Showing papers in "Biochimica Et Biophysica Acta - Reviews On Cancer in 2022"
TL;DR: A review of inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy are presented in this paper , where inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors.
Abstract: Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy.
35 citations
TL;DR: In this article , the role of cyclin-dependent kinase (CDK) in DNA damage response (DDR) has emerged, and the impact of CDKs on DNA repair is discussed.
Abstract: The cyclin-dependent kinase (CDK) family plays a critical role in a variety of signaling pathways that regulate transcription and cell-cycle progression. Recently, the role of CDKs in DNA damage response (DDR) has emerged. CDKs affect both damage signaling and DNA repair, contributing to the fidelity of the cell division process as well as the maintenance of genomic integrity following DNA damage. This is due to the modulatory role of CDKs on double-strand break repair (DSBR) components, including their influence on enzymes involved in homologous recombination (HR) and non-homologous end-joining (NHEJ). In this review, the impact of CDKs on DDR and DNA repair is discussed.
30 citations
TL;DR: A comprehensive review of methylation-based biomarkers for colorectal cancer can be found in this paper , where the authors provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues.
Abstract: DNA methylation is an epigenetic mechanism regulating gene expression. Changes in DNA methylation were suggested to be useful biomarkers for diagnosis, and for the determination of prognosis and treatment response. Here, we provide an overview of methylation-based biomarkers in colorectal cancer. First, we start with the two methylation-based diagnostic biomarkers already approved for colorectal cancer, SEPT9 and the combination of NDRG4 and BMP3. Then, we provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues. The most often identified markers like SDC2, VIM, APC, MGMT, SFRP1, SFRP2, and NDRG4 have distinct functions previously linked to tumor progression. Although numerous studies have identified tumor-specific methylation changes, most of these alterations were observed in a single study only. The lack of validation in independent samples means low reproducibility and is a major limitation. The genome-wide determination of methylation status (methylome) can provide data to solve these issues. In the third section of the review, methylome studies focusing on different aspects related to CRC, including precancerous lesions, CRC-specific changes, molecular subtypes, aging, and chemotherapy response are summarized. Notably, techniques simultaneously analyzing a large set of regions can also uncover epigenetic regulation of genes which have not yet been associated with tumorigenesis previously. A remaining constraint of studies published to date is the low patient number utilized in these preventing the identification of clinically valuable biomarker candidates. Either future large-scale studies or the integration of already available methylome-level data will be necessary to uncover biomarkers sufficiently robust for clinical application.
24 citations
TL;DR: In this paper , the authors highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
Abstract: One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
22 citations
TL;DR: In this article , the complex roles of neutrophils in TME and highlights the strategies in neutrophil targeting in cancer treatment with a particular focus on the progresses of ongoing clinical trials involving neutrophin-targeted therapies.
Abstract: Neutrophils are the frontline cells in response to microbial infections and are involved in a range of inflammatory disorders in the body. In recent years, neutrophils have gained considerable attention in their involvement of complex roles in tumor development and progression. Tumor-associated neutrophils (TANs) that accumulate in local region could be triggered by external stimuli from tumor microenvironment (TME) and switch between anti- and pro-tumor phenotypes. The anti-tumor neutrophils kill tumor cells through direct cytotoxic effects as well as indirect effects by activating adaptive immune responses. In contrast, the pro-tumor phenotype of neutrophils might be associated with cell proliferation, angiogenesis, and immunosuppression in TME. More recently, neutrophils have been proposed as a potential target in cancer therapy for their ability to diminish the pro-tumor pathways, such as by immune checkpoint blockade. This review discusses the complex roles of neutrophils in TME and highlights the strategies in neutrophil targeting in cancer treatment with a particular focus on the progresses of ongoing clinical trials involving neutrophil-targeted therapies.
19 citations
TL;DR: In this paper , the authors summarized the dynamic functions of EZH2 on different components of the tumor microenvironment, including tumor cells, T cells, macrophages, natural killer cells, myeloid-derived suppressor cells, dendritic cells, fibroblasts, and mesenchymal stem cells.
