Molecular and Signaling Networks in Cancer Development and Progression

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 26912

Special Issue Editors


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Guest Editor
Institute for Experimental Endocrinology and Oncology "G. Salvatore" (IEOS) - Second Unit, National Research Council, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: molecular oncology; cellular and molecular biology; biochemistry; golgi complex; GRASP65
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, I-50134 Florence, Italy
Interests: tumor; prostate cancer; tumor microenvironment; cancer associated fibroblasts; metabolism

Special Issue Information

Dear Colleagues,

Over recent decades, various studies have argued that cancer development and progression are caused by the intrinsic properties of cancer cells, which are the result of the accumulation of both genetic and epigenetic alterations and alterations of the molecular and signaling pathways of tumor cells. Developmental signaling pathways, signaling transduction pathways, and cell cycle checkpoints are frequently dysregulated in cancer. However, recent evidence suggests that cancer development and malignant progression are also the result of the bidirectional, dynamic, and intricate complex interactions between the cells of the stromal tissue and cancer cells in the tumor microenvironment. Tumor cells recruit and activate nonmalignant cells of stromal tissue, which acquire a protumoral phenotype and, in turn, respond by secreting several factors that produce a unique microenvironment that can modify the neoplastic properties of the tumor cells. In turn, the tumor cells feed signals back to the stroma, thus contributing to the further modification of the tumor microenvironment. Therefore, cancer development and malignant progression are the results of both the intrinsic and extrinsic signaling networks of tumor cells.

In this Special Issue of Cells, we would like to include original research and review articles that contribute to the unraveling of the intrinsic and extrinsic signaling networks altered in cancer with the aim of promoting the exchange of ideas, concepts, and findings in this area of cancer. These findings represent an important issue for both dissecting the molecular bases of cancer and the development of new therapeutic agents that can fight both the initiation and recurrence of cancer. All scientists working in this field are cordially invited to submit their manuscripts.

Dr. Daniela Spano
Dr. Giuseppina Comito
Guest Editors

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Keywords

  • molecular network
  • signaling pathways
  • tumor microenvironment
  • cancer
  • cell communication

Published Papers (8 papers)

