Biological Basis of Anti-tumor Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 32217

Special Issue Editor

Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Interests: cell therapy, nanomedicine, angiogenesis, proteases

Special Issue Information

Dear Colleagues,

Cancer treatment is undoubtedly one of the greatest challenges of this century. Current knowledge on the nature of cancer has taught the scientific community that cancer must be treated according to the needs of each specific patient, introducing the concept of "personalized medicine", a therapeutic approach capable of adapting not only to different types of cancer, but especially to different patients with the same type of cancer. These concepts have given rise to a series of new therapeutic approaches, aimed at the personalization of therapies, focusing the efforts of researchers on new topics such as personalized vaccines, cell therapy, gene editing, the microbiome and in particular the individual enteroma. The biological basis of each of these approaches consists in the attempt to identify the main alterations induced by the mutation of key genes in each individual patient and to create therapeutic tools capable of correcting them. These new approaches can be helped by therapeutic interventions aimed at controlling characteristics "shared" by the majority of tumors but that may be differentially expressed in each single patients, such as the mechanisms of acidification of the tumor microenvironment, the aberrant formation of blood vessels, the major factors that control invasive and metastatic processes, the differential presence of stem cells in the primary and metastatic tumors.

Prof. Mario Del Rosso
Guest Editor

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Keywords

  • personalized medicine
  • Anti-tumor Therapies
  • biological basis
  • genes alterations

Published Papers (9 papers)

