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26 pages, 18826 KiB

Open AccessArticle

Vinorelbine Alters lncRNA Expression in Association with EGFR Mutational Status and Potentiates Tumor Progression Depending on NSCLC Cell Lines’ Genetic Profile

by Hasan Alsharoh, Paul Chiroi, Andreea Nutu, Lajos Raduly, Oana Zanoaga and Ioana Berindan-Neagoe

Biomedicines 2023, 11(12), 3298; https://doi.org/10.3390/biomedicines11123298 - 13 Dec 2023

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Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most common type. In addition, NSCLC has a high mortality rate and an overall adverse patient outcome. Although significant improvements have been made in therapeutic [...] Read more.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most common type. In addition, NSCLC has a high mortality rate and an overall adverse patient outcome. Although significant improvements have been made in therapeutic options, effectiveness is still limited in late stages, so the need for a better understanding of the genomics events underlying the current therapies is crucial to aid future drug development. Vinorelbine (VRB) is an anti-mitotic chemotherapy drug (third-generation vinca alkaloid) used to treat several malignancies, including NSCLC. However, despite its widespread clinical use, very little is known about VRB-associated genomic alterations in different subtypes of NSCLC. This article is an in vitro investigation of the cytotoxic effects of VRB on three different types of NSCLC cell lines, A549, Calu-6, and H1792, with a closer focus on post-treatment genetic alterations. Based on the obtained results, VRB cytotoxicity produces modifications on a cellular level, altering biological processes such as apoptosis, autophagy, cellular motility, cellular adhesion, and cell cycle, but also at a genomic level, dysregulating the expression of some coding genes, such as EGFR, and long non-coding RNAs (lncRNAs), including CCAT1, CCAT2, GAS5, MALAT1, NEAT1, NORAD, XIST, and HOTAIR, that are implicated in the mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, although extensive validation is required, these results pave the way towards a better understanding of the cellular and genomic alterations underlying the cytotoxicity of VRB. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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13 pages, 2579 KiB

Open AccessArticle

The “StemDif Sensor Test”: A Straightforward, Non-Invasive Assay to Characterize the Secreted Stemness and/or Differentiation Activities of Tumor-Derived Cancer Cell Lines

by Aya Abou Hammoud, Julie Giraud, Xavier Gauthereau, Camille Blanchard, Sophie Daburon, Marco Zese, Silvia Molina-Castro, Pierre Dubus, Christine Varon and Helene Boeuf

Biomedicines 2023, 11(12), 3293; https://doi.org/10.3390/biomedicines11123293 - 13 Dec 2023

Viewed by 940

Abstract

Cancer stem cells are a subpopulation of tumor cells characterized by their ability to self-renew, induce tumors upon engraftment in animals and exhibit strong resistance to chemotherapy and radiotherapy. These cells exhibit numerous characteristics in common with embryonic stem cells, expressing some of [...] Read more.

Cancer stem cells are a subpopulation of tumor cells characterized by their ability to self-renew, induce tumors upon engraftment in animals and exhibit strong resistance to chemotherapy and radiotherapy. These cells exhibit numerous characteristics in common with embryonic stem cells, expressing some of their markers, typically absent in non-pathological adult differentiated cells. The aim of this study was to investigate the potential of conditioned media from cancer stem cells to modulate the fate of Leukemia Inhibitory Factor (LIF)-dependent murine embryonic stem cells (mESCs) as a way to obtain a direct readout of the secretome of cancer cells. A functional assay, “the StemDif sensor test”, was developed with two types of cancer stem cells derived from grade IV glioblastoma (adult and pediatric) or from gastric adenocarcinoma. We show that conditioned media from the selection of adult but not pediatric Glioma-Inducing Cells (GICs) maintain mESCs’ pluripotency in correlation with LIF secretion and activation of STAT3 protein. In contrast, conditioned media from gastric adenocarcinoma cells display LIF-independent stemness and differentiation activities on mESC. Our test stands out for its user-friendly procedures, affordability and straightforward output, positioning it as a pioneering tool for in-depth exploration of cancer stem cell secretome characteristics. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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21 pages, 13443 KiB

Open AccessArticle

ERK Signaling Pathway Is Constitutively Active in NT2D1 Non-Seminoma Cells and Its Inhibition Impairs Basal and HGF-Activated Cell Proliferation

by Luisa Gesualdi, Marika Berardini, Bianca Maria Scicchitano, Clotilde Castaldo, Mariano Bizzarri, Antonio Filippini, Anna Riccioli, Chiara Schiraldi, Francesca Ferranti, Domenico Liguoro, Rita Mancini, Giulia Ricci and Angela Catizone