Abstract: Immune checkpoint blockade (ICB) is regarded as a promising strategy for cancer therapy. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), has been implicated in the carcinogenesis of numerous solid tumors. However, the underlying mechanism of EZH2 in cancer immunotherapeutic resistance remains unknown. EZH2 orchestrates the regulation of the innate and adaptive immune systems of the tumor microenvironment (TME). Profound epigenetic and transcriptomic changes induced by EZH2 in tumor cells and immune cells mobilize the elements of the TME, leading to immune-suppressive activity of solid tumors. In this review, we summarized the dynamic functions of EZH2 on the different components of the TME, including tumor cells, T cells, macrophages, natural killer cells, myeloid-derived suppressor cells, dendritic cells, fibroblasts, and mesenchymal stem cells. Several ongoing anti-tumor clinical trials using EZH2 inhibitors have also been included as translational perspectives. In conclusion, based combinational therapy to enable ICB could offer a survival benefit in patients with cancer.
15 citations
TL;DR: In this article , the authors present the biological and clinical role of tumor-draining lymph nodes and propose strategies to include in the design of immuno-radiotherapy trials aiming to eradicate cancer at a local and distant level.
Abstract: The tumor-draining lymph nodes (TDLNs) are the primary sites of the development of anti-tumor immunity. Primary tumor irradiation promotes 'radio-vaccination' by enhancing the release of tumor antigens and activating the interferon type-I pathway. Activated intratumoral dendritic cells (DCs) enter the lymphatics to reach the TDLNs. The adaptive anti-tumor immune responses are developed, as DCs will present tumor-related antigens to activate CD4+ and CD8+ T-cells. Strong experimental evidence suggests that post-irradiation tumor clearance is strongly dependent on the accumulation of such cytotoxic T-cells in the tumors. However, TDLNs are heavily irradiated during Radiotherapy to eradicate the clinical and subclinical metastatic disease. At the same time, irradiation depletes the critical immune cell population residing in TDLNs and primary tumors, blocking immune response and compromising the effectiveness of immuno-stimulatory interventions. Since TDLNs are essential for T-cell activation by inbound dendritic cells previously activated in the tumor environment, the practice of TDLN-irradiation demands re-evaluation. Interventions to preserve and handle the functional state of regional TDLNs or remote nodes, during or after Radiotherapy, may have great therapeutic importance. TDLNs represent the main playground for educating and expanding tumor-specific cytotoxic immune cells and controlling a delicate balance between immune surveillance and tumor spread. Their activation state may define the outcome of Radiotherapy and the manifestation of abscopal effects. In this critical review, we present the biological and clinical role of TDLNs and propose strategies to include in the design of immuno-radiotherapy trials aiming to eradicate cancer at a local and distant level.
14 citations
TL;DR: In this paper , the mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation, and stress responses.
Abstract: The mitogen-activated protein kinase (MAPK) signaling pathway is the primary regulatory module of various cellular processes such as cell proliferation, differentiation, and stress responses. This pathway converts external stimuli to cellular responses via three major kinases: mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase kinase (MAPKK), and mitogen-activated protein kinase kinase kinase (MAPKKK). Ubiquitination is a post-translational modification of proteins with ubiquitin, which results in the formation of mono- or poly-ubiquitin chains of substrate proteins. Conversely, removal of the ubiquitin by deubiquitinating enzymes (DUBs) is known as deubiquitination. This review summarizes mechanisms of the MAPK signaling pathways (ERK1/2, ERK5, p38, and JNK1/2/3 signaling pathway) in cancers, and of E3 ligases and DUBs that target the MAPK signaling components such as Raf, MEK1/2, ERK1/2, MEKK2/3, MEKK1-4, TAK1, DLK1, MLK1-4, ASK1/2, and MKK3-7.
