Deregulated transcription factors in the emerging cancer hallmarks.

Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.

Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches.

Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.

Proteomics mining of cancer hallmarks on a single-cell resolution.

Dysregulated proteome is an essential contributor in carcinogenesis. Protein fluctuations fuel the progression of malignant transformation, such as uncontrolled proliferation, metastasis, and chemo/radiotherapy resistance, which severely impair therapeutic effectiveness and cause disease recurrence and eventually mortality among cancer patients. Cellular heterogeneity is widely observed in cancer and numerous cell subtypes have been characterized that greatly influence cancer progression. Population-averaged research may not fully reveal the heterogeneity, leading to inaccurate conclusions. Thus, deep mining of the multiplex proteome at the single-cell resolution will provide new insights into cancer biology, to develop prognostic biomarkers and treatments. Considering the recent advances in single-cell proteomics, herein we review several novel technologies with particular focus on single-cell mass spectrometry analysis, and summarize their advantages and practical applications in the diagnosis and treatment for cancer. Technological development in single-cell proteomics will bring a paradigm shift in cancer detection, intervention, and therapy.

The role of NF-κB in carcinogenesis of cervical cancer: opportunities and challenges.

The nuclear factor-κB (NF-κB) family, consisting of several transcription factors, has been implicated in the regulation of cell proliferation and invasion, as well as inflammatory reactions and tumor development. Cervical cancer (CC) results from long-term interactions of multiple factors, among which persistent high-risk human papillomavirus (hrHPV) infection is necessary. During different stages from early to late after HPV infection, the activity of NF-κB varies and plays various roles in carcinogenesis and progress of CC. As the center of the cell signaling transduction network, NF-κB can be activated through classical and non-classical pathways, and regulate the expression of downstream target genes involved in regulating the tumor microenvironment and acquiring hallmark traits of CC cells. Targeting NF-κB may help treat CC and overcome the resistance to radiation and chemotherapy. Even though NF-κB inhibitors have not been applied in clinical treatment as yet, due to limitations such as dose-restrictive toxicity and poor tumor-specificity, it is still considered to have significant therapeutic potential and application prospects. In this review, we focus on the role of NF-κB in the process of CC occurrence and hallmark capabilities acquisition. Finally, we summarize relevant NF-κB-targeted treatments, providing ideas for the prevention and treatment of CC.

Emerging roles of the cellular prion protein (PrPC) and 37/67 kDa laminin receptor (RPSA) interaction in cancer biology.

The cellular prion protein (PrPC) is well-known for its involvement, under its pathogenic protease-resistant form (PrPSc), in a group of neurodegenerative diseases, known as prion diseases. PrPC is expressed in nervous system, as well as in other peripheral organs, and has been found overexpressed in several types of solid tumors. Notwithstanding, studies in recent years have disclosed an emerging role for PrPC in various cancer associated processes. PrPC has high binding affinity for 37/67 kDa laminin receptor (RPSA), a molecule that acts as a key player in tumorigenesis, affecting cell growth, adhesion, migration, invasion and cell death processes. Recently, we have characterized at cellular level, small molecules able to antagonize the direct PrPC binding to RPSA and their intracellular trafficking. These findings are very crucial considering that the main function of RPSA is to modulate key events in the metastasis cascade. Elucidation of the role played by PrPC/RPSA interaction in regulating tumor development, progression and response to treatment, represents a very promising challenge to gain pathogenetic information and discover novel specific biomarkers and/or therapeutic targets to be exploited in clinical settings. This review attempts to convey a detailed description of the complexity surrounding these multifaceted proteins from the perspective of cancer hallmarks, but with a specific focus on the role of their interaction in the control of proliferation, migration and invasion, genome instability and mutation, as well as resistance to cell death controlled by autophagic pathway.

Allicin and Cancer Hallmarks.