Biomedicines 2023, 11(7), 1894; https://doi.org/10.3390/biomedicines11071894 - 04 Jul 2023

Cited by 1 | Viewed by 1030

Abstract

c-MET/hepatocyte growth factor (HGF) system deregulation is a well-known feature of malignancy in several solid tumors, and for this reason this system and its pathway have been considered as potential targets for therapeutic purposes. In previous manuscripts we reported c-MET/HGF expression and the [...] Read more.

c-MET/hepatocyte growth factor (HGF) system deregulation is a well-known feature of malignancy in several solid tumors, and for this reason this system and its pathway have been considered as potential targets for therapeutic purposes. In previous manuscripts we reported c-MET/HGF expression and the role in testicular germ cell tumors (TGCTs) derived cell lines. We demonstrated the key role of c-Src and phosphatidylinositol 3-kinase (PI3K)/AKT adaptors in the HGF-dependent malignant behavior of the embryonal carcinoma cell line NT2D1, finding that the inhibition of these onco-adaptor proteins abrogates HGF triggered responses such as proliferation, migration, and invasion. Expanding on these previous studies, herein we investigated the role of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathways in the HGF-dependent and HGF-independent NT2D1 cells biological responses. To inhibit MAPK/ERK pathways we chose a pharmacological approach, by using U0126 inhibitor, and we analyzed cell proliferation, collective migration, and chemotaxis. The administration of U0126 together with HGF reverts the HGF-dependent activation of cell proliferation but, surprisingly, does not exert the same effect on NT2D1 cell migration. In addition, we found that the use of U0126 alone significantly promotes the acquisition of NT2D1 «migrating phenotype», while collective migration of NT2D1 cells was stimulated. Notably, the inhibition of ERK activation in the absence of HGF stimulation resulted in the activation of the AKT-mediated pathway, and this let us speculate that the paradoxical effects obtained by using U0126, which are the increase of collective migration and the acquisition of partial epithelium–mesenchyme transition (pEMT), are the result of compensatory pathways activation. These data highlight how the specific response to pathway inhibitors, should be investigated in depth before setting up therapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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15 pages, 4428 KiB

Open AccessArticle

The Effect of Radiotherapy on Cell Survival and Inflammatory Cytokine and Chemokine Secretion in a Co-Culture Model of Head and Neck Squamous Cell Carcinoma and Normal Cells

by Sybilla Matuszczak, Krzysztof Szczepanik, Aleksandra Grządziel, Alina Drzyzga, Tomasz Cichoń, Justyna Czapla, Ewelina Pilny and Ryszard Smolarczyk

Biomedicines 2023, 11(6), 1773; https://doi.org/10.3390/biomedicines11061773 - 20 Jun 2023

Cited by 1 | Viewed by 1414

Abstract

Radiotherapy (RT) is one of the main treatments for head and neck squamous cell carcinomas (HNSCCs). Unfortunately, radioresistance is observed in many cases of HNSCCs. The effectiveness of RT depends on both the direct effect inducing cell death and the indirect effect of [...] Read more.

Radiotherapy (RT) is one of the main treatments for head and neck squamous cell carcinomas (HNSCCs). Unfortunately, radioresistance is observed in many cases of HNSCCs. The effectiveness of RT depends on both the direct effect inducing cell death and the indirect effect of changing the tumor microenvironment (TME). Knowledge of interactions between TME components after RT may help to design a new combined treatment with RT. In the study, we investigated the effect of RT on cell survival and cell secretion in a co-culture model of HNSCCs in vitro. We examined changes in cell proliferation, colony formation, cell cycle phases, type of cell death, cell migration and secretion after irradiation. The obtained results suggest that the presence of fibroblasts and endothelial cells in co-culture with HNSCCs inhibits the function of cell cycle checkpoints G₁/S and G₂/M and allows cells to enter the next phase of the cell cycle. We showed an anti-apoptotic effect in co-culture of HNSCCs with fibroblasts or endothelial cells in relation to the execution phase of apoptosis, although we initially observed increased activation of the early phase of apoptosis in the co-cultures after irradiation. We hypothesize that the anti-apoptotic effect depends on increased secretion of IL-6 and MCP-1. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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22 pages, 2353 KiB

Open AccessArticle

Small RNA-Seq Transcriptome Profiling of Mesothelial and Mesothelioma Cell Lines Revealed microRNA Dysregulation after Exposure to Asbestos-like Fibers

by Veronica Filetti, Claudia Lombardo, Carla Loreto, George Dounias, Massimo Bracci, Serena Matera, Lucia Rapisarda, Venerando Rapisarda, Caterina Ledda and Ermanno Vitale

Biomedicines 2023, 11(2), 538; https://doi.org/10.3390/biomedicines11020538 - 13 Feb 2023

Cited by 3 | Viewed by 1677

Abstract

Environmental exposure to fibers of respirable size has been identified as a risk for public health. Experimental evidence has revealed that a variety of fibers, including fluoro-edenite, can develop chronic respiratory diseases and elicit carcinogenic effects in humans. Fluoro-edenite (FE) is a silicate [...] Read more.