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Research

Jump to: Review

22 pages, 3545 KiB  
Article
The Functional Role and Regulatory Mechanism of Bromodomain-Containing Protein 9 in Human Uterine Leiomyosarcoma
by Qiwei Yang, Maria Victoria Bariani, Ali Falahati, Azad Khosh, Ricardo R. Lastra, Hiba Siblini, Thomas G. Boyer and Ayman Al-Hendy
Cells 2022, 11(14), 2160; https://doi.org/10.3390/cells11142160 - 10 Jul 2022
Cited by 7 | Viewed by 2754
Abstract
Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma associated with poor prognosis, high rates of recurrence, and metastasis. There is currently limited information about uLMS molecular mechanisms of origin and development. Bromodomain (BRD)-containing proteins are involved in many biological processes, [...] Read more.
Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma associated with poor prognosis, high rates of recurrence, and metastasis. There is currently limited information about uLMS molecular mechanisms of origin and development. Bromodomain (BRD)-containing proteins are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD protein dysfunction has been linked to many diseases including tumorigenesis. However, the role of BRD proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BRD9 is aberrantly overexpressed in uLMS tissues compared to adjacent myometrium. BRD9 expression is also upregulated in uLMS cell lines compared to benign uterine fibroid and myometrium cell lines. Inhibition of BRD9 using the specific inhibitor (TP-472) suppressed uLMS cell proliferation via inducing apoptosis and cell cycle arrest. To further characterize the mechanistic basis for TP-472 inhibition of uLMS cell growth, we performed a comparative RNA-seq analysis of vehicle-treated and TP-472-treated uLMS cells (n = 4 each). Bioinformatics analysis revealed that TP-472 treatment distinctly altered the uLMS cell transcriptome. Gene set enrichment analysis identified critical pathways altered by BRD9 inhibition, including interferon-alpha response, KRAS signaling, MYC targets, TNF-a signaling via NFkB, and MTORC1 signaling. Parsimonious gene correlation network analysis identified nine enriched modules, including cell cycle and apoptosis modules. Moreover, the ENCODE Histone Modifications gene set and TargetScan microRNA analysis in Enrichr suggested that TP-472-induced BRD9 inhibition may alter the uLMS cell transcriptome by reprograming the oncogenic epigenome and inducing miRNA-mediated gene regulation. Therefore, BRD9 constitutes a specific vulnerability in malignant uLMS, and targeting non-BET BRD proteins in uLMS may provide a promising and novel strategy for treating patients with this aggressive uterine cancer. Full article
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16 pages, 2320 KiB  
Article
Cytoplasmic LMO2-LDB1 Complex Activates STAT3 Signaling through Interaction with gp130-JAK in Glioma Stem Cells
by Cheol Gyu Park, Sang-Hun Choi, Seon Yong Lee, Kiyoung Eun, Min Gi Park, Junseok Jang, Hyeon Ju Jeong, Seong Jin Kim, Sohee Jeong, Kanghun Lee and Hyunggee Kim
Cells 2022, 11(13), 2031; https://doi.org/10.3390/cells11132031 - 26 Jun 2022
Cited by 4 | Viewed by 2531
Abstract
The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) [...] Read more.
The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus. Full article
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14 pages, 5147 KiB  
Article
Proteomics Approach Highlights Early Changes in Human Fibroblasts-Pancreatic Ductal Adenocarcinoma Cells Crosstalk
by Verena Damiani, Maria Concetta Cufaro, Maurine Fucito, Beatrice Dufrusine, Claudia Rossi, Piero Del Boccio, Luca Federici, Maria Caterina Turco, Michele Sallese, Damiana Pieragostino and Vincenzo De Laurenzi
Cells 2022, 11(7), 1160; https://doi.org/10.3390/cells11071160 - 29 Mar 2022
Cited by 4 | Viewed by 2326
