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Cancers
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Molecular Pathways in Cancers
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Molecular Pathways in Cancers

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 48179

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Ion Cristóbal

E-Mail Website
Guest Editor
Translational Oncology Division, Oncohealth Institute, IIS-Fundación Jiménez Díaz-UAM, 28040 Madrid, Spain
Interests: oncology; hematology; patient outcome; prognostic markers; healthcare quality; innovation; molecular processes
Special Issues, Collections and Topics in MDPI journals
Dr. Marta Rodríguez Moreno

E-Mail Website
Guest Editor
1. Pathology Department, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain
2. Center for the Biomedical Research Network in Oncology (CIBERONC), E-28040 Madrid, Spain
Interests: lymphoproliferative neoplasias; lymphoma; NOTCH signaling pathway; liquid biopsy; cancer bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the continuous advances in anticancer therapies, the survival rates in most tumor types remain very poor, especially in those patients with advanced stages of the disease. There is a direct relationship between our level of understanding of each cancer’s molecular pathogenesis and our capacity to develop novel and effective therapeutic strategies.
For this Special Issue, we welcome contributions that improve our knowledge of the molecular alterations that deregulate key signaling pathways and govern tumor progression in highly prevalent human cancers. We would like to focus this Special Issue on studies that combine basic and translational research and provide significant findings with a clear clinical and therapeutic impact.

Dr. Ion Cristóbal
Dr. Marta Rodríguez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • highly prevalent cancers
  • tumor microenvironment
  • oncogenesis
  • progression
  • novel targeted therapy
  • prognosis

Published Papers (14 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 192 KiB  
Editorial
Advances in the Knowledge of the Molecular Pathogenesis of High-Prevalence Tumors and Its Relevance for Their Future Clinical Management
by Marta Rodríguez and Ion Cristóbal
Cancers 2021, 13(23), 6053; https://doi.org/10.3390/cancers13236053 - 01 Dec 2021
Viewed by 1027
Abstract
This Special Issue aims to include relevant works that increase our knowledge about the molecular pathways that govern the development and progression of high-prevalence human cancers, which are responsible for most cancer-related deaths worldwide [...] Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)

