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12 pages, 2137 KiB

Open AccessArticle

Senescent Fibroblasts Generate a CAF Phenotype through the Stat3 Pathway

by Hao Li, Lei Qiu, Qing Liu, Zelong Ma, Xiaoli Xie, Ying Luo and Xiaoming Wu

Genes 2022, 13(9), 1579; https://doi.org/10.3390/genes13091579 - 2 Sep 2022

Cited by 15 | Viewed by 3484

Abstract

Aging has been recently reported to promote lung cancer initiation and progression. Senescent fibroblasts gain a cancer-associated fibroblast (CAF) phenotype, and exert a powerful influence on cancer behavior, such as tumor cell growth and metastasis. However, mechanisms linking fibroblast senescence with CAF activation [...] Read more.

Aging has been recently reported to promote lung cancer initiation and progression. Senescent fibroblasts gain a cancer-associated fibroblast (CAF) phenotype, and exert a powerful influence on cancer behavior, such as tumor cell growth and metastasis. However, mechanisms linking fibroblast senescence with CAF activation remain poorly understood. Our study shows that senescent fibroblasts displayed CAF properties, including the highly expressed CAF markers, α-SMA and Vimentin, and CAF-specific factors, CXCL12, FGF10, IL6 and COL1A1, which significantly increased collagen contractile activity and promoted the migration and invasion of lung cancer cells, H1299 and A549. We were further able to show that CAF characteristics in senescent fibroblasts could be regulated by the Stat3 pathway. Intracellular ROS accumulation activates the Stat3 pathway during senescence. Thus, our findings indicate that senescent fibroblasts mediate a CAF function with the Stat3 pathway. We further propose a novel Stat3 dependent targetable mechanism, which is instrumental in mediating the migration and invasion of lung cancer cells. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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20 pages, 6018 KiB

Open AccessArticle

Ginsenoside Rg5 Sensitizes Paclitaxel—Resistant Human Cervical-Adeno-Carcinoma Cells to Paclitaxel—And Enhances the Anticancer Effect of Paclitaxel

by Janani Ramesh, Rejani Chalikkaran Thilakan, Raja Mohan Gopalakrishnan, Singaravel Vijayapoopathi, Arianna Dorschel and Bhuvarahamurthy Venugopal

Genes 2022, 13(7), 1142; https://doi.org/10.3390/genes13071142 - 24 Jun 2022

Cited by 11 | Viewed by 3303

Abstract

In cervical cancer chemotherapy, paclitaxel (PTX) chemoresistance has become a major difficulty, and it also affects the survival rate of numerous tumor patients. Thus, for the reversal of chemoresistance, it is imperative to develop combinatory drugs with petite or almost no side effects [...] Read more.

In cervical cancer chemotherapy, paclitaxel (PTX) chemoresistance has become a major difficulty, and it also affects the survival rate of numerous tumor patients. Thus, for the reversal of chemoresistance, it is imperative to develop combinatory drugs with petite or almost no side effects to sensitize cells to paclitaxel. Ginsenoside Rg5 (GRg5) may act as a chemosensitizer by reversing multidrug resistance. The present study aimed to determine the potential of GRg5 as a chemosensitizer in PTX-resistant human cervical adeno-carcinoma cell lines (HeLa cells). MTT assay was carried out to assess whether GRg5 can potentiate the cytotoxic effect of PTX in PTX- resistant HeLa cells; using flow cytometry-based annexin V-FITC assay, cellular apoptosis was analyzed; the rate of expression of the cell cycle, apoptosis and major cell-survival-signaling-related genes and its proteins were examined using RT-PCR and Western blotting technique. We found increased mRNA expression of Bak, Bax, Bid, and PUMA genes, whereas the mRNA expression of Bcl2, Bcl-XL, c-IAP-1, and MCL-1 were low; GRg5 combination triggered the efficacy of paclitaxel, which led to increased expression of Bax with an enhanced caspase-9/-3 activation, and apoptosis. Moreover, the study supports GRg5 as an inhibitor of two key signaling proteins, Akt and NF-κB, by which GRg5 augments the susceptibility of cervical cancer cells to PTX chemotherapy. GRg5 drastically potentiated the antiproliferative and pro-apoptotic activity of paclitaxel in PTX-resistant human cervical cancer cells in a synergistic mode. Moreover, in the clinical context, combining paclitaxel with GRg5 may prove to be a new approach for enhancing the efficacy of the paclitaxel. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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Review

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29 pages, 676 KiB

Open AccessEditor’s ChoiceReview

NF-κB: Governing Macrophages in Cancer

by Jessica Cornice, Daniela Verzella, Paola Arboretto, Davide Vecchiotti, Daria Capece, Francesca Zazzeroni and Guido Franzoso

Genes 2024, 15(2), 197; https://doi.org/10.3390/genes15020197 - 31 Jan 2024

Cited by 21 | Viewed by 6184

Abstract

Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: [...] Read more.