14 citations
TL;DR: In this article , a basic workflow of the scRNA-seq technology, existing limitations and improvement areas are discussed, and in-depth understanding in TME, exhausting T cells, CSCs, CTCs, tumor-associated macrophages, dendritic cells in hepatocellular carcinoma (HCC) facilitates implementation of personalized and precise therapy in an era of availability with an array of systemic regimens.
Abstract: Unsatisfied clinical outcome drives to better understand hepatic carcinogenesis, microenvironment and escape of immune surveillance in hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-Seq) has generated enormous data to pinpoint pathophysiologic alterations in tumor microenvironment (TME) or trace lineage development in cancer stem cells (CSCs), circulating tumor cells (CTCs), and subsets of immune cells, such as exhausting T cells, tumor-associated macrophages (TAMs), dendritic cells or other lineages. New insights have significantly advanced current understanding in progression, poor responses to molecular-targeted therapeutics or immune checkpoint inhibitors, metastasis in both basic research and clinical practice. The present review intends to cover a basic workflow of the scRNA-seq technology, existing limitations and improvement areas. Moreover, in-depth understanding in TME, exhausting T cells, CSCs, CTCs, tumor-associated macrophages, dendritic cells in HCC facilitates implementation of personalized and precise therapy in an era of availability with an array of systemic regimens.
14 citations
TL;DR: In this article , the authors collected and investigated m6A modification in pediatric cancers based on mRNA and non-coding RNA, finding that m6As were involved in glioma, hepatoblastoma, nephroblastoma, neuroblastoma and neuroosarcoma.
Abstract: With the development of RNA modification research, the importance of N6-methyladenosine (m6A) in tumors cannot be ignored. m6A promotes the self-renewal of tumor stem cells and the proliferation of tumor cells. It affects post-transcriptional gene expression through epigenetic mechanisms, combining various factors to determine proteins' fate and altering the biological function. This modification process runs through the entire tumors, and genes affected by m6A modification may be the critical targets for cancers breakthroughs. Though generally less dangerous than adult cancer, pediatric cancer accounts for a significant proportion of child deaths. What is more alarming is that the occurrences of adult tumors are highly associated with the poor prognoses of pediatric tumors. Therefore, it is necessary to pay attention to the importance of pediatric cancer and discover new therapeutic targets, which will help improve the therapeutic effect and prognoses of the diseases. We collected and investigated m6A modification in pediatric cancers based on mRNA and non-coding RNA, finding that m6A factors were involved in glioma, hepatoblastoma, nephroblastoma, neuroblastoma, osteosarcoma, medulloblastoma, retinoblastoma, and acute lymphoblastic leukemia. Consequently, we summarized the relationships between the m6A factors and these pediatric cancers.
14 citations
TL;DR: In this article , the authors reviewed the molecular mechanism behind activation of the FLT3 protein due to mutations and argued that difference in mutation sequences and especially location might be coupled to prognosis.
Abstract: Acute myeloid leukemia is an aggressive cancer, which, in spite of increasingly better understanding of its genetic background remains difficult to treat. Mutations in the FLT3 gene are observed in ≈30% of the patients. Most of these mutations are internal tandem duplications (ITDs) of a sequence within the protein coding region, an activation mechanism that is almost non-existent with other genes and cancers. As patients each carry their own unique set of mutations, it is challenging to understand how ITDs activate the protein, and ascertain the risk for each individual patient. Available treatment options are limited due to development of drug resistance. Here, recent studies are reviewed that help to better understand the molecular mechanism behind activation of the FLT3 protein due to mutations. It is argued that difference in mutation sequences and especially location might be coupled to prognosis. When it comes to FLT3 inhibitors, key differences between them can be attributed to the mode of inhibition (type-1 and type-2 inhibitors), effective inhibitory coefficient in the blood plasma and off-target binding. Accounting for the position and length of insertions may in the future be used to predict prognosis and rationalise treatment. Development of new inhibitors must take into account the potential for resistance mutations. Inhibitors aimed at multiple specific targets are currently being developed. These, and as well as combination therapies will hopefully lead to longer periods during which targeted FLT3 therapy will remain effective.