Research

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15 pages, 3177 KiB  
Article
Genomic Mapping of Splicing-Related Genes Identify Amplifications in LSM1, CLNS1A, and ILF2 in Luminal Breast Cancer
by María del Mar Noblejas-López, Igor López-Cade, Jesús Fuentes-Antrás, Gonzalo Fernández-Hinojal, Ada Esteban-Sánchez, Aránzazu Manzano, José Ángel García-Sáenz, Pedro Pérez-Segura, Miguel de la Hoya, Atanasio Pandiella, Balázs Győrffy, Vanesa García-Barberán and Alberto Ocaña
Cancers 2021, 13(16), 4118; https://doi.org/10.3390/cancers13164118 - 16 Aug 2021
Cited by 8 | Viewed by 2465
Abstract
Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations [...] Read more.
Alternative splicing is an essential biological process, which increases the diversity and complexity of the human transcriptome. In our study, 304 splicing pathway-related genes were evaluated in tumors from breast cancer patients (TCGA dataset). A high number of alterations were detected, including mutations and copy number alterations (CNAs), although mutations were less frequently present compared with CNAs. In the four molecular subtypes, 14 common splice genes showed high level amplification in >5% of patients. Certain genes were only amplified in specific breast cancer subtypes. Most altered genes in each molecular subtype clustered to a few chromosomal regions. In the Luminal subtype, amplifications of LSM1, CLNS1A, and ILF2 showed a strong significant association with prognosis. An even more robust association with OS and RFS was observed when expression of these three genes was combined. Inhibition of LSM1, CLNS1A, and ILF2, using siRNA in MCF7 and T47D cells, showed a decrease in cell proliferation. The mRNA expression of these genes was reduced by treatment with BET inhibitors, a family of epigenetic modulators. We map the presence of splicing-related genes in breast cancer, describing three novel genes, LSM1, CLNS1A, and ILF2, that have an oncogenic role and can be modulated with BET inhibitors. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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23 pages, 3597 KiB  
Article
The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models
by Marta Sanz-Álvarez, Ester Martín-Aparicio, Melani Luque, Sandra Zazo, Javier Martínez-Useros, Pilar Eroles, Ana Rovira, Joan Albanell, Juan Madoz-Gúrpide and Federico Rojo
Cancers 2021, 13(11), 2778; https://doi.org/10.3390/cancers13112778 - 03 Jun 2021
Cited by 5 | Viewed by 2386
Abstract
The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement [...] Read more.
The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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11 pages, 1399 KiB  
Article
Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients
by Marta Sanz-Álvarez, Ion Cristóbal, Melani Luque, Andrea Santos, Sandra Zazo, Juan Madoz-Gúrpide, Cristina Caramés, Cheng-Ming Chiang, Jesús García-Foncillas, Pilar Eroles, Joan Albanell and Federico Rojo
Cancers 2021, 13(6), 1246; https://doi.org/10.3390/cancers13061246 - 12 Mar 2021
Cited by 8 | Viewed by 1908
Abstract
The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype [...] Read more.
The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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21 pages, 8368 KiB  
Article
Downregulation of Snail by DUSP1 Impairs Cell Migration and Invasion through the Inactivation of JNK and ERK and Is Useful as a Predictive Factor in the Prognosis of Prostate Cancer
by Desirée Martínez-Martínez, María-Val Toledo Lobo, Pablo Baquero, Santiago Ropero, Javier C. Angulo, Antonio Chiloeches and Marina Lasa
Cancers 2021, 13(5), 1158; https://doi.org/10.3390/cancers13051158 - 08 Mar 2021
Cited by 16 | Viewed by 2730
Abstract
Dual specificity phosphatase 1 (DUSP1) is crucial in prostate cancer (PC), since its expression is downregulated in advanced carcinomas. Here, we investigated DUSP1 effects on the expression of mesenchymal marker Snail, cell migration and invasion, analyzing the underlying mechanisms mediated by mitogen-activated protein [...] Read more.
