Immunosuppressive microenvironment in oral cancer: implications for cancer immunotherapy

Head and neck squamous cell carcinoma (HNSCC) is a relatively widespread cancer with high mortality rates. Many patients with locally advanced disease are treated with combinations of surgery, radiation, and chemotherapy, while others are considered incurable and develop recurrent/metastatic(R/M) disease. Despite these treatment modalities, the 5-year survival rate of HNSCC has remained at 50% due to limited treatment options in patients with recurrent disease. Immunotherapy has been shown to induce durable responses in R/M patients, but only a minority of patients currently respond. A major hurdle in tumor immunotherapy is identifying the non-responders and markers to predict resistance in patients who at first responded to the therapy. In HNSCC patients, the tumor microenvironment (TME) assumes a vital role to either diminish or augment immune responses. There is an urgent need for extensive studies to be undertaken to better understand how tumor cells escape immune surveillance and resist immune attack. In this review, the impact of TME on the efficiency of immunotherapy, addressing the factors that mediate therapy resistance are highlighted. The composition of the TME encompassing the immunosuppressive cells including myeloid-derived suppressor cell (MDSC), regulatory T cells (Treg), mesenchymal stem cell (MSC), cancer-associated fibroblast (CAF), and tumor-associated macrophages (TAMs) and intrinsic factors like hypoxia, reactive oxygen species (ROS),extracellular matrix (ECM), angiogenesis, and epithelial-mesenchymal transition (EMT), how this debilitates immunosurveillance, and also discuss existing and potential strategies aimed at targeting these cellular and molecular TME components are reviewed. Understanding the interactions between the TME and immunotherapy is not only important in dissevering the mechanisms of action of immunosuppression but also offers scope for developing newer strategies to improve the competence of current immunotherapies.

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CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

Cells ◽

10.3390/cells9071651 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1651

Author(s):

María Auxiliadora Olivares-Urbano ◽

Carmen Griñán-Lisón ◽

Juan Antonio Marchal ◽

María Isabel Núñez

Keyword(s):

Tumor Microenvironment ◽

Cancer Patients ◽

Epithelial Mesenchymal Transition ◽

Treatment Modalities ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Combination Strategies ◽

Technological Advances ◽

Oncologic Treatment ◽

The Impact

Radiotherapy (RT) is a modality of oncologic treatment that can be used to treat approximately 50% of all cancer patients either alone or in combination with other treatment modalities such as surgery, chemotherapy, immunotherapy, and therapeutic targeting. Despite the technological advances in RT, which allow a more precise delivery of radiation while progressively minimizing the impact on normal tissues, issues like radioresistance and tumor recurrence remain important challenges. Tumor heterogeneity is responsible for the variation in the radiation response of the different tumor subpopulations. A main factor related to radioresistance is the presence of cancer stem cells (CSC) inside tumors, which are responsible for metastases, relapses, RT failure, and a poor prognosis in cancer patients. The plasticity of CSCs, a process highly dependent on the epithelial–mesenchymal transition (EMT) and associated to cell dedifferentiation, complicates the identification and eradication of CSCs and it might be involved in disease relapse and progression after irradiation. The tumor microenvironment and the interactions of CSCs with their niches also play an important role in the response to RT. This review provides a deep insight into the characteristics and radioresistance mechanisms of CSCs and into the role of CSCs and tumor microenvironment in both the primary tumor and metastasis in response to radiation, and the radiobiological principles related to the CSC response to RT. Finally, we summarize the major advances and clinical trials on the development of CSC-based therapies combined with RT to overcome radioresistance. A better understanding of the potential therapeutic targets for CSC radiosensitization will provide safer and more efficient combination strategies, which in turn will improve the live expectancy and curability of cancer patients.