TL;DR: A comprehensive overview of the ubiquitination/de-ubiquitination regulation of PTEN could help improve clinical conceptualization and treatment of cancer can be found in this article .
Abstract: Tumor suppressor activation or reactivation has long been a sought-after, yet elusive, therapeutic strategy for human cancer. Phosphatase and tensin homolog (PTEN) is one of the most frequently mutated tumor suppressor genes that regulate many biological processes, including proliferation, survival, cellular architecture, motility, energy metabolism, and genomic stability. As a dose-dependent tumor suppressor, subtle reductions in PTEN protein levels and activity will alter the gene-expression profiles involved in tumor progression, laying the foundation for PTEN reactivation in cancer treatment. However, treatment strategies that manipulate and/or replace PTEN activity to successfully block and reverse the destructive progression of cancer are not yet available. Ubiquitination/de-ubiquitination is one of the major regulatory mechanisms of PTEN by influencing its stability, subcellular localization, and activity. Recent discoveries, including new ubiquitination sites, E3 ubiquitin ligases, de-ubiquitinases of PTEN, and participation of accessory and adaptor proteins, have revealed new modes of PTEN ubiquitination regulation. Furthermore, either pharmaceutical or gene-targeted inhibition of E3 ligase-mediated ubiquitination of PTEN potently releases PTEN's anticancer activity and suppresses tumorigenesis. These findings shed light on therapeutic strategies for reactivating PTEN in cancer that target ubiquitination/de-ubiquitination. Therefore, a comprehensive understanding of the ubiquitination/de-ubiquitination regulation of PTEN could help improve clinical conceptualization and treatment of cancer. This review aimed to summarize and discuss recent discoveries on PTEN ubiquitination and de-ubiquitination, with the goal of providing a systematic summary in the field and promoting clinical transformation of targeting ubiquitination for PTEN reactivation in the treatment of cancer.
TL;DR: In this paper , the authors provide a comprehensive discussion of benign tumors in the context of their evolution and ecology as well as interactions with their hosts, and suggest that a better understanding of the differences and similarities between benign and malignant tumors is fundamental to our understanding of malignancy both at mechanistic and evolutionary levels.
Abstract: Tumors are usually classified into two main categories - benign or malignant, with much more attention being devoted to the second category given that they are usually associated with more severe health issues (i.e., metastatic cancers). Here, we argue that the mechanistic distinction between benign and malignant tumors has narrowed our understanding of neoplastic processes. This review provides the first comprehensive discussion of benign tumors in the context of their evolution and ecology as well as interactions with their hosts. We compare the genetic and epigenetic profiles, cellular activities, and the involvement of viruses in benign and malignant tumors. We also address the impact of intra-tumoral cell composition and its relationship with the tumoral microenvironment. Lastly, we explore the differences in the distribution of benign and malignant neoplasia across the tree of life and provide examples on how benign tumors can also affect individual fitness and consequently the evolutionary trajectories of populations and species. Overall, our goal is to bring attention to the non-cancerous manifestations of tumors, at different scales, and to stimulate research on the evolutionary ecology of host-tumor interactions on a broader scale. Ultimately, we suggest that a better appreciation of the differences and similarities between benign and malignant tumors is fundamental to our understanding of malignancy both at mechanistic and evolutionary levels.
TL;DR: A review of the role of extracellular vesicles, their subtypes and their oncogenic cargo (as characterised by targeted studies as well as agnostic '-omics' analyses) in the pathobiology of pancreatic cancer is presented in this paper .
Abstract: Pancreatic cancer (PC) is a devastating disease, offering poor mortality rates for patients. The current challenge being faced is the inability to diagnose patients in a timely manner, where potentially curative resection provides the best chance of survival. Recently, small/nanosized extracellular vesicles (sEVs), including exosomes, have gained significant preclinical and clinical attention due to their emerging roles in cancer progression and diagnosis. Extracellular vesicles (EVs) possess endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype of recipient cells. This review provides an overview of the role of EVs, their subtypes and their oncogenic cargo (as characterised by targeted studies as well as agnostic '-omics' analyses) in the pathobiology of pancreatic cancer. The discussion covers the progress of 'omics technology' that has enabled elucidation of the molecular mechanisms that mediate the role of EVs and their cargo in pancreatic cancer progression.
