Author(s):

Mei Du ◽

Piping Gong ◽

Yun Zhang ◽

Yanguo Liu ◽

Xiaozhen Liu ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Survival Rates ◽

Normal Lung ◽

Control Group ◽

Cancer Tissue ◽

Mesenchymal Transition ◽

Cancer Symptoms ◽

Mechanistic Analysis

Abstract Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~15%, which is attributes to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

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