Dual specificity phosphatase 1 (DUSP1) is crucial in prostate cancer (PC), since its expression is downregulated in advanced carcinomas. Here, we investigated DUSP1 effects on the expression of mesenchymal marker Snail, cell migration and invasion, analyzing the underlying mechanisms mediated by mitogen-activated protein kinases (MAPKs) inhibition. To this purpose, we used different PC cells overexpressing or lacking DUSP1 or incubated with MAPKs inhibitors. Moreover, we addressed the correlation of DUSP1 expression with Snail and activated MAPKs levels in samples from patients diagnosed with benign hyperplasia or prostate carcinoma, studying its implication in tumor prognosis and survival. We found that DUSP1 downregulates Snail expression and impairs migration and invasion in PC cells. Similar results were obtained following the inhibition of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK). In clinical samples, we evidenced an inverse correlation between DUSP1 expression and Snail levels, which are further associated with JNK and ERK activation. Consequently, the pattern DUSP1high/activated JNKlow/activated ERKlow/Snaillow is associated with an overall extended survival of PC patients. In summary, the ratio between DUSP1 and Snail expression, with additional JNK and ERK activity measurement, may serve as a potential biomarker to predict the clinical outcome of PC patients. Furthermore, DUSP1 induction or inhibition of JNK and ERK pathways could be useful to treat PC. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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18 pages, 1805 KiB  
Article
NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output
by Md Imtiaz Khalil, Ishita Ghosh, Vibha Singh, Jing Chen, Haining Zhu and Arrigo De Benedetti
Cancers 2020, 12(12), 3666; https://doi.org/10.3390/cancers12123666 - 07 Dec 2020
Cited by 17 | Viewed by 4597
Abstract
Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) [...] Read more.
Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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26 pages, 10863 KiB  
Article
Two Secreted Proteoglycans, Activators of Urothelial Cell–Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression
by Vasiliki Papadaki, Ken Asada, Julie K. Watson, Toshiya Tamura, Alex Leung, Jack Hopkins, Margaret Dellett, Noriaki Sasai, Hongorzul Davaapil, Serena Nik-Zainal, Rebecca Longbottom, Makoto Nakakido, Ryo Torii, Abhi Veerakumarasivam, Syuzo Kaneko, Mandeep S. Sagoo, Gillian Murphy, Akihisa Mitani, Kohei Tsumoto, John D. Kelly, Ryuji Hamamoto and Shin-ichi Ohnumaadd Show full author list remove Hide full author list
Cancers 2020, 12(11), 3362; https://doi.org/10.3390/cancers12113362 - 13 Nov 2020
Cited by 11 | Viewed by 3817
Abstract
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated [...] Read more.
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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23 pages, 14767 KiB  
Article
CD99–PTPN12 Axis Suppresses Actin Cytoskeleton-Mediated Dimerization of Epidermal Growth Factor Receptor
by Kyoung-Jin Lee, Yuri Kim, Min Seo Kim, Hyun-Mi Ju, Boyoung Choi, Hansoo Lee, Dooil Jeoung, Ki-Won Moon, Dongmin Kang, Jiwon Choi, Jong In Yook and Jang-Hee Hahn
Cancers 2020, 12(10), 2895; https://doi.org/10.3390/cancers12102895 - 09 Oct 2020
Cited by 8 | Viewed by 2720
Abstract
The epidermal growth factor receptor (EGFR), a member of ErbB receptor tyrosine kinase (RTK) family, is activated through growth factor-induced reorganization of the actin cytoskeleton and subsequent dimerization. We herein explored the molecular mechanism underlying the suppression of ligand-induced EGFR dimerization by CD99 [...] Read more.
The epidermal growth factor receptor (EGFR), a member of ErbB receptor tyrosine kinase (RTK) family, is activated through growth factor-induced reorganization of the actin cytoskeleton and subsequent dimerization. We herein explored the molecular mechanism underlying the suppression of ligand-induced EGFR dimerization by CD99 agonists and its relevance to tumor growth in vivo. Epidermal growth factor (EGF) activated the formation of c-Src/focal adhesion kinase (FAK)-mediated intracellular complex and subsequently induced RhoA-and Rac1-mediated actin remodeling, resulting in EGFR dimerization and endocytosis. In contrast, CD99 agonist facilitated FAK dephosphorylation through the HRAS/ERK/PTPN12 signaling pathway, leading to inhibition of actin cytoskeletal reorganization via inactivation of the RhoA and Rac1 signaling pathways. Moreover, CD99 agonist significantly suppressed tumor growth in a BALB/c mouse model injected with MDA-MB-231 human breast cancer cells. Taken together, these results indicate that CD99-derived agonist ligand inhibits epidermal growth factor (EGF)-induced EGFR dimerization through impairment of cytoskeletal reorganization by PTPN12-dependent c-Src/FAK inactivation, thereby suppressing breast cancer growth. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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Review