TL;DR: In this article , the main cellular components in the tumor microenvironment (TME): CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.
Abstract: Colorectal cancer (CRC) is one of the most common cancers worldwide, which ranks third in terms of incidence and the second leading cause of cancer-related mortality. Metabolic reprogramming within the tumor microenvironment (TME) has been proved intimately involved in the initiation and malignant progression of CRC. Signal messengers, including cytokines, metabolites, and exosomes among others, derived from cancer cells can be utilized by the surrounding cells within the TME to induce metabolic alteration and cancer-associated transformation. In turn, the cargos secreted from cancer-associate cells further provide the nutrition and energy supply for cancer cells, supporting their metabolic reprogramming to promote proliferation, migration, metastasis, and radiochemoresistance. In this review, we focus on the main cellular components in the TME: CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.
TL;DR: In this paper , the authors discuss the application of OoC platforms integrated with conventional 2D cell lines, 3D organoids and spheroid models, and the organotypic tissue slices, including patient-derived and xenograft tumor slice cultures in cancer treatment responses.
Abstract: Despite tremendous advancements in oncology research and therapeutics, cancer remains a primary cause of death worldwide. One of the significant factors in this critical challenge is a precise diagnosis and limited knowledge on how the tumor microenvironment (TME) behaves to the treatment and its role in chemo-resistance. Therefore, it is critical to understand the contribution of a heterogeneous TME in cancer drug response in individual patients for effective therapy management. Micro-physiological systems along with tissue engineering have facilitated the development of more physiologically relevant platforms, known as Organ-on-Chips (OoC). OoC platforms recapitulate the critical hallmarks of the TME in vitro and subsequently abet in sensitivity and efficacy testing of anti-cancer drugs before clinical trials. The OoC platforms incorporating conventional in vitro models enable researchers to control the cellular, molecular, chemical, and biophysical parameters of the TME in precise combinations while analyzing how they contribute to tumor progression and therapy response. This review discusses the application of OoC platforms integrated with conventional 2D cell lines, 3D organoids and spheroid models, and the organotypic tissue slices, including patient-derived and xenograft tumor slice cultures in cancer treatment responses. We summarize the relevance and drawbacks of conventional in vitro models in assessing cancer treatment response, challenges and limitations associated with OoC models, and future opportunities enabled by the OoC technologies towards developing personalized cancer diagnostics and therapeutics.
TL;DR: In this article , the authors describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
Abstract: Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.
TL;DR: In this article , a systematic review aimed to address recent research (from January 2000 to September 2021) on the anticancer activity of anthocyanins assessed by in vitro assays.
Abstract: Anthocyanins have been associated with beneficial effects on human health. Cancer has been one of the main public health issues due to its aggressiveness and high mortality rate. This systematic review aimed to address recent research (from January 2000 to September 2021) on the anticancer activity of anthocyanins assessed by in vitro assays. The selected studies revealed that anthocyanins have anticancer potential by inhibiting cancer cell viability and proliferation, controlling cell cycle, and promoting apoptosis.,
TL;DR: In this paper , a review aims to consolidate the current evidence of SERPINA3 in various cancers, highlighting its association with the cancer hallmarks and ratifying its status as an emerging cancer biomarker.
Abstract: SERine Protease INhibitor clade A member 3 (SERPINA3), a member of the SERine-Protease INhibitor (SERPIN) superfamily, principally works as a protease inhibitor in maintaining cellular homeostasis. It is a matricellular acute-phase glycoprotein that appears to be the sole nuclear-binding secretory serpin. Several studies have emerged in recent years demonstrating its link to cancer and disease biology. SERPINA3 seems to have cancer- and compartment-specific biological functions, acting either as a tumour promoter or suppressor in different cancers. However, the localization, mechanism of action and the effectors of SERPINA3 in physiological and pathological scenarios remain obscure. Our review aims to consolidate the current evidence of SERPINA3 in various cancers, highlighting its association with the cancer hallmarks and ratifying its status as an emerging cancer biomarker. The elucidation of SERPINA3-mediated cancer progression and its targeting might shed light on the realm of cancer therapeutics.