Environmental exposure to fibers of respirable size has been identified as a risk for public health. Experimental evidence has revealed that a variety of fibers, including fluoro-edenite, can develop chronic respiratory diseases and elicit carcinogenic effects in humans. Fluoro-edenite (FE) is a silicate mineral first found in Biancavilla (Sicily, Italy) in 1997. Environmental exposure to its fibers has been correlated with a cluster of malignant pleural mesotheliomas. This neoplasm represents a public health problem due to its long latency and to its aggression not alerted by specific symptoms. Having several biomarkers providing us with data on the health state of those exposed to FE fibers or allowing an early diagnosis on malignant pleural mesothelioma, still asymptomatic patients, would be a remarkable goal. To these purposes, we reported the miRNA transcriptome in human normal mesothelial cell line (MeT-5A) and in the human malignant mesothelioma cell line (JU77) exposed and not exposed to FE fibers. The results showed a difference in the number of deregulated miRNAs between tumor and nontumor samples both exposed and not exposed to FE fibers. As a matter of fact, the effect of exposure to FE fibers is more evident in the expression of miRNA in the tumor samples than in the nontumor samples. In the present paper, several pathways involved in the pathogenesis of malignant pleural mesothelioma have been analyzed. We especially noticed the involvement of pathways that have important functions in inflammatory processes, angiogenesis, apoptosis, and necrosis. Besides this amount of data, further studies will be designed for the selection of the most significant miRNAs to test and validate their diagnostic potential, alone or in combination with other protein biomarkers, in high-risk individuals’ liquid biopsy to have a noninvasive tool of diagnosis for this neoplasm. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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13 pages, 3315 KiB

Open AccessArticle

Molecular Imaging of Oxygenation Changes during Immunotherapy in Combination with Paclitaxel in Triple Negative Breast Cancer

by Tiara S. Napier, Shannon E. Lynch, Yun Lu, Patrick N. Song, Andrew C. Burns and Anna G. Sorace

Biomedicines 2023, 11(1), 125; https://doi.org/10.3390/biomedicines11010125 - 04 Jan 2023

Cited by 4 | Viewed by 2217

Abstract

Hypoxia is a common feature of the tumor microenvironment, including that of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with a high five-year mortality rate. Using [¹⁸F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging, we aimed to monitor changes in [...] Read more.

Hypoxia is a common feature of the tumor microenvironment, including that of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with a high five-year mortality rate. Using [¹⁸F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging, we aimed to monitor changes in response to immunotherapy (IMT) with chemotherapy in TNBC. TNBC-tumor-bearing mice received paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 and anti-cytotoxic T-lymphocyte 4. FMISO-PET imaging was performed on treatment days 0, 6, and 12. Max and mean standard uptake values (SUV_max and SUV_mean, respectively), histological analyses, and flow cytometry results were compared. FMISO-PET imaging revealed differences in tumor biology between treatment groups prior to tumor volume changes. 4T1 responders showed SUV_mean 1.6-fold lower (p = 0.02) and 1.8-fold lower (p = 0.02) than non-responders on days 6 and 12, respectively. E0771 responders showed SUV_mean 3.6-fold lower (p = 0.001) and 2.7-fold lower (p = 0.03) than non-responders on days 6 and 12, respectively. Immunohistochemical analyses revealed IMT plus PTX decreased hypoxia and proliferation and increased vascularity compared to control. Combination IMT/PTX recovered the loss of CD4+ T-cells observed with single-agent therapies. PET imaging can provide timely, longitudinal data on the TNBC tumor microenvironment, specifically intratumoral hypoxia, predicting therapeutic response to IMT plus chemotherapy. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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15 pages, 3321 KiB

Open AccessArticle

Indisulam Reduces Viability and Regulates Apoptotic Gene Expression in Pediatric High-Grade Glioma Cells

by Caio C. D. Monção, Carlos A. Scrideli, Augusto F. Andrade, Mariano S. Viapiano, Carlos G. Carlotti, Daniel Antunes Moreno, Mirella Baroni, Luiz G. Tone and Silvia A. Teixeira

Biomedicines 2023, 11(1), 68; https://doi.org/10.3390/biomedicines11010068 - 27 Dec 2022

Cited by 2 | Viewed by 1933

Abstract

Pediatric high-grade glioma (pHGG) is one of the most aggressive brain tumors. Treatment includes surgery, radiotherapy, chemotherapy, or combination therapy in children older than 3–5 years of age. These devastating tumors are influenced by the hypoxic microenvironment that coordinatively increases the expression of [...] Read more.