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19 pages, 2462 KiB  
Review
The Complement System in Ovarian Cancer: An Underexplored Old Path
by Yaiza Senent, Daniel Ajona, Antonio González-Martín, Ruben Pio and Beatriz Tavira
Cancers 2021, 13(15), 3806; https://doi.org/10.3390/cancers13153806 - 28 Jul 2021
Cited by 6 | Viewed by 2937
Abstract
Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest results in ovarian [...] Read more.
Ovarian cancer is one of the most lethal gynecological cancers. Current therapeutic strategies allow temporary control of the disease, but most patients develop resistance to treatment. Moreover, although successful in a range of solid tumors, immunotherapy has yielded only modest results in ovarian cancer. Emerging evidence underscores the relevance of the components of innate and adaptive immunity in ovarian cancer progression and response to treatment. Particularly, over the last decade, the complement system, a pillar of innate immunity, has emerged as a major regulator of the tumor microenvironment in cancer immunity. Tumor-associated complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. Recent insights suggest an important role of complement effectors, such as C1q or anaphylatoxins C3a and C5a, and their receptors C3aR and C5aR1 in ovarian cancer progression. Nevertheless, the implication of these factors in different clinical contexts is still poorly understood. Detailed knowledge of the interplay between ovarian cancer cells and complement is required to develop new immunotherapy combinations and biomarkers. In this context, we discuss the possibility of targeting complement to overcome some of the hurdles encountered in the treatment of ovarian cancer. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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15 pages, 543 KiB  
Review
Role of Oncogenic Pathways on the Cancer Immunosuppressive Microenvironment and Its Clinical Implications in Hepatocellular Carcinoma
by Naoshi Nishida
Cancers 2021, 13(15), 3666; https://doi.org/10.3390/cancers13153666 - 21 Jul 2021
Cited by 26 | Viewed by 4327
Abstract
The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma [...] Read more.
The tumor immune microenvironment, including hepatocellular carcinoma (HCC), is complex, consisting of crosstalk among tumor components such as the cancer cells, stromal cells and immune cells. It is conceivable that phenotypic changes in cancer cells by genetic and epigenetic alterations affect the cancer–stroma interaction and anti-cancer immunity through the expression of immune checkpoint molecules, growth factors, cytokines, chemokines and metabolites that may act on the immune system in tumors. Therefore, predicting the outcome of ICI therapy requires a thorough understanding of the oncogenic signaling pathways in cancer and how they affect tumor immune evasion. In this review, we have detailed how oncogenic signaling pathways can play a role in altering the condition of the cellular components of the tumor immune microenvironment such as tumor-associated macrophages, regulatory T cells and myeloid-derived suppressor cells. The RAS/MAPK, PI3K/Akt, Wnt/β-catenin and JAK/STAT pathways have all been implicated in anti-tumor immunity. We also found that factors that reflect the immune microenvironment of the tumor, including the status of oncogenic pathways such as the volume of tumor-infiltrating T cells, expression of the immune checkpoint protein PD-1 and its ligand PD-L1, and activation of the Wnt/β-catenin signaling pathway, predict a response to ICI therapy in HCC cases. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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28 pages, 2154 KiB  
Review
Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments
by Javier Martinez-Useros, Mario Martin-Galan, Maria Florez-Cespedes and Jesus Garcia-Foncillas
Cancers 2021, 13(13), 3209; https://doi.org/10.3390/cancers13133209 - 27 Jun 2021
Cited by 23 | Viewed by 4025
Abstract
Highly aggressive tumors are characterized by a highly invasive phenotype, and they display chemoresistance. Furthermore, some of the tumors lack expression of biomarkers for target therapies. This is the case of small-cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, glioblastoma, metastatic melanoma, [...] Read more.
Highly aggressive tumors are characterized by a highly invasive phenotype, and they display chemoresistance. Furthermore, some of the tumors lack expression of biomarkers for target therapies. This is the case of small-cell lung cancer, triple-negative breast cancer, pancreatic ductal adenocarcinoma, glioblastoma, metastatic melanoma, and advanced ovarian cancer. Unfortunately, these patients show a low survival rate and most of the available drugs are ineffective. In this context, epigenetic modifications have emerged to provide the causes and potential treatments for such types of tumors. Methylation and hydroxymethylation of DNA, and histone modifications, are the most common targets of epigenetic therapy, to influence gene expression without altering the DNA sequence. These modifications could impact both oncogenes and tumor suppressor factors, which influence several molecular pathways such as epithelial-to-mesenchymal transition, WNT/β–catenin, PI3K–mTOR, MAPK, or mismatch repair machinery. However, epigenetic changes are inducible and reversible events that could be influenced by some environmental conditions, such as UV exposure, smoking habit, or diet. Changes in DNA methylation status and/or histone modification, such as acetylation, methylation or phosphorylation, among others, are the most important targets for epigenetic cancer therapy. Therefore, the present review aims to compile the basic information of epigenetic modifications, pathways and factors, and provide a rationale for the research and treatment of highly aggressive tumors with epigenetic drugs. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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14 pages, 1688 KiB  
Review
Revisiting Mitochondria Scored Cancer Progression and Metastasis
by Rohit Gundamaraju, Wenying Lu and Rishya Manikam
Cancers 2021, 13(3), 432; https://doi.org/10.3390/cancers13030432 - 23 Jan 2021
Cited by 11 | Viewed by 3429
Abstract
The Warburg effect has immensely succored the study of cancer biology, especially in highlighting the role of mitochondria in cancer stemness and their benefaction to the malignancy of oxidative and glycolytic cancer cells. Mitochondrial genetics have represented a focal point in cancer therapeutics [...] Read more.
The Warburg effect has immensely succored the study of cancer biology, especially in highlighting the role of mitochondria in cancer stemness and their benefaction to the malignancy of oxidative and glycolytic cancer cells. Mitochondrial genetics have represented a focal point in cancer therapeutics due to the involvement of mitochondria in programmed cell death. The mitochondrion has been well established as a switch in cell death decisions. The mitochondrion’s instrumental role in central bioenergetics, calcium homeostasis, and translational regulation has earned it its fame in metastatic dissemination in cancer cells. Here, we revisit and review mechanisms through which mitochondria influence oncogenesis and metastasis by underscoring the oncogenic mitochondrion that is capable of transferring malignant capacities to recipient cells. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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Graphical abstract