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Research

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13 pages, 2888 KiB  
Article
Growth and Migration Blocking Effect of Nanaomycin K, a Compound Produced by Streptomyces sp., on Prostate Cancer Cell Lines In Vitro and In Vivo
by Yuto Hirata, Katsumi Shigemura, Michika Moriwaki, Masato Iwatsuki, Yuki Kan, Tooru Ooya, Koki Maeda, Youngmin Yang, Takuji Nakashima, Hirotaka Matsuo, Jun Nakanishi and Masato Fujisawa
Cancers 2023, 15(10), 2684; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15102684 - 10 May 2023
Cited by 1 | Viewed by 1521
Abstract
Since castration-resistant prostate cancer (CRPC) acquires resistance to molecularly targeted drugs, discovering a class of drugs with different mechanisms of action is needed for more efficient treatment. In this study, we investigated the anti-tumor effects of nanaomycin K, derived from “Streptomyces rosa [...] Read more.
Since castration-resistant prostate cancer (CRPC) acquires resistance to molecularly targeted drugs, discovering a class of drugs with different mechanisms of action is needed for more efficient treatment. In this study, we investigated the anti-tumor effects of nanaomycin K, derived from “Streptomyces rosa subsp. notoensis” OS-3966. The cell lines used were LNCaP (non-CRPC), PC-3 (CRPC), and TRAMP-C2 (CRPC). Experiments included cell proliferation analysis, wound healing analysis, and Western blotting. In addition, nanaomycin K was administered intratumorally to TRAMP-C2 carcinoma-bearing mice to assess effects on tumor growth. Furthermore, immuno-histochemistry staining was performed on excised tissues. Nanaomycin K suppressed cell proliferation in all cell lines (p < 0.001) and suppressed wound healing in TRAMP-C2 (p = 0.008). Nanaomycin K suppressed or showed a tendency to suppress the expression of N-cadherin, Vimentin, Slug, and Ras in all cell lines, and suppressed the phosphorylation of p38, SAPK/JNK, and Erk1/2 in LNCaP and TRAMP-C2. In vivo, nanaomycin K safely inhibited tumor growth (p = 0.001). In addition, suppression of phospho-Erk1/2 and increased expression of E-cadherin and cleaved-Caspase3 were observed in excised tumors. Nanaomycin K inhibits tumor growth and suppresses migration by inhibiting epithelial-mesenchymal transition in prostate cancer. Its mechanism of action is related to the inhibition of phosphorylation of the MAPK signaling pathway. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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18 pages, 4241 KiB  
Article
Novel Insights into Redox-Based Mechanisms for Auranofin-Induced Rapid Cancer Cell Death
by Elie Hatem, Nadine El Banna, Amélie Heneman-Masurel, Dorothée Baïlle, Laurence Vernis, Sylvie Riquier, Marie-Pierre Golinelli-Cohen, Olivier Guittet, Cindy Vallières, Jean-Michel Camadro, Xue Qiu, Niko Hildebrandt, Michel Lepoivre and Meng-Er Huang
Cancers 2022, 14(19), 4864; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194864 - 05 Oct 2022
Cited by 6 | Viewed by 2251
Abstract
Auranofin (Ridaura®, AUF) is a gold complex originally approved as an antirheumatic agent that has emerged as a potential candidate for multiple repurposed therapies. The best-studied anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR). However, a number of [...] Read more.
Auranofin (Ridaura®, AUF) is a gold complex originally approved as an antirheumatic agent that has emerged as a potential candidate for multiple repurposed therapies. The best-studied anticancer mechanism of AUF is the inhibition of thioredoxin reductase (TrxR). However, a number of reports indicate a more complex and multifaceted mode of action for AUF that could be cancer cell type- and dose-dependent. In this study, we observed that AUF displayed variable cytotoxicity in five triple-negative breast cancer cell lines. Using representative MDA-MB-231 cells treated with moderate and cytotoxic doses of AUF, we evidenced that an AUF-mediated TrxR inhibition alone may not be sufficient to induce cell death. Cytotoxic doses of AUF elicited rapid and drastic intracellular oxidative stress affecting the mitochondria, cytoplasm and nucleus. A “redoxome” proteomics investigation revealed that a short treatment with a cytotoxic dose AUF altered the redox state of a number of cysteines-containing proteins, pointing out that the cell proliferation/cell division/cell cycle and cell–cell adhesion/cytoskeleton structure were the mostly affected pathways. Experimentally, AUF treatment triggered a dose-dependent S-phase arrest and a rapid disintegration of the actin cytoskeleton structure. Our study shows a new spectrum of AUF-induced early effects and should provide novel insights into the complex redox-based mechanisms of this promising anticancer molecule. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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20 pages, 32847 KiB  
Article
Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells
by Ya-Hui Chen, Jyun-Xue Wu, Shun-Fa Yang, Chueh-Ko Yang, Tze-Ho Chen and Yi-Hsuan Hsiao
Cancers 2022, 14(7), 1824; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071824 - 04 Apr 2022
Cited by 20 | Viewed by 3567
Abstract
Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects [...] Read more.
Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin β1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin β1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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19 pages, 2035 KiB  
Article
Prognostic Significance of CSF-1R Expression in Early Invasive Breast Cancer
by Nazia Riaz, Samantha Burugu, Angela S. Cheng, Samuel C. Y. Leung, Dongxia Gao and Torsten O. Nielsen
Cancers 2021, 13(22), 5769; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225769 - 18 Nov 2021
Cited by 11 | Viewed by 2741
Abstract
Colony-stimulating factor-1 receptor (CSF-1R) signaling promotes an immune suppressive microenvironment enriched in M2 macrophages. Given that CSF-1R inhibitors are under investigation in clinical trials, including in breast cancer, CSF-1R expression and association with immune biomarkers could identify patients who derive greater benefit from [...] Read more.
Colony-stimulating factor-1 receptor (CSF-1R) signaling promotes an immune suppressive microenvironment enriched in M2 macrophages. Given that CSF-1R inhibitors are under investigation in clinical trials, including in breast cancer, CSF-1R expression and association with immune biomarkers could identify patients who derive greater benefit from combination with immunotherapies. TIMER2.0 and bc-GenExMiner v4.7 were used to assess the correlation of CSF1R mRNA with immune infiltrates and prognosis. Following a prespecified training–validation approach, an optimized immunohistochemistry assay was applied to assess CSF-1R on carcinoma cells and macrophages on breast cancer tissue microarray series representing 2384 patients, coupled to comprehensive clinicopathological, biomarker, and outcome data. Significant positive correlations were observed between CSF1R mRNA and immune infiltrates. High carcinoma CSF-1R correlated with grade 3 tumors >2 cm, hormone receptor negativity, high Ki67, immune checkpoint biomarkers, and macrophages expressing CSF-1R and CD163. High carcinoma CSF-1R was significantly associated with poor survival in univariate and multivariate analyses. Adverse prognostic associations were retained in ER+ cases regardless of the presence of CD8+ T cells. CSF-1R+ macrophages were not prognostic. High carcinoma CSF-1R is associated with aggressive breast cancer biology and poor prognosis, particularly in ER+ cases, and identifies patients in whom biomarker-directed CSF-1R therapies may yield superior therapeutic responses. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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18 pages, 5156 KiB  
Article
Crosstalk between Macrophages and Myxoid Liposarcoma Cells Increases Spreading and Invasiveness of Tumor Cells
by Michele Minopoli, Sabrina Sarno, Lucia Cannella, Salvatore Tafuto, Gosuè Scognamiglio, Michele Gallo, Flavio Fazioli, Rosa Azzaro, Gaetano Apice, Biagio De Angelis, Elena Tamborini, Cecilia Garofalo, Ymera Pignochino, Laura Mercatali, Toni Ibrahim, Rita Falcioni, Beatrice Valenti, Roberta Maestro, Katia Scotlandi, Annarosaria De Chiara and Maria Vincenza Carrieroadd Show full author list remove Hide full author list
Cancers 2021, 13(13), 3298; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133298 - 30 Jun 2021
Cited by 5 | Viewed by 2312
Abstract
Myxoid liposarcoma (MLPS) is the second most common subtype of liposarcoma and has tendency to metastasize to soft tissues. To date, the mechanisms of invasion and metastasis of MLPS remain unclear, and new therapeutic strategies that improve patients’ outcomes are expected. In this [...] Read more.
Myxoid liposarcoma (MLPS) is the second most common subtype of liposarcoma and has tendency to metastasize to soft tissues. To date, the mechanisms of invasion and metastasis of MLPS remain unclear, and new therapeutic strategies that improve patients’ outcomes are expected. In this study, we analyzed by immunohistochemistry the immune cellular components and microvessel density in tumor tissues from patients affected by MLPS. In order to evaluate the effects of primary human MLPS cells on macrophage polarization and, in turn, the ability of macrophages to influence invasiveness of MLPS cells, non-contact and 3D organotypic co-cultures were set up. High grade MLPS tissues were found heavily vascularized, exhibited a CD3, CD4, and CD8 positive T lymphocyte-poor phenotype and were massively infiltrated by CD163 positive M2-like macrophages. Conversely, low grade MLPS tissues were infiltrated by a discrete amount of CD3, CD4, and CD8 positive T lymphocytes and a scarce amount of CD163 positive macrophages. Kaplan–Meier analysis revealed a shorter Progression Free Survival in MLPS patients whose tumor tissues were highly vascularized and heavily infiltrated by CD163 positive macrophages, indicating a clear-cut link between M2-like macrophage abundance and poor prognosis in patients. Moreover, we documented that, in co-culture, soluble factors produced by primary human MLPS cells induce macrophage polarization toward an M2-like phenotype which, in turn, increases MLPS cell capability to spread into extracellular matrix and to cross endothelial monolayers. The identification of M2-like polarization factors secreted by MLPS cells may allow to develop novel targeted therapies counteracting MLPS progression. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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Review