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality worldwide. Non-specific symptoms, lack of biomarkers in the early stages, and drug resistance due to the presence of a dense fibrous stroma all contribute to the poor outcome of this disease. The [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer mortality worldwide. Non-specific symptoms, lack of biomarkers in the early stages, and drug resistance due to the presence of a dense fibrous stroma all contribute to the poor outcome of this disease. The extracellular matrix secreted by activated fibroblasts contributes to the desmoplastic tumor microenvironment formation. Given the importance of fibroblast activation in PDAC pathology, it is critical to recognize the mechanisms involved in the transformation of normal fibroblasts in the early stages of tumorigenesis. To this aim, we first identified the proteins released from the pancreatic cancer cell line MIA-PaCa2 by proteomic analysis of their conditioned medium (CM). Second, normal fibroblasts were treated with MIA-PaCa2 CM for 24 h and 48 h and their proteostatic changes were detected by proteomics. Pathway analysis indicated that treated fibroblasts undergo changes compatible with the activation of migration, vasculogenesis, cellular homeostasis and metabolism of amino acids and reduced apoptosis. These biological activities are possibly regulated by ITGB3 and TGFB1/2 followed by SMAD3, STAT3 and BAG3 activation. In conclusion, this study sheds light on the crosstalk between PDAC cells and associated fibroblasts. Data are available via ProteomeXchange with identifier PXD030974. Full article
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16 pages, 3706 KiB  
Article
Distinctive Prognostic Value and Cellular Functions of Osteopontin Splice Variants in Human Gastric Cancer
by Chengcheng Hao, Yuxin Cui, Jane Lane, Shuqin Jia, Jiafu Ji and Wen G. Jiang
Cells 2021, 10(7), 1820; https://doi.org/10.3390/cells10071820 - 19 Jul 2021
Cited by 7 | Viewed by 2278
Abstract
Background: Osteopontin (OPN) splice variants are identified as predictors of tumour progression and therapeutic resistance in certain types of solid tumours. However, their roles in gastric cancer (GC) remain poorly characterized. The current study sought to assess the prognostic value of the three [...] Read more.
Background: Osteopontin (OPN) splice variants are identified as predictors of tumour progression and therapeutic resistance in certain types of solid tumours. However, their roles in gastric cancer (GC) remain poorly characterized. The current study sought to assess the prognostic value of the three OPN splice variants (namely OPN-a, OPN-b, and OPN-c) in gastric cancer and their potential functions within gastric cancer cells. Methods: RNA extraction and reverse transcription were performed using our clinical cohort of gastric carcinomas and matched normal tissues (n = 324 matched pairs). Transcript levels were determined using real-time quantitative PCR. Three OPN splice variants overexpressed cell lines were created from the gastric cancer cell line HGC-27. Subsequently, biological functions, including cell growth, adhesion, migration, and invasion, were studied. The potential effects of OPN isoforms on cisplatin and 5-Fu were evaluated by detecting cellular reactive oxygen species (ROS) levels in the HGC-27-derived cell lines. Results: Compared with normal tissues, the expression levels of three splice variants were all elevated in gastric cancer tissues in an order of OPN-a > OPN-b > OPN-c. The OPN-a level significantly increased with increasing TNM staging and worse clinical outcome. There appeared to be a downregulation for OPN-c in increasing lymph node status (p < 0.05), increasing TNM staging, and poor differentiation. High levels of OPN-a and OPN-b were correlated with short overall survival and disease-free survival of gastric cancer patients. However, the low expression of OPN-c was significantly associated with a poor prognosis. Functional analyses further showed that ectopic expression of OPN-c suppressed in vitro proliferation, adhesiveness, migration, and invasion properties of HGC-27 cells, while the opposite role was seen for OPN-a. Cellular ROS detection indicated that OPN-a and OPN-c significantly promoted ROS production after treatment with 5-Fu comparing to OPN-vector, while only OPN-a markedly induced ROS production after treatment with cisplatin. Conclusion: Our results suggest that OPN splice variants have distinguished potential to predict the prognosis of gastric cancer. Three OPN variants exert distinctive functions in gastric cancer cells. Focusing on specific OPN isoforms could be a novel direction for developing diagnostic and therapeutic approaches in gastric cancer. Full article
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Review