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Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21114002 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4002 ◽

Cited By ~ 9

Author(s):

Milad Ashrafizadeh ◽

Ali Zarrabi ◽

Kiavash Hushmandi ◽

Mahshad Kalantari ◽

Reza Mohammadinejad ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Nuclear Factor Κb ◽

Molecular Pathways ◽

Cancer Resistance ◽

Mesenchymal Transition ◽

The Impact

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

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Targeting epithelial–mesenchymal plasticity in cancer: clinical and preclinical advances in therapy and monitoring

Biochemical Journal ◽

10.1042/bcj20160782 ◽

2017 ◽

Vol 474 (19) ◽

pp. 3269-3306 ◽

Cited By ~ 34

Author(s):

Sugandha Bhatia ◽

James Monkman ◽

Alan Kie Leong Toh ◽

Shivashankar H. Nagaraj ◽

Erik W. Thompson

Keyword(s):

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Carcinoma Cells ◽

Related Phenomenon ◽

Mesenchymal Transition ◽

Control Loops ◽

Monitoring Strategies ◽

The Impact ◽

Ability To Drive

The concept of epithelial–mesenchymal plasticity (EMP), which describes the dynamic flux within the spectrum of phenotypic states that invasive carcinoma cells may reside, is being increasingly recognised for its role in cancer progression and therapy resistance. The myriad of events that are able to induce EMP, as well as the more recently characterised control loops, results in dynamic transitions of cancerous epithelial cells to more mesenchymal-like phenotypes through an epithelial–mesenchymal transition (EMT), as well as the reverse transition from mesenchymal phenotypes to an epithelial one. The significance of EMP, in its ability to drive local invasion, generate cancer stem cells and facilitate metastasis by the dissemination of circulating tumour cells (CTCs), highlights its importance as a targetable programme to combat cancer morbidity and mortality. The focus of this review is to consolidate the existing knowledge on the strategies currently in development to combat cancer progression via inhibition of specific facets of EMP. The prevalence of relapse due to therapy resistance and metastatic propensity that EMP endows should be considered when designing therapy regimes, and such therapies should synergise with existing chemotherapeutics to benefit efficacy. To further improve upon EMP-targeted therapies, it is imperative to devise monitoring strategies to assess the impact of such treatments on EMP-related phenomenon such as CTC burden, chemosensitivity/-resistance and micrometastasis in patients.

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Transcriptional mediators of treatment resistance in lethal prostate cancer

10.1101/2020.03.19.998450 ◽

2020 ◽

Cited By ~ 1

Author(s):

Meng Xiao He ◽

Michael S. Cuoco ◽

Jett Crowdis ◽

Alice Bosma-Moody ◽

Zhenwei Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Epithelial Mesenchymal Transition ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Significant Proportion ◽

Treatment Resistance ◽

Treatment Modalities ◽

Castration Resistant Prostate Cancer ◽

Mesenchymal Transition ◽

Clinical Resistance

ABSTRACTMetastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

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

Tumor Biology ◽

10.3233/tub-200051 ◽

2021 ◽

Vol 43 (1) ◽

pp. 77-96

Author(s):

T. Jeethy Ram ◽

Asha Lekshmi ◽

Thara Somanathan ◽

K. Sujathan

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Cellular Level ◽

Clinical Samples ◽

Innovative Strategy ◽

Mesenchymal Transition ◽

Galectin 3

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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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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Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Science Advances ◽

10.1126/sciadv.abd7974 ◽

2021 ◽

Vol 7 (9) ◽

pp. eabd7974

Author(s):

Michela Serresi ◽

Sonia Kertalli ◽

Lifei Li ◽

Matthias Jürgen Schmitt ◽

Yuliia Dramaretska ◽

...

Keyword(s):

Cancer Cells ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Developmental Process ◽

Epithelial Mesenchymal Transition ◽

Chromatin Remodelers ◽

Mesenchymal Transition ◽

Signature Genes ◽

Chromatin Regulators ◽

The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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Cell Plasticity and Prostate Cancer: The Role of Epithelial–Mesenchymal Transition in Tumor Progression, Invasion, Metastasis and Cancer Therapy Resistance

Cancers ◽

10.3390/cancers13112795 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2795

Author(s):

Sofia Papanikolaou ◽

Aikaterini Vourda ◽

Spyros Syggelos ◽

Kostis Gyftopoulos

Keyword(s):

Prostate Cancer ◽

Cancer Therapy ◽

Tumor Progression ◽

Epithelial Mesenchymal Transition ◽

Metastatic Tumor ◽

Therapy Resistance ◽

Cellular Process ◽

Cell Plasticity ◽

Mesenchymal Transition

Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial–mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell–cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.

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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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