Tumor-associated macrophages (TAMs) are the major component of the tumor microenvironment (TME), where they sustain tumor progression and or-tumor immunity. Due to their plasticity, macrophages can exhibit anti- or pro-tumor functions through the expression of different gene sets leading to distinct macrophage phenotypes: M1-like or pro-inflammatory and M2-like or anti-inflammatory. NF-κB transcription factors are central regulators of TAMs in cancers, where they often drive macrophage polarization toward an M2-like phenotype. Therefore, the NF-κB pathway is an attractive therapeutic target for cancer immunotherapy in a wide range of human tumors. Hence, targeting NF-κB pathway in the myeloid compartment is a potential clinical strategy to overcome microenvironment-induced immunosuppression and increase anti-tumor immunity. In this review, we discuss the role of NF-κB as a key driver of macrophage functions in tumors as well as the principal strategies to overcome tumor immunosuppression by targeting the NF-κB pathway. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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17 pages, 1335 KiB

Open AccessReview

Unlocking Dendritic Cell-Based Vaccine Efficacy through Genetic Modulation—How Soon Is Now?

by Ahmed Elwakeel, Hannah E. Bridgewater and Jason Bennett

Genes 2023, 14(12), 2118; https://doi.org/10.3390/genes14122118 - 23 Nov 2023

Cited by 5 | Viewed by 2969

Abstract

The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion into the cancer patient. This strategy stemmed from the idea that to induce a robust anti-tumour immune response, it was necessary [...] Read more.

The dendritic cell (DC) vaccine anti-cancer strategy involves tumour-associated antigen loading and maturation of autologous ex vivo cultured DCs, followed by infusion into the cancer patient. This strategy stemmed from the idea that to induce a robust anti-tumour immune response, it was necessary to bypass the fundamental immunosuppressive mechanisms of the tumour microenvironment that dampen down endogenous innate immune cell activation and enable tumours to evade immune attack. Even though the feasibility and safety of DC vaccines have long been confirmed, clinical response rates remain disappointing. Hence, the full potential of DC vaccines has yet to be reached. Whether this cellular-based vaccination approach will fully realise its position in the immunotherapy arsenal is yet to be determined. Attempts to increase DC vaccine immunogenicity will depend on increasing our understanding of DC biology and the signalling pathways involved in antigen uptake, maturation, migration, and T lymphocyte priming to identify amenable molecular targets to improve DC vaccine performance. This review evaluates various genetic engineering strategies that have been employed to optimise and boost the efficacy of DC vaccines. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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29 pages, 5257 KiB

Open AccessReview

Molecular Mechanisms Underpinning Immunometabolic Reprogramming: How the Wind Changes during Cancer Progression

by Irene Flati, Mauro Di Vito Nolfi, Francesca Dall'Aglio, Davide Vecchiotti, Daniela Verzella, Edoardo Alesse, Daria Capece and Francesca Zazzeroni

Genes 2023, 14(10), 1953; https://doi.org/10.3390/genes14101953 - 17 Oct 2023

Viewed by 2507

Abstract

Metabolism and the immunological state are intimately intertwined, as defense responses are bioenergetically expensive. Metabolic homeostasis is a key requirement for the proper function of immune cell subsets, and the perturbation of the immune–metabolic balance is a recurrent event in many human diseases, [...] Read more.

Metabolism and the immunological state are intimately intertwined, as defense responses are bioenergetically expensive. Metabolic homeostasis is a key requirement for the proper function of immune cell subsets, and the perturbation of the immune–metabolic balance is a recurrent event in many human diseases, including cancer, due to nutrient fluctuation, hypoxia and additional metabolic changes occurring in the tumor microenvironment (TME). Although much remains to be understood in the field of immunometabolism, here, we report the current knowledge on both physiological and cancer-associated metabolic profiles of immune cells, and the main molecular circuits involved in their regulation, highlighting similarities and differences, and emphasizing immune metabolic liabilities that could be exploited in cancer therapy to overcome immune resistance. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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45 pages, 1654 KiB

Open AccessEditor’s ChoiceReview

The Interplay between T Cells and Cancer: The Basis of Immunotherapy

by Christina Chen, Xin Liu, Che-Yu Chang, Helen Y. Wang and Rong-Fu Wang

Genes 2023, 14(5), 1008; https://doi.org/10.3390/genes14051008 - 28 Apr 2023

Cited by 18 | Viewed by 6353

Abstract

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor [...] Read more.