Natural products, particularly medicinal plants, are crucial in combating cancer and aiding in the discovery and development of new therapeutic agents owing to their biologically active compounds. They offer a promising avenue for developing effective anticancer medications because of their low toxicity, diverse chemical structures, and ability to target various cancers. Allicin is one of the main ingredients in garlic (Allium sativum L.). It is a bioactive sulfur compound maintained in various plant sections in a precursor state. Numerous studies have documented the positive health benefits of this natural compound on many chronic conditions, including gastric, hepatic, breast, lung, cervical, prostate, and colon cancer. Moreover, allicin may target several cancer hallmarks or fundamental biological traits and functions that influence cancer development and spread. Cancer hallmarks include sustained proliferation, evasion of growth suppressors, metastasis, replicative immortality, angiogenesis, resistance to cell death, altered cellular energetics, and immune evasion. The findings of this review should provide researchers and medical professionals with a solid basis to support fundamental and clinical investigations of allicin as a prospective anticancer drug. This review outlines the anticancer role of allicin in each hallmark of cancer.

Targeting Cancer Hallmarks with Epigallocatechin Gallate (EGCG): Mechanistic Basis and Therapeutic Targets.

Epigallocatechin gallate (EGCG) is a catechin, which is a type of flavonoid found in high concentrations in green tea. EGCG has been studied extensively for its potential health benefits, particularly in cancer. EGCG has been found to exhibit anti-proliferative, anti-angiogenic, and pro-apoptotic effects in numerous cancer cell lines and animal models. EGCG has demonstrated the ability to interrupt various signaling pathways associated with cellular proliferation and division in different cancer types. EGCG anticancer activity is mediated by interfering with various cancer hallmarks. This article summarize and highlight the effects of EGCG on cancer hallmarks and focused on the impacts of EGCG on these cancer-related hallmarks. The studies discussed in this review enrich the understanding of EGCG's potential as a therapeutic tool against cancer, offering a substantial foundation for scientists and medical experts to advance scientific and clinical investigations regarding EGCG's possibility as a potential anticancer treatment.

In Vitro Approaches to Determine the Potential Carcinogenic Risk of Environmental Pollutants.

One important environmental/health challenge is to determine, in a feasible way, the potential carcinogenic risk associated with environmental agents/exposures. Since a significant proportion of tumors have an environmental origin, detecting the potential carcinogenic risk of environmental agents is mandatory, as regulated by national and international agencies. The challenge mainly implies finding a way of how to overcome the inefficiencies of long-term trials with rodents when thousands of agents/exposures need to be tested. To such an end, the use of in vitro cell transformation assays (CTAs) was proposed, but the existing prevalidated CTAs do not cover the complexity associated with carcinogenesis processes and present serious limitations. To overcome such limitations, we propose to use a battery of assays covering most of the hallmarks of the carcinogenesis process. For the first time, we grouped such assays as early, intermediate, or advanced biomarkers which allow for the identification of the cells in the initiation, promotion or aggressive stages of tumorigenesis. Our proposal, as a novelty, points out that using a battery containing assays from all three groups can identify if a certain agent/exposure can pose a carcinogenic risk; furthermore, it can gather mechanistic insights into the mode of the action of a specific carcinogen. This structured battery could be very useful for any type of in vitro study, containing human cell lines aiming to detect the potential carcinogenic risks of environmental agents/exposures. In fact, here, we include examples in which these approaches were successfully applied. Finally, we provide a series of advantages that, we believe, contribute to the suitability of our proposed approach for the evaluation of exposure-induced carcinogenic effects and for the development of an alternative strategy for conducting an exposure risk assessment.

Ethacrynic Acid: A Promising Candidate for Drug Repurposing as an Anticancer Agent.

Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for the treatment of edema caused by excessive body fluid. However, its clinical use is limited due to its low bioavailability and side effects, such as liver damage and hearing loss at high doses. Despite this, ECA has recently emerged as a potential anticancer agent through the approach of drug repositioning, with a novel mechanism of action. ECA has been shown to regulate cancer hallmark processes such as proliferation, apoptosis, migration and invasion, angiogenesis, inflammation, energy metabolism, and the increase of inhibitory growth factors through various mechanisms. Additionally, ECA has been used as a scaffold for synthesizing a new material, and various derivatives have been synthesized. This review explores the potential of ECA and its derivatives as anticancer agents, both alone and in combination with adjuvants, by examining their effects on ten hallmarks of cancer and neuronal contribution to cancer. Furthermore, we investigated the trend of synthesis research of a series of ECA derivatives to improve the bioavailability of ECA. This review highlights the importance of ECA research and its potential to provide a cost-effective alternative to new drug discovery and development for cancer treatment.