TL;DR: In this paper , the authors summarize how albumin with unique properties affects chemotherapeutic drugs efficacy from the aspects of drug outcome in blood, toxicity, tumor accumulation and direct or indirect interactions with fatty acids, plus application of albuminbased carriers for anti-tumor drug delivery.
Abstract: Albumin, as the most abundant plasma protein, plays an integral role in the transport of a variety of exogenous and endogenous ligands in the bloodstream and extravascular spaces. For exogenous drugs, especially chemotherapeutic drugs, binding to and being delivered by albumin can significantly affect their efficacy. Meanwhile, albumin can also bind to many endogenous ligands, such as fatty acids, with important physiological significance that can affect tumor proliferation and metabolism. In this review, we summarize how albumin with unique properties affects chemotherapeutic drugs efficacy from the aspects of drug outcome in blood, toxicity, tumor accumulation and direct or indirect interactions with fatty acids, plus application of albumin-based carriers for anti-tumor drug delivery.
TL;DR: Pancreatic ductal metaplasia (PDM) is the transformation of potentially many type of cells in pancreas into ductal or ductal-like cells, which eventually replace the existing differentiated somatic cell type(s) as mentioned in this paper .
Abstract: Pancreatic ductal metaplasia (PDM) is the transformation of potentially many type of cells in pancreas into ductal or ductal-like cells, which eventually replace the existing differentiated somatic cell type(s). PDM is usually triggered by and manifests its ability to adapt to environmental and cellular stimuli and stresses. Acinar to ductal metaplasia (ADM) is the predominant form of ductal metaplasia in pancreas. The cellular heterogeneity of PDM informs the differences in cellular origin, triggering events, functional subpopulations and evolution pathways of PDM. Currently it remains uncertain what are the exact cellular origins and functional significance of PDM, and how this process is regulated at cellular and molecular levels. The development of PDM to atypical hyperplasia is an important risk factor for pancreatic precursors, including intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Otherwise, the cellular plasticity in PDM contribute to the regeneration of both exocrine and endocrine components of pancreas. This Review will systematically describe current knowledge on the understanding of PDM biology with an emphasis on its underlying mechanisms and implications in pancreatic regeneration, inflammation and tumorigenesis.
TL;DR: In this article , the involvement of p53 signaling reactivation in pancreatic cancer treatment as well as its underlying molecular mechanisms is discussed. But, the authors do not discuss the role of the p53 gene mutations or protein dysfunction in the occurrence, progression, invasion, and resistance to therapy, of malignancies.
Abstract: Globally, pancreatic cancer (PC) is a common and highly malignant gastrointestinal tumor that is characterized by an insidious onset and ready metastasis and recurrence. Over recent decades, the incidence of PC has been increasing on an annual basis; however, the pathogenesis of this condition remains enigmatic. PC is not sensitive to radio- or chemotherapy, and except for early surgical resection, there is no curative treatment regime; consequently, the prognosis for patients with PC is extremely poor. Transcription factor p53 is known to play key roles in many important biological processes in vertebrates, including normal cell growth, differentiation, cell cycle progression, senescence, apoptosis, metabolism, and DNA damage repair. However, there is a significant paucity of basic and clinical studies to describe how p53 gene mutations or protein dysfunction facilitate the occurrence, progression, invasion, and resistance to therapy, of malignancies, including PC. Herein, we describe the involvement of p53 signaling reactivation in PC treatment as well as its underlying molecular mechanisms, thereby providing useful insights for targeting p53-related signal pathways in PC therapy.
TL;DR: In this paper , the role of myoglobin in the regulation of cancer was discussed and potential roles and regulatory networks of MB in cancer in different tissues, beyond the muscle lineage, including cancers.
