Showing papers in "Trends in cancer in 2020"

Turning Cold into Hot: Firing up the Tumor Microenvironment.

Abstract: Cancers develop within complex tissue environments consisting of diverse innate and adaptive immune cells, along with stromal cells, vascular networks, and many other cellular and noncellular components. The high heterogeneity within the tumor microenvironment (TME) remains a key obstacle in understanding and treating cancer. Understanding the dynamic functional interplay within this intricate ecosystem will provide important insights into the design of effective combinatorial strategies against cancer. Here, we present recent technical advances to explore the complexity of the TME. Then, we discuss how innate immune sensing machinery, genetic alterations of oncogenic signaling, cellular metabolism, and epigenetic factors are involved in modulating the TME. Finally, we summarize the potential strategies to boost antitumor immunity by therapeutically exploiting the TME.

Circular RNAs in Cancer: Biogenesis, Function, and Clinical Significance.

Abstract: Circular RNA (circRNA) is a class of single-stranded molecules with tissue/development-specific expression patterns. Unlike linear RNA, circRNA forms a covalently closed loop produced from 'back-splicing' of primary transcripts, conferring on them inherent resistance to exonucleolytic RNA decay. Increasing evidence demonstrates that many circRNAs exert important biological functions by acting as miRNA inhibitors ('sponges'), protein 'decoys', or by encoding small peptides. Importantly, circRNAs are aberrantly expressed in cancer and play indispensable oncogenic or tumor suppressive roles during tumor development and progression. In this review, we summarize the biogenesis, turnover, and involvements of circRNAs in cancer and also discuss their potential as diagnostic biomarkers or therapeutic targets.

Senescent Cells in Cancer Therapy: Friends or Foes?

Abstract: Several cancer interventions induce DNA damage and promote senescence in cancer and nonmalignant cells. Senescent cells secrete a collection of proinflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). SASP factors are able to potentiate various aspects of tumorigenesis, including proliferation, metastasis, and immunosuppression. Moreover, the accumulation and persistence of therapy-induced senescent cells can promote tissue dysfunction and the early onset of various age-related symptoms in treated cancer patients. Here, we review in detail the mechanisms by which cellular senescence contributes to cancer development and the side effects of cancer therapies. We also review how pharmacological interventions to eliminate senescent cells or inhibit SASP production can mitigate these negative effects and propose therapeutic strategies based on the age of the patient.

Glioblastoma Stem Cells: Driving Resilience through Chaos.

Abstract: Glioblastoma is an aggressive and heterogeneous tumor in which glioblastoma stem cells (GSCs) are at the apex of an entropic hierarchy and impart devastating therapy resistance. The high entropy of GSCs is driven by a permissive epigenetic landscape and a mutational landscape that revokes crucial cellular checkpoints. The GSC population encompasses a complex array of diverse microstates that are defined and maintained by a wide variety of attractors including the complex tumor ecosystem and therapeutic intervention. Constant dynamic transcriptional fluctuations result in a highly adaptable and heterogeneous entity primed for therapy evasion and survival. Analyzing the transcriptional, epigenetic, and metabolic landscapes of GSC dynamics in the context of a stochastically fluctuating tumor network will provide novel strategies to target resistant populations of GSCs in glioblastoma.

The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View

Abstract: The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach.

Exosomes as a Multicomponent Biomarker Platform in Cancer.

Abstract: Cancer is a complex disease that is associated with genetic aberrations and subsequent cellular and noncellular host responses. Tumors harbor diverse cell types that engage in a dynamic interplay to sustain cancer-specific signaling networks. A component of such cellular communication is the production and exchange of various types of extracellular vesicle (EV). Exosomes are small EVs with growing recognition for their role in cancer progression and resistance to therapy. The unique biogenesis of exosomes, their ubiquitous production by all cell types, and their biological features in liquid biopsies have generated excitement for their potential as cancer biomarkers. Here, we discuss the challenges and utility of exosomes as multiparameter biomarker platforms for the detection of cancer. Exosomes reflect heterogeneous biological changes associated with growing tumors, potentially offering a more comprehensive assessment of cancer diagnosis, prognosis, and progression.