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31 pages, 1206 KiB  
Review
Golgi Complex: A Signaling Hub in Cancer
by Daniela Spano and Antonino Colanzi
Cells 2022, 11(13), 1990; https://doi.org/10.3390/cells11131990 - 21 Jun 2022
Cited by 11 | Viewed by 2634
Abstract
The Golgi Complex is the central hub in the endomembrane system and serves not only as a biosynthetic and processing center but also as a trafficking and sorting station for glycoproteins and lipids. In addition, it is an active signaling hub involved in [...] Read more.
The Golgi Complex is the central hub in the endomembrane system and serves not only as a biosynthetic and processing center but also as a trafficking and sorting station for glycoproteins and lipids. In addition, it is an active signaling hub involved in the regulation of multiple cellular processes, including cell polarity, motility, growth, autophagy, apoptosis, inflammation, DNA repair and stress responses. As such, the dysregulation of the Golgi Complex-centered signaling cascades contributes to the onset of several pathological conditions, including cancer. This review summarizes the current knowledge on the signaling pathways regulated by the Golgi Complex and implicated in promoting cancer hallmarks and tumor progression. Full article
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12 pages, 901 KiB  
Review
Circular RNA as a Novel Biomarker and Therapeutic Target for HCC
by Hongwu Meng, Ruowen Niu, Cheng Huang and Jun Li
Cells 2022, 11(12), 1948; https://doi.org/10.3390/cells11121948 - 17 Jun 2022
Cited by 22 | Viewed by 3240
Abstract
Circular RNA (circRNA) is a kind of endogenous non-coding RNA (ncRNA), which is produced by the reverse splicing of precursor mRNA (pre mRNA). It is widely expressed in a variety of biological cells. Due to the special formation mode, circRNA does not have [...] Read more.
Circular RNA (circRNA) is a kind of endogenous non-coding RNA (ncRNA), which is produced by the reverse splicing of precursor mRNA (pre mRNA). It is widely expressed in a variety of biological cells. Due to the special formation mode, circRNA does not have a 5′ terminal cap and 3′ poly (A) tail structure. Compared with linear RNA, circRNA is more stable to exonuclease and ribonuclease. In addition, circRNA is structurally conserved, has a stable sequence and is tissue-specific. With the development of high-throughput sequencing and bioinformatics technology, more and more circRNAs have been found. CircRNA plays an important pathophysiological role in the occurrence and development of alcoholic liver injury (ALI), hepatic fibrosis (HF), hepatocellular carcinoma (HCC), and other liver diseases. Our group has been committed to the research of liver disease diagnosis and treatment targets. We review the function and mechanism of circRNA in ALI, HF and HCC, expecting to provide new ideas for the diagnosis, treatment, and prognosis of liver diseases. Full article
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34 pages, 2174 KiB  
Review
Endocannabinoid System and Tumour Microenvironment: New Intertwined Connections for Anticancer Approaches
by Marta Iozzo, Giovanna Sgrignani, Giuseppina Comito, Paola Chiarugi and Elisa Giannoni
Cells 2021, 10(12), 3396; https://doi.org/10.3390/cells10123396 - 02 Dec 2021
Cited by 12 | Viewed by 5527
Abstract
The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites [...] Read more.
The tumour microenvironment (TME) is now recognised as a hallmark of cancer, since tumour:stroma crosstalk supports the key steps of tumour growth and progression. The dynamic co-evolution of the tumour and stromal compartments may alter the surrounding microenvironment, including the composition in metabolites and signalling mediators. A growing number of evidence reports the involvement of the endocannabinoid system (ECS) in cancer. ECS is composed by a complex network of ligands, receptors, and enzymes, which act in synergy and contribute to several physiological but also pathological processes. Several in vitro and in vivo evidence show that ECS deregulation in cancer cells affects proliferation, migration, invasion, apoptosis, and metastatic potential. Although it is still an evolving research, recent experimental evidence also suggests that ECS can modulate the functional behaviour of several components of the TME, above all the immune cells, endothelial cells and stromal components. However, the role of ECS in the tumour:stroma interplay remains unclear and research in this area is particularly intriguing. This review aims to shed light on the latest relevant findings of the tumour response to ECS modulation, encouraging a more in-depth analysis in this field. Novel discoveries could be promising for novel anti-tumour approaches, targeting the microenvironmental components and the supportive tumour:stroma crosstalk, thereby hindering tumour development. Full article
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27 pages, 2037 KiB  
Review
Exosomes in the Tumor Microenvironment: From Biology to Clinical Applications
by Vitor Rodrigues da Costa, Rodrigo Pinheiro Araldi, Hugo Vigerelli, Fernanda D’Ámelio, Thais Biude Mendes, Vivian Gonzaga, Bruna Policíquio, Gabriel Avelar Colozza-Gama, Cristiane Wenceslau Valverde and Irina Kerkis
Cells 2021, 10(10), 2617; https://doi.org/10.3390/cells10102617 - 01 Oct 2021
Cited by 29 | Viewed by 4356
Abstract
Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment [...] Read more.
Cancer is one of the most important health problems and the second leading cause of death worldwide. Despite the advances in oncology, cancer heterogeneity remains challenging to therapeutics. This is because the exosome-mediated crosstalk between cancer and non-cancer cells within the tumor microenvironment (TME) contributes to the acquisition of all hallmarks of cancer and leads to the formation of cancer stem cells (CSCs), which exhibit resistance to a range of anticancer drugs. Thus, this review aims to summarize the role of TME-derived exosomes in cancer biology and explore the clinical potential of mesenchymal stem-cell-derived exosomes as a cancer treatment, discussing future prospects of cell-free therapy for cancer treatment and challenges to be overcome. Full article
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