How Can the Microbiome Induce Carcinogenesis and Modulate Drug Resistance in Cancer Therapy?

Over the years, cancer has been affecting the lives of many people globally and it has become one of the most studied diseases. Despite the efforts to understand the cell mechanisms behind this complex disease, not every patient seems to respond to targeted therapies or immunotherapies. Drug resistance in cancer is one of the limiting factors contributing to unsuccessful therapies; therefore, understanding how cancer cells acquire this resistance is essential to help cure individuals affected by cancer. Recently, the altered microbiome was observed to be an important hallmark of cancer and therefore it represents a promising topic of cancer research. Our review aims to provide a global perspective of some cancer hallmarks, for instance how genetic and epigenetic modifications may be caused by an altered human microbiome. We also provide information on how an altered human microbiome can lead to cancer development as well as how the microbiome can influence drug resistance and ultimately targeted therapies. This may be useful to develop alternatives for cancer treatment, i.e., future personalized medicine that can help in cases where traditional cancer treatment is unsuccessful.

The Landscape of Aberrant Alternative Splicing Events in Steatotic Liver Graft Post Transplantation via Transcriptome-Wide Analysis.

The application of steatotic liver graft has been increased significantly due to the severe donor shortage and prevalence of non-alcoholic fatty liver disease. However, steatotic donor livers are vulnerable to acute phase inflammatory injury, which may result in cancer recurrence. Alternative splicing events (ASEs) are critical for diverse transcriptional variants in hepatocellular carcinoma (HCC). Here, we aimed to depict the landscape of ASEs, as well as to identify the differential ASEs in steatotic liver graft and their association with tumor recurrence after transplantation. The overall portrait of intragraft transcripts and ASEs were elucidated through RNA sequencing with the liver graft biopsies from patients and rat transplant models. Various differential ASEs were identified in steatotic liver grafts. CYP2E1, ADH1A, CYP2C8, ADH1C, and HGD, as corresponding genes to the common pathways involved differential ASEs in human and rats, were significantly associated with HCC patients' survival. The differential ASEs related RNA-binding proteins (RBPs) were enriched in metabolic pathways. The altered immune cell distribution, particularly macrophages and neutrophils, were perturbated by differential ASEs. The cancer hallmarks were enriched in steatotic liver grafts and closely associated with differential ASEs. Our work identified the differential ASE network with metabolic RBPs, immune cell distribution, and cancer hallmarks in steatotic liver grafts. We verified the link between steatotic liver graft injury and tumor recurrence at post-transcriptional level, offered new evidence to explore metabolism and immune responses, and provided the potential prognostic and therapeutic markers for tumor recurrence.

Ursolic Acid's Alluring Journey: One Triterpenoid vs. Cancer Hallmarks.

Cancer is a multifactorial disease characterized by various hallmarks, including uncontrolled cell growth, evasion of apoptosis, sustained angiogenesis, tissue invasion, and metastasis, among others. Traditional cancer therapies often target specific hallmarks, leading to limited efficacy and the development of resistance. Thus, there is a growing need for alternative strategies that can address multiple hallmarks concomitantly. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, has recently emerged as a promising candidate for multitargeted cancer therapy. This review aims to summarize the current knowledge on the anticancer properties of UA, focusing on its ability to modulate various cancer hallmarks. The literature reveals that UA exhibits potent anticancer effects through diverse mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of angiogenesis, inhibition of metastasis, and modulation of the tumor microenvironment. Additionally, UA has demonstrated promising activity against different cancer types (e.g., breast, lung, prostate, colon, and liver) by targeting various cancer hallmarks. This review discusses the molecular targets and signaling pathways involved in the anticancer effects of UA. Notably, UA has been found to modulate key signaling pathways, such as PI3K/Akt, MAPK/ERK, NF-κB, and Wnt/ß-catenin, which play crucial roles in cancer development and progression. Moreover, the ability of UA to destroy cancer cells through various mechanisms (e.g., apoptosis, autophagy, inhibiting cell growth, dysregulating cancer cell metabolism, etc.) contributes to its multitargeted effects on cancer hallmarks. Despite promising anticancer effects, this review acknowledges hurdles related to UA's low bioavailability, emphasizing the need for enhanced therapeutic strategies.