Pediatric high-grade glioma (pHGG) is one of the most aggressive brain tumors. Treatment includes surgery, radiotherapy, chemotherapy, or combination therapy in children older than 3–5 years of age. These devastating tumors are influenced by the hypoxic microenvironment that coordinatively increases the expression of carbonic anhydrases (CA9 and CA12) that are involved in pH regulation, metabolism, cell invasion, and resistance to therapy. The synthetic sulphonamide Indisulam is a potent inhibitor of CAs. The aim of this study was to evaluate the effects of Indisulam on CA9 and CA12 enzymes in pHGG cell lines. Our results indicated that, under hypoxia, the gene and protein expression of CA9 and CA12 are increased in pHGG cells. The functional effects of Indisulam on cell proliferation, clonogenic capacity, and apoptosis were measured in vitro. CA9 and CA12 gene and protein expression were analyzed by RT-PCR and western blot. The treatment with Indisulam significantly reduced cell proliferation (dose-time-dependent) and clonogenic capacity (p < 0.05) and potentiated the effect of apoptosis (p < 0.01). Indisulam promoted an imbalance in the anti-apoptotic BCL2 and pro-apoptotic BAX protein expression. Our results demonstrate that Indisulam contributes to apoptosis via imbalance of apoptotic proteins (BAX/BCL2) and suggests a potential to overcome chemotherapy resistance caused by the regulation these proteins. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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Review

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19 pages, 3510 KiB

Open AccessReview

Interaction between Gut Microbiota and Dendritic Cells in Colorectal Cancer

by Kawther Zaher and Fatemah Basingab

Biomedicines 2023, 11(12), 3196; https://doi.org/10.3390/biomedicines11123196 - 01 Dec 2023

Viewed by 1363

Abstract

Colorectal cancer (CRC) is a malignancy that manifests in serial stages and has been observed to have an escalating incidence in modern societies, causing a significant global health problem. The development of CRC is influenced by various exogenous factors, including lifestyle, diet, nutrition, [...] Read more.

Colorectal cancer (CRC) is a malignancy that manifests in serial stages and has been observed to have an escalating incidence in modern societies, causing a significant global health problem. The development of CRC is influenced by various exogenous factors, including lifestyle, diet, nutrition, environment, and microbiota, that can affect host cells, including immune cells. Various immune dysfunctions have been recognized in patients with CRC at different stages of this disease. The signature of microbiota in the development of CRC—inflammation related to obesity, diet, and reactive host cells, such as dendritic cells (DCs)—has been highlighted by many studies. This study focuses on DCs, the primary cellular mediators linking innate and adaptive immune responses against cancer. In addition, this review focuses on the role of microbiota in dysbiosis and how it affects DCs and, in turn, the immune response and progression of CRC by stimulating different sets of T cells. Additionally, DCs’ role in protecting this delicate balance is examined. This is to determine how gene yields of commensal microbiota may be critical in restoring this balance when disrupted. The stages of the disease and major checkpoints are discussed, as well as the role of the C-type lectin receptor of immature DCs pattern recognition receptor in CRC. Finally, based on a thorough examination of worldwide clinical studies and recent advancements in cancer immunotherapy, it is recommended that innovative approaches that integrate DC vaccination strategies with checkpoint inhibitors be considered. This approach holds great promise for improving CRC management. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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20 pages, 1436 KiB

Open AccessReview

The Potential Role of the T2 Ribonucleases in TME-Based Cancer Therapy

by Paola Campomenosi, Lorenzo Mortara, Barbara Bassani, Roberto Valli, Giovanni Porta, Antonino Bruno and Francesco Acquati

Biomedicines 2023, 11(8), 2160; https://doi.org/10.3390/biomedicines11082160 - 01 Aug 2023

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Abstract

In recent years, there has been a growing interest in developing innovative anticancer therapies targeting the tumor microenvironment (TME). The TME is a complex and dynamic milieu surrounding the tumor mass, consisting of various cellular and molecular components, including those from the host [...] Read more.