23 pages, 1357 KiB  
Review
Oncogenic Effects of HIV-1 Proteins, Mechanisms Behind
by Maria Isaguliants, Ekaterina Bayurova, Darya Avdoshina, Alla Kondrashova, Francesca Chiodi and Joel M. Palefsky
Cancers 2021, 13(2), 305; https://doi.org/10.3390/cancers13020305 - 15 Jan 2021
Cited by 46 | Viewed by 5734
Abstract
People living with human immunodeficiency virus (HIV-1) are at increased risk of developing cancer, such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancer, and other cancers associated with chronic viral infections. Traditionally, this is linked to HIV-1-induced immune suppression with depletion of [...] Read more.
People living with human immunodeficiency virus (HIV-1) are at increased risk of developing cancer, such as Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL), cervical cancer, and other cancers associated with chronic viral infections. Traditionally, this is linked to HIV-1-induced immune suppression with depletion of CD4+ T-helper cells, exhaustion of lymphopoiesis and lymphocyte dysfunction. However, the long-term successful implementation of antiretroviral therapy (ART) with an early start did not preclude the oncological complications, implying that HIV-1 and its antigens are directly involved in carcinogenesis and may exert their effects on the background of restored immune system even when present at extremely low levels. Experimental data indicate that HIV-1 virions and single viral antigens can enter a wide variety of cells, including epithelial. This review is focused on the effects of five viral proteins: envelope protein gp120, accessory protein negative factor Nef, matrix protein p17, transactivator of transcription Tat and reverse transcriptase RT. Gp120, Nef, p17, Tat, and RT cause oxidative stress, can be released from HIV-1-infected cells and are oncogenic. All five are in a position to affect “innocent” bystander cells, specifically, to cause the propagation of (pre)existing malignant and malignant transformation of normal epithelial cells, giving grounds to the direct carcinogenic effects of HIV-1. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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24 pages, 4382 KiB  
Systematic Review
A Broad Overview of Signaling in Ph-Negative Classic Myeloproliferative Neoplasms
by Ana Guijarro-Hernández and José Luis Vizmanos
Cancers 2021, 13(5), 984; https://doi.org/10.3390/cancers13050984 - 26 Feb 2021
Cited by 16 | Viewed by 4168
Abstract
Ph-negative myeloproliferative neoplasms (polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)) are infrequent blood cancers characterized by signaling aberrations. Shortly after the discovery of the somatic mutations in JAK2, MPL, and CALR that cause these diseases, researchers extensively studied the [...] Read more.
Ph-negative myeloproliferative neoplasms (polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)) are infrequent blood cancers characterized by signaling aberrations. Shortly after the discovery of the somatic mutations in JAK2, MPL, and CALR that cause these diseases, researchers extensively studied the aberrant functions of their mutant products. In all three cases, the main pathogenic mechanism appears to be the constitutive activation of JAK2/STAT signaling and JAK2-related pathways (MAPK/ERK, PI3K/AKT). However, some other non-canonical aberrant mechanisms derived from mutant JAK2 and CALR have also been described. Moreover, additional somatic mutations have been identified in other genes that affect epigenetic regulation, tumor suppression, transcription regulation, splicing and other signaling pathways, leading to the modification of some disease features and adding a layer of complexity to their molecular pathogenesis. All of these factors have highlighted the wide variety of cellular processes and pathways involved in the pathogenesis of MPNs. This review presents an overview of the complex signaling behind these diseases which could explain, at least in part, their phenotypic heterogeneity. Full article
(This article belongs to the Special Issue Molecular Pathways in Cancers)
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