Cancer Epigenetics, Tumor Immunity, and Immunotherapy

Abstract: Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and chromatin structure regulation, are critical for the interactions between tumor and immune cells. Emerging evidence shows that tumors commonly hijack various epigenetic mechanisms to escape immune restriction. As a result, the pharmaceutical modulation of epigenetic regulators, including 'writers', 'readers', 'erasers', and 'remodelers', is able to normalize the impaired immunosurveillance and/or trigger antitumor immune responses. Thus, epigenetic targeting agents are attractive immunomodulatory drugs and will have major impacts on immuno-oncology. Here, we discuss epigenetic regulators of the cancer-immunity cycle and current advances in developing epigenetic therapies to boost anticancer immune responses, either alone or in combination with current immunotherapies.

Targeting Glycosylation: A New Road for Cancer Drug Discovery

Abstract: Cancer is a deadly disease that encompasses numerous cellular modifications. Among them, alterations in glycosylation are a proven reliable hallmark of cancer, with most biomarkers used in the clinic detecting cancer-associated glycans. Despite their clear potential as therapy targets, glycans have been overlooked in drug discovery strategies. The complexity associated with the glycosylation process, and lack of specific methodologies to study it, have long hampered progress. However, recent advances in new methodologies, such as glycoengineering of cells and high-throughput screening (HTS), have opened new avenues of discovery. We envision that glycan-based targeting has the potential to start a new era of cancer therapy. In this article, we discuss the promise of cancer-associated glycosylation for the discovery of effective cancer drugs.

Emerging Mechanisms by which EMT Programs Control Stemness.

Abstract: Tissue regeneration relies on adult stem cells (SCs) that possess the ability to self-renew and produce differentiating progeny. In an analogous manner, the development of certain cancers depends on a subset of tumor cells, called cancer stem cells (CSCs), with SC-like properties. In addition to being responsible for tumorigenesis, CSCs exhibit elevated resistance to therapy and thus drive tumor relapse post-treatment. The epithelial–mesenchymal transition (EMT) programs promote SC and CSC stemness in many epithelial tissues. Here, we provide an overview of the mechanisms underlying the relationship between stemness and EMT programs, which may represent therapeutic vulnerabilities for the treatment of cancers.

Clinical Development of BRAF plus MEK Inhibitor Combinations.

Abstract: Genomic profiling shows that many solid tumors are characterized by specific driver aberrations, and this has expanded the therapeutic options for many patients. The mitogen-activated protein kinase (MAPK) pathway is a key cell signaling pathway involved in regulating cellular growth, proliferation, and survival. Driver mutations in the BRAF gene, a key player in the MAPK pathway, are described in multiple tumor types, including subsets of melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC), making BRAF a desirable target for inhibition. BRAF inhibitors have shown efficacy in several cancers; however, most patients eventually develop resistance. To delay or prevent resistance, combination therapy targeting BRAF and MEK, a downstream signaling target of BRAF in the MAPK pathway, was evaluated and demonstrated synergistic benefit. BRAF and MEK inhibitor combinations have been approved for use in various cancers by the US FDA. We review the clinical data for various BRAF plus MEK combination regimens in three cancer types with underlying BRAF driver mutations: melanoma, NSCLC, and ATC. We also discuss practical treatment considerations and management of selected combination therapy toxicities.

Targeting EMT in Cancer with Repurposed Metabolic Inhibitors

Abstract: Epithelial-to-mesenchymal transition (EMT) determines the most lethal features of cancer, metastasis formation and chemoresistance, and therefore represents an attractive target in oncology. However, direct targeting of EMT effector molecules is, in most cases, pharmacologically challenging. Since emerging research has highlighted the distinct metabolic circuits involved in EMT, we propose the use of metabolism-specific inhibitors, FDA approved or under clinical trials, as a drug repurposing approach to target EMT in cancer. Metabolism-inhibiting drugs could be coupled with standard chemo- or immunotherapy to combat EMT-driven resistant and aggressive cancers.

RNA Splicing and Cancer.

Abstract: RNA splicing is an essential process that governs many aspects of cellular proliferation, survival, and differentiation. Considering the importance of RNA splicing in gene regulation, alterations in this pathway have been implicated in many human cancers. Large-scale genomic studies have uncovered a spectrum of splicing machinery mutations that contribute to tumorigenesis. Moreover, cancer cells are capable of hijacking the expression of RNA-binding proteins (RBPs), leading to dysfunctional gene splicing and tumor-specific dependencies. Advances in next-generation RNA sequencing have revealed tumor-specific isoforms associated with these alterations, including the presence of neoantigens, which serve as potential immunotherapeutic targets. In this review, we discuss the various mechanisms by which cancer cells exploit RNA splicing to promote tumor growth and the current therapeutic landscape for splicing-based therapies.