Violacein negatively modulates the colorectal cancer survival and epithelial-mesenchymal transition.

Violacein is a secondary metabolite produced by several microorganisms including Chromobacterium violaceum, and it is already used in food and cosmetics. However, due to its potent anticancer and low side effects, its molecular action needs to be deeply scrutinized. Therefore, the main objective of this study was to evaluate the violacein's ability to interfere with three cancer hallmarks: growth factors receptor-dependent signaling, proliferation, and epithelial-mesenchymal transition (EMT). Violacein has been associated with the induction of apoptosis in colorectal cancer (CRC) cells. Here, we demonstrate that this molecule is also active in CRC spheroids and inhibits cell migration. Violacein treatment reduced the amount of EGFR and AXL receptors in the HT29 cell line. Accordingly, the inhibition of the AKT, ERK, and PKCδ kinases, which are downstream mediators of the signaling pathways triggered by EGFR and AXL, is detected. Another interesting finding was that even when the cells were stimulated with transforming growth factor-ß, the EMT marker (N-cadherin) decreased. Therefore, this study provides further evidence that reinforces the potential of violacein as an antitumor agent, once this biomolecule can "switch off" properties associated with cancer plasticity.

Positron emission tomography molecular imaging-based cancer phenotyping.

During the past several decades, numerous studies have provided insights into biological characteristics of cancer cells and identified various hallmarks of cancer acquired in the tumorigenic processes. However, it is still challenging to image these distinctive traits of cancer to facilitate the management of patients in clinical settings. The rapidly evolving field of positron emission tomography (PET) imaging has provided opportunities to investigate cancer's biological characteristics in vivo. This article reviews the current status of PET imaging on characterizing hallmarks of cancer and discusses the future directions of PET imaging strategies facilitating in vivo cancer phenotyping.

Roles of TGF-ß in cancer hallmarks and emerging onco-therapeutic design.

Transforming growth factor-beta (TGF-ß) is a double-edged sword in cancer treatment because of its pivotal yet complex and roles played during cancer initiation/development. Current anti-cancer strategies involving TGF-ß largely view TGF-ß as an onco-therapeutic target that not only substantially hinders its full utilisation for cancer control, but also considerably restricts innovations in this field. Thereby, how to take advantages of therapeutically favourable properties of TGF-ß for cancer management represents an interesting and less investigated problem. Here, by categorising cancer hallmarks into four critical transition events and one enabling characteristic controlling cancer initiation and progression, and delineating TGF-ß complexities according to these cancer traits, we identify the suppressive role of TGF-ß in tumour initiation and early-stage progression and its promotive functionalities in cancer metastasis as well as other cancer hallmarks. We also propose the feasibility and possible scenarios of combining cold atmospheric plasma (CAP) with onco-therapeutics utilising TGF-ß for cancer control given the intrinsic properties of CAP against cancer hallmarks.

Phytosterols and phytostanols and the hallmarks of cancer in model organisms: A systematic review and meta-analysis.

Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products whose intake is inversely associated with incidence and prognosis of several cancers. Randomized cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signaling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screened leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Phytosterols were most commonly studied and found to reduce primary and metastatic tumor burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis (alkaline phosphatase, matrix metalloproteases, epithelial to mesenchymal transcription factors, lung and brain colonization), angiogenesis (vascular endothelial growth factor, CD31), and proliferation (Ki67, proliferating cell nuclear antigen) were consistently reduced by phytosterol treatment in breast and colorectal cancer. Very high dose treatment (equivalent to 0.2-1 g/kg body weight not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Phytosterols and phytostanols are already clinically recommended for cardiovascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action.