Abstract: Myoglobin (MB) belongs to the well-studied globin proteins superfamily. It has been extensively studied for its physiological roles in oxygen storage and transport for about a century now. However, the last two decades shed the light on unexpected aspects for MB research. Myoglobin has been suggested as a scavenger for nitric oxide and reactive oxygen species (ROS). Furthermore, MB was found to be expressed and regulated in different tissues, beyond the muscle lineage, including cancers. Current evidence suggest that MB is directly regulated by hypoxia and might be contributing to the metabolic rewiring in cancer tissues. In this article, we first discuss the MB physiological roles and then focus on the latter potential roles and regulatory networks of MB in cancer.
TL;DR: In this article , a review of clinical applications of CTCs in liquid biopsy-based personalized cancer treatment and critically appraised limitations in routine clinical practice on the path to precision medicine is presented.
Abstract: Ovarian cancer (OC) is the most lethal gynecologic malignance worldwide. Considering its metastasis nature, oncologists shift focus towards circulating tumor cells (CTCs), a progenitor that originates from primary tumor and undergoes morphologic/genetic alterations to enter bloodstream and invade nearby tissues. Mountains of evidence suggested that CTCs could provide deep insights into genomic, transcriptomic, and proteomic profiling of OC metastatic cascades. To pave the way for precision medicine, researchers exert great efforts to develop isolation/detection methodologies and construct CTCs-derived propagation platforms, including traditional cell cultures, patient-derived xenografts (PDXs), and organoids. From bench to bedside, CTCs provide minimally-invasive means to inform early diagnosis, predict prognosis, and guide treatment decisions. This review shined a spotlight on biology, detection technologies, and propagation platforms for CTCs. Of note, we also reviewed clinical applications of CTCs in liquid biopsy-based personalized cancer treatment and critically appraised limitations in routine clinical practice on the path to precision medicine.
TL;DR: In this article , the authors summarize physiological stress response pathways, like the HPA, SNS, and MGB axes, that modulate the release of stress hormones with potential carcinogenic properties, and discuss in detail the mechanisms behind these chronic stimulations contributing to the initiation and progression of cancer through direct regulation of cancer hallmarks-related signaling or indirect promotion of cancer risk factors.
Abstract: Psychological distress, such as chronic depression and anxiety, is a topical problem. In the context of cancer patients, prevalence rates of psychological distress are four-times higher than in the general population and often confer worse outcomes. In addition to evidence from epidemiological studies confirming the links between psychological distress and cancer progression, a growing body of cellular and molecular studies have also revealed the complex signaling networks which are modulated by psychological distress-derived chronic stress during cancer progression. In this review, aiming to uncover the intertwined networks of chronic stress-driven oncogenesis and progression, we summarize physiological stress response pathways, like the HPA, SNS, and MGB axes, that modulate the release of stress hormones with potential carcinogenic properties. Furthermore, we discuss in detail the mechanisms behind these chronic stimulations contributing to the initiation and progression of cancer through direct regulation of cancer hallmarks-related signaling or indirect promotion of cancer risk factors (including obesity, disordered circadian rhythms, and premature senescence), suggesting a novel research direction into cancer prevention and therapy on the basis of psychological interventions.
TL;DR: In this article , the authors describe the distinct roles of YAP and TAZ focusing particularly on cancer, and present a review of strategies targeting either YAP or TAZ proteins or only one of them.
Abstract: The transcriptional regulators YAP and TAZ are involved in numerous physiological processes including organ development, growth, immunity and tissue regeneration. YAP and TAZ dysregulation also contribute to tumorigenesis, thereby making them attractive cancer therapeutic targets. Arbitrarily, YAP and TAZ are often considered as a single protein, and are referred to as YAP/TAZ in most studies. However, increasing experimental evidences documented that YAP and TAZ perform both overlapping and distinct functions in several physiological and pathological processes. In addition to regulating distinct processes, YAP and TAZ are also regulated by distinct upstream cues. The aim of the review is to describe the distinct roles of YAP and TAZ focusing particularly on cancer. Therapeutic strategies targeting either YAP and TAZ proteins or only one of them should be carefully evaluated. Selective targeting of YAP or TAZ may in fact impair different pathways and determine diverse clinical outputs.