In recent years, there has been a growing interest in developing innovative anticancer therapies targeting the tumor microenvironment (TME). The TME is a complex and dynamic milieu surrounding the tumor mass, consisting of various cellular and molecular components, including those from the host organism, endowed with the ability to significantly influence cancer development and progression. Processes such as angiogenesis, immune evasion, and metastasis are crucial targets in the search for novel anticancer drugs. Thus, identifying molecules with “multi-tasking” properties that can counteract cancer cell growth at multiple levels represents a relevant but still unmet clinical need. Extensive research over the past two decades has revealed a consistent anticancer activity for several members of the T2 ribonuclease family, found in evolutionarily distant species. Initially, it was believed that T2 ribonucleases mainly acted as anticancer agents in a cell-autonomous manner. However, further investigation uncovered a complex and independent mechanism of action that operates at a non-cell-autonomous level, affecting crucial processes in TME-induced tumor growth, such as angiogenesis, evasion of immune surveillance, and immune cell polarization. Here, we review and discuss the remarkable properties of ribonucleases from the T2 family in the context of “multilevel” oncosuppression acting on the TME. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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10 pages, 757 KiB

Open AccessReview

Overcoming EGFR Resistance in Metastatic Colorectal Cancer Using Vitamin C: A Review

by Ahmad Machmouchi, Laudy Chehade, Sally Temraz and Ali Shamseddine

Biomedicines 2023, 11(3), 678; https://doi.org/10.3390/biomedicines11030678 - 23 Feb 2023

Cited by 1 | Viewed by 2213

Abstract

Targeted monoclonal antibody therapy against Epidermal Growth Factor Receptor (EGFR) is a leading treatment modality against metastatic colorectal cancer (mCRC). However, with the emergence of KRAS and BRAF mutations, resistance was inevitable. Cells harboring these mutations overexpress Glucose Transporter 1 (GLUT1) and sodium-dependent [...] Read more.

Targeted monoclonal antibody therapy against Epidermal Growth Factor Receptor (EGFR) is a leading treatment modality against metastatic colorectal cancer (mCRC). However, with the emergence of KRAS and BRAF mutations, resistance was inevitable. Cells harboring these mutations overexpress Glucose Transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2), which enables intracellular vitamin C transport, leading to reactive oxygen species generation and finally cell death. Therefore, high dose vitamin C is proposed to overcome this resistance. A comprehensive search strategy was adopted using Pubmed and MEDLINE databases (up to 11 August 2022). There are not enough randomized clinical trials to support its use in the clinical management of mCRC, except for a subgroup analysis from a phase III study. High dose vitamin C shows a promising role in overcoming EGFR resistance in mCRC with wild KRAS mutation with resistance to anti-epidermal growth factor inhibitors and in patients with KRAS and BRAF mutations. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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14 pages, 457 KiB

Open AccessReview

What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors?

by Elham Mehranzadeh, Olatz Crende, Iker Badiola and Patricia Garcia-Gallastegi

Biomedicines 2022, 10(12), 3292; https://doi.org/10.3390/biomedicines10123292 - 19 Dec 2022

Cited by 5 | Viewed by 1783

Abstract

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases [...] Read more.

Protein convertases (PCs) play a significant role in post-translational procedures by transforming inactive precursor proteins into their active forms. The role of PCs is crucial for cellular homeostasis because they are involved in cell signaling. They have also been described in many diseases such as Alzheimer’s and cancer. Cancer cells are secretory cells that send signals to the tumor microenvironment (TME), remodeling the surrounding space for their own benefits. One of the most important components of the TME is the immune system of the tumor. In this review, we describe recent discoveries that link PCs to the immune escape of tumors. Among PCs, many findings have determined the role of Furin (PC3) as a paramount enzyme causing the TME to induce tumor immune evasion. The overexpression of various cytokines and proteins, for instance, IL10 and TGF-B, moves the TME towards the presence of Tregs and, consequently, immune tolerance. Furthermore, Furin is implicated in the regulation of macrophage activity that contributes to the increased impairment of DCs (dendritic cells) and T effector cells. Moreover, Furin interferes in the MHC Class_1 proteolytic cleavage in the trans-Golgi network. In tumors, the T cytotoxic lymphocytes (CTLs) response is impeded by the PD1 receptor (PD1-R) located on CTLs and its ligand, PDL1, located on cancer cells. The inhibition of Furin is a subtle means of enhancing the antitumor response by repressing PD-1 expression in tumors or macrophage cells. The impacts of other PCs in tumor immune escape have not yet been clarified to the extent that Furin has. Accordingly, the influence of other types of PCs in tumor immune escape is a promising topic for further consideration. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Therapy)

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