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20 pages, 907 KiB  
Review
Present Status, Challenges, and Prospects of Dihydromyricetin in the Battle against Cancer
by Jiajun Wu, Zuowei Xiao, Hongfang Li, Neng Zhu, Jia Gu, Wenmao Wang, Chao Liu, Wei Wang and Li Qin
Cancers 2022, 14(14), 3487; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143487 - 18 Jul 2022
Cited by 9 | Viewed by 2999
Abstract
Dihydromyricetin (DHM) is a natural flavonoid compound extracted from Ampelopsis grossedentata that has been used for centuries in traditional Chinese medicine. DHM has attracted intensive attention due to its numerous beneficial activities, such as hepatoprotection, cardioprotection, antioxidant, and anti-inflammation. In addition, DHM inhibits [...] Read more.
Dihydromyricetin (DHM) is a natural flavonoid compound extracted from Ampelopsis grossedentata that has been used for centuries in traditional Chinese medicine. DHM has attracted intensive attention due to its numerous beneficial activities, such as hepatoprotection, cardioprotection, antioxidant, and anti-inflammation. In addition, DHM inhibits the progression of cancers such as lung cancer, hepatocellular cancer, breast cancer, melanoma, and malignant reproductive systems through multiple mechanisms, including antiangiogenesis, antiproliferation, apoptosis, and inhibition of invasion and migration. Notably, DHM also activates autophagy at different levels, exerting a dual-regulatory effect on cancers. Mechanistically, DHM can effectively regulate mammalian target of rapamycin (mTOR), noncoding RNA-mediated signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, nuclear factor-κB (NF-κB), p53, and endoplasmic reticulum stress (ER stress)-driven signaling in different types of cancers. DHM has also been shown to have inhibitory effects on various regulators that trigger epithelial–mesenchymal transition (EMT). Furthermore, DHM exhibits a remarkable anticancer reversal ability when used in combination with drugs such as adriamycin, nedaplatin, and other drugs. However, the low bioavailability of DHM limits its potential applications, which are improved through structural modification and the exploration of novel dosage forms. Therefore, DHM may become a promising candidate for treating malignancies alone or combined with conventional anticancer strategies used in clinical practice. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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45 pages, 6472 KiB  
Review
The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities
by Virginia Metrangolo, Michael Ploug and Lars H. Engelholm
Cancers 2021, 13(21), 5376; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215376 - 27 Oct 2021
Cited by 25 | Viewed by 4800
Abstract
One of the largest challenges to the implementation of precision oncology is identifying and validating selective tumor-driving targets to enhance the therapeutic efficacy while limiting off-target toxicity. In this context, the urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising therapeutic [...] Read more.
One of the largest challenges to the implementation of precision oncology is identifying and validating selective tumor-driving targets to enhance the therapeutic efficacy while limiting off-target toxicity. In this context, the urokinase-type plasminogen activator receptor (uPAR) has progressively emerged as a promising therapeutic target in the management of aggressive malignancies. By focalizing the plasminogen activation cascade and subsequent extracellular proteolysis on the cell surface of migrating cells, uPAR endows malignant cells with a high proteolytic and migratory potential to dissolve the restraining extracellular matrix (ECM) barriers and metastasize to distant sites. uPAR is also assumed to choreograph multiple other neoplastic stages via a complex molecular interplay with distinct cancer-associated signaling pathways. Accordingly, high uPAR expression is observed in virtually all human cancers and is frequently associated with poor patient prognosis and survival. The promising therapeutic potential unveiled by the pleiotropic nature of this receptor has prompted the development of distinct targeted intervention strategies. The present review will focus on recently emerged cytotoxic approaches emphasizing the novel technologies and related limits hindering their application in the clinical setting. Finally, future research directions and emerging opportunities in the field of uPAR targeting are also discussed. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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18 pages, 325 KiB  
Review
Glucose Transporters as a Target for Anticancer Therapy
by Monika Pliszka and Leszek Szablewski
Cancers 2021, 13(16), 4184; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164184 - 20 Aug 2021
Cited by 74 | Viewed by 5131
Abstract
Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only [...] Read more.
Tumor growth causes cancer cells to become hypoxic. A hypoxic condition is a hallmark of cancer. Metabolism of cancer cells differs from metabolism of normal cells. Cancer cells prefer the process of glycolysis as a source of ATP. Process of glycolysis generates only two molecules of ATP per one molecule of glucose, whereas the complete oxidative breakdown of one molecule of glucose yields 36 molecules of ATP. Therefore, cancer cells need more molecules of glucose in comparison with normal cells. Increased uptake of glucose by these cells is due to overexpression of glucose transporters, especially GLUT1 and GLUT3, that are hypoxia responsive, as well as other glucose transport proteins. Increased expression of these carrier proteins may be used in anticancer therapy. This phenomenon is used in diagnostic techniques such as FDG-PET. It is also suggested, and there are observations, that therapeutic inhibition of glucose transporters may be a method in treatment of cancer patients. On the other hand, there are described cases, in which upregulation of glucose transporters, as, for example, NIS, which is used in radioiodine therapy, can help patients with cancer. The aim of this review is the presentation of possibilities, and how glucose transporters can be used in anticancer therapy. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
32 pages, 701 KiB  
Review
ALT Positivity in Human Cancers: Prevalence and Clinical Insights
by Danny MacKenzie, Jr., Andrea K. Watters, Julie T. To, Melody W. Young, Jonathan Muratori, Marni H. Wilkoff, Rita G. Abraham, Maria M. Plummer and Dong Zhang
Cancers 2021, 13(10), 2384; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102384 - 14 May 2021
Cited by 37 | Viewed by 5540
Abstract
Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism [...] Read more.
Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients. Full article
(This article belongs to the Special Issue Biological Basis of Anti-tumor Therapies)
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