TL;DR: In this paper , the authors discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
Abstract: Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
TL;DR: In this article , the authors provide an overview of strategies employed in screening for E2-E3 interactions based on up-to-date studies focusing on the E2 and E3 interface motifs.
Abstract: The ubiquitin-proteasome system (UPS) modulates carcinogenesis through ubiquitination of cancer-related target proteins, leading to their degradation in the proteasome. This may deactivate tumor suppressors or activate tumor promoters- either way causing homeostatic imbalance. As major components of the UPS, the E2 and E3 enzymes are recognized as pivotal determinants of substrate recognition and ubiquitination. Identification of E2-E3 pairing selectivity is particularly pertinent to early diagnosis and potential development of targeted cancer therapeutics. This review is motivated by recent findings and new insights into the molecular dynamics of ubiquitination triggered by specific E2-E3 pairing, leading to cancer initiation and progression if cancer suppressors are degraded or cancer suppression (if cancer promoters are degraded), respectively. We provide an overview of strategies employed in screening for E2-E3 interactions based on up-to-date studies focusing on the E2-E3 interface motifs. Of considerable recent interest is how E2 and E3 might switch their functional partnerships via UBE2O, which suggests an emerging significance on how UBE2O might influence E2-E3 pairing. Thus, a reflection on the role of UBE2O is included. Finally, we deliberate on the rational and cautious development of anti-cancer cocktail drugs which specifically target E2-E3 interacting residues for precision in cancer-killing with minimal side-effects. To this end, a list of potential future research is proposed.
TL;DR: In this paper , a review of nanoparticles that have been used for the detection and treatment of cancer is presented, focusing on physicochemical properties and surface modifications that achieve efficient accumulation at tumor sites.
Abstract: Nanomaterials are at the forefront of health research and development. Among different nanomaterials, nanoparticles are especially promising for cancer theranostics. However, despite great potential, the clinical translation of nano-based applications continues to face obstacles. A major hurdle to the localized eradication of tumors is the efficient targeting of nanomaterials to the desired tissues and cells. In particular, nanoparticle properties and the route of administration impact the efficacy of precision nanomedicine. This review focuses on nanoparticles that have been produced for the detection and treatment of cancer. Common and tissue-specific barriers that limit the accumulation of nanoparticles in malignant tumors are discussed. The in-depth discussion focuses on the physicochemical properties of nanoparticles and the surface modifications that achieve efficient accumulation at tumor sites. Furthermore, limitations of current strategies and open questions are presented. The review concludes with an outlook on future directions and the trajectories that will drive the field forward to advance nano-oncology in the clinic.
TL;DR: In this paper , the authors discuss recent advances in CAR T cell therapy against solid tumors, with a focus on targeting the tumor vasculature, and discuss opportunities to overcome challenges and barriers through engineering of CAR T cells to enhance trafficking, safety and efficacy.
Abstract: For successful application of chimeric antigen receptor (CAR) T cell therapy in solid tumors, major hurdles have to be overcome. CAR T cells have to cross the vascular barrier, which is hampered by the anergic state of the tumor vasculature, characterized by suppressed levels of leukocyte adhesion molecules on the endothelium. Additional immunosuppressive mechanisms in the solid tumor microenvironment can affect infiltration, activity and persistence of CAR T cells. Redirecting CAR T cells towards the tumor vasculature poses a possible solution, as molecular targets of tumor endothelial cells can be directly engaged from within the blood. In this review, we discuss recent advances in CAR T cell therapy against solid tumors, with a focus on targeting the tumor vasculature. Furthermore, we discuss opportunities to overcome challenges and barriers through engineering of CAR T cells to enhance trafficking, safety and efficacy.