Low molecular weight protein tyrosine phosphatase as signaling hub of cancer hallmarks.

In the past decade, significant progress has been made in understanding the role of protein tyrosine phosphatase as a positive regulator of tumor progression. In this scenario, our group was one of the first to report the involvement of the low molecular weight protein tyrosine phosphatase (LMWPTP or ACP1) in the process of resistance and migration of tumor cells. Later, we and others demonstrated a positive correlation between the amount of this enzyme in human tumors and the poor prognosis. With this information in mind, we asked if LMWPTP contribution to metastasis, would it have an action beyond the primary tumor site. We know that the amount of this enzyme in the tumor cell correlates positively with the ability of cancer cells to interact with platelets, an indication that this enzyme is also important for the survival of these cells in the bloodstream. Here, we discuss several molecular aspects that support the idea of LMWPTP as a signaling hub of cancer hallmarks. Chemical and genetic modulation of LMWPTP proved to shut down signaling pathways associated with cancer aggressiveness. Therefore, advances in the development of LMWPTP inhibitors have great applicability in human diseases such as cancer.

The dark-side of the outside: how extracellular heat shock proteins promote cancer.

In addition to exerting several essential house-keeping activities in the cell, heat shock proteins (HSPs) are crucial players in a well-structured molecular program activated in response to stressful challenges. Among the different activities carried out by HSPs during emergency, they reach the extracellular milieu, from where they scout the surroundings, regulate extracellular protein activity and send autocrine and paracrine signals. Cancer cells permanently experience stress conditions due to their altered equilibrium and behaviour, and constantly secrete heat shock proteins as a result. Other than supporting anti-tumour immunity, extracellular heat shock proteins (eHSPs), can also exacerbate cancer cell growth and malignancy by sustaining different cancer hallmarks. eHSPs are implicated in extracellular matrix remodelling, resistance to apoptosis, promotion of cell migration and invasion, induction of epithelial to mesenchymal transition, angiogenesis and activation of stromal cells, supporting ultimately, metastasis dissemination. A broader understanding of eHSP activity and contribution to tumour development and progression is leading to new opportunities in the diagnosis and treatment of cancer.

The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications.

Proteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; it includes the serine-protease urokinase-type plasminogen activator (uPA). uPA binds to a specific cellular receptor (uPAR), which concentrates proteolytic activity at the cell surface, thus supporting cell migration. However, a large body of evidence clearly showed uPAR involvement in the biology of cancer cell independently of the proteolytic activity of its ligand. In this review we will first describe this multifunctional molecule and then we will discuss how uPAR can sustain most of cancer hallmarks, which represent the biological capabilities acquired during the multistep cancer development. Finally, we will illustrate the main data available in the literature on uPAR as a cancer biomarker and a molecular target in anti-cancer therapy.

Decoding the Roles of Long Noncoding RNAs in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. HCC is associated with several etiological factors, including HBV/HCV infections, cirrhosis, and fatty liver diseases. However, the molecular mechanism underlying HCC development remains largely elusive. The advent of high-throughput sequencing has unveiled an unprecedented discovery of a plethora of long noncoding RNAs (lncRNAs). Despite the lack of coding capacity, lncRNAs have key roles in gene regulation through interacting with various biomolecules. It is increasingly evident that the dysregulation of lncRNAs is inextricably linked to HCC cancer phenotypes, suggesting that lncRNAs are potential prognostic markers and therapeutic targets. In light of the emerging research in the study of the regulatory roles of lncRNAs in HCC, we discuss the association of lncRNAs with HCC. We link the biological processes influenced by lncRNAs to cancer hallmarks in HCC and describe the associated functional mechanisms. This review sheds light on future research directions, including the potential therapeutic applications of lncRNAs.