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body’s defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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16 pages, 1043 KiB

Open AccessReview

Exploiting Autophagy-Dependent Neoantigen Presentation in Tumor Microenvironment

by Evangelos Koustas, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos Papadopoulos, Konstantinos Papanikolopoulos, Georgios Aloizos, Christos Damaskos, Nikolaos Garmpis, Anna Garmpi, Dimitris Matthaios and Michalis V. Karamouzis

Genes 2023, 14(2), 474; https://doi.org/10.3390/genes14020474 - 13 Feb 2023

Cited by 9 | Viewed by 2977

Abstract

Autophagy constitutes a well-known homeostatic and catabolic process that is responsible for degradation and recycling of cellular components. It is a key regulatory mechanism for several cellular functions, whereas its dysregulation is associated with tumorigenesis, tumor–stroma interactions and resistance to cancer therapy. A [...] Read more.

Autophagy constitutes a well-known homeostatic and catabolic process that is responsible for degradation and recycling of cellular components. It is a key regulatory mechanism for several cellular functions, whereas its dysregulation is associated with tumorigenesis, tumor–stroma interactions and resistance to cancer therapy. A growing body of evidence has proven that autophagy affects the tumor microenvironment, while it is also considered a key factor for function of several immune cells, such as APCs, T-cells, and macrophages. Moreover, it is implicated in presentation of neo-antigens of tumor cells in both MHC-I and MHC-II in dendritic cells (DCs) in functional activity of immune cells by creating T-cell memory, as well as in cross-presentation of neo-antigens for MHC-I presentation and the internalization process. Currently, autophagy has a crucial role in immunotherapy. Emergence of cancer immunotherapy has already shown some remarkable results, having changed therapeutic strategy in clinical practice for several cancer types. Despite these promising long-term responses, several patients seem to lack the ability to respond to immune checkpoint inhibitors. Thus, autophagy through neo-antigen presentation is a potential target in order to strengthen or attenuate the effects of immunotherapy against different types of cancer. This review will shed light on the recent advances and future directions of autophagy-dependent neo-antigen presentation and consequently its role in immunotherapy for malignant tumors. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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18 pages, 1190 KiB

Open AccessReview

The Emerging Role of MicroRNAs and Autophagy Mechanism in Pancreatic Cancer Progression: Future Therapeutic Approaches

by Evangelos Koustas, Eleni-Myrto Trifylli, Panagiotis Sarantis, Nikolaos Papadopoulos, Konstantinos Papanikolopoulos, Georgios Aloizos, Christos Damaskos, Nikolaos Garmpis, Anna Garmpi and Michalis V. Karamouzis

Genes 2022, 13(10), 1868; https://doi.org/10.3390/genes13101868 - 15 Oct 2022

Cited by 6 | Viewed by 2476

Abstract

Pancreatic cancer constitutes the fourth most frequent cause of death due to malignancy in the US. Despite the new therapeutic modalities, the management of pancreatic ductal adenocarcinoma (PDAC) is considered a difficult task for clinicians due to the fact that is usually diagnosed [...] Read more.

Pancreatic cancer constitutes the fourth most frequent cause of death due to malignancy in the US. Despite the new therapeutic modalities, the management of pancreatic ductal adenocarcinoma (PDAC) is considered a difficult task for clinicians due to the fact that is usually diagnosed in already advanced stages and it is relatively resistant to the current chemotherapeutic agents. The molecular background analysis of pancreatic malignant tumors, which includes various epigenetic and genetic alterations, opens new horizons for the development of novel diagnostic and therapeutic strategies. The interplay between miRNAs, autophagy pathway, and pancreatic carcinogenesis is in the spotlight of the current research. There is strong evidence that miRNAs take part in carcinogenesis either as tumor inhibitors that combat the oncogene expression or as promoters (oncomiRs) by acting as oncogenes by interfering with various cell functions such as proliferation, programmed cell death, and metabolic and signaling pathways. Deregulation of the expression levels of various miRNAs is closely associated with tumor growth, progression, and dissemination, as well as low sensitivity to chemotherapeutic agents. Similarly, autophagy despite constituting a pivotal homeostatic mechanism for cell survival has a binary role in PDAC, either as an inhibitor or promoter of carcinogenesis. The emerging role of miRNAs in autophagy gets a great deal of attention as it opens new opportunities for the development of novel therapeutic strategies for the management of this aggressive and chemoresistant malignancy. In this review, we will shed light on the interplay between miRNAs and the autophagy mechanism for pancreatic cancer development and progression. Full article

(This article belongs to the Special Issue Cell Signalling and Inflammation in Cancer)

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