Tumor Functional Heterogeneity Unraveled by scRNA-seq Technologies.

Abstract: Effective cancer treatment has been precluded by the presence of various forms of intratumoral complexity that drive treatment resistance and metastasis. Recent single-cell sequencing technologies are significantly facilitating the characterization of tumor internal architecture during disease progression. New applications and advances occurring at a fast pace predict an imminent broad application of these technologies in many research areas. As occurred with next-generation sequencing (NGS) technologies, once applied to clinical samples across tumor types, single-cell sequencing technologies could trigger an exponential increase in knowledge of the molecular pathways involved in cancer progression and contribute to the improvement of cancer treatment.

Promoter DNA Hypermethylation and Paradoxical Gene Activation

Abstract: DNA methylation is a stable epigenetic modification that contributes to the spatiotemporal regulation of gene expression. The manner in which DNA methylation contributes to transcriptional control is dependent on the biological context, including physiological state and the properties of the DNA itself. Classically, dense promoter DNA methylation is associated with transcriptional repression. However, growing evidence suggests that this association may not always hold true, and promoter hypermethylation now also appears to be associated with high transcriptional activity. Furthermore, in a selection of contexts, increasing levels of promoter methylation correlate directly with increased gene expression. These findings postulate a context-dependent model whereby epigenetic contributions to transcriptional regulation occur in a more complex and dynamic manner. We present current evidence documenting promoter hypermethylation and high levels of gene expression, offer insights into the possible mechanisms by which this occurs, and discuss the potential implications for both research and clinical applications.

Tumour Cell Secretome in Chemoresistance and Tumour Recurrence

Abstract: Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.

The Influence of Lung Microbiota on Lung Carcinogenesis, Immunity, and Immunotherapy

Abstract: Microbiota have emerged as key modulators of both the carcinogenic process and the immune response against cancer cells, and, thus, it seems to influence the efficacy of immunotherapy. While most studies have focused on analyzing the influence of gut microbiota, its composition substantially differs from that in the lung. Here, we describe how microbial life in the lungs is associated with host immune status in the lungs and, thus, how the identification of the microbial populations in the lower respiratory tract rather than in the gut might be key to understanding the lung carcinogenic process and to predict the efficacy of different treatments. Understanding the influence of lung microbiota on host immunity may identify new therapeutic targets and help to design new immunotherapy approaches to treat lung cancer.

MGMT Status as a Clinical Biomarker in Glioblastoma.

Abstract: Glioblastoma is the most common primary malignant brain tumor. Although current standard therapy extends median survival to ~15 months, most patients do not have a sustained response to treatment. While O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) promoter methylation status is accepted as a prognostic and promising predictive biomarker in glioblastoma, its value in informing treatment decisions for glioblastoma patients remains debatable. Discrepancies between MGMT promoter methylation status and treatment response in some patients may stem from inconsistencies between MGMT methylation and expression levels in glioblastoma. Here, we discuss MGMT as a biomarker and elucidate the discordance between MGMT methylation, expression, and patient outcome, which currently challenges the implementation of this biomarker in clinical practice.

Advanced Prostate Cancer: Treatment Advances and Future Directions

Abstract: Prostate cancer affects one in every nine men in the USA and is the second leading cause of cancer-related death. The treatment landscape of advanced prostate cancer is changing rapidly. Multiple agents including abiraterone, enzalutamide, apalutamide, darolutamide, docetaxel, cabazitaxel, radium-223, and sipuleucel-T have been approved for advanced prostate cancer. Appropriate drug selection remains crucial in this evolving landscape to derive maximum benefit for the patients. We summarize clinical trials leading to recent drug approvals and discuss optimal treatment selection. We also review recent advances in genomics including its evolving role in prognosis, in elucidating mechanisms of treatment resistance, and in guiding treatment decisions.

Immune Cell-Derived Exosomes in the Cancer-Immunity Cycle.

Abstract: Cells can communicate through extracellular vesicle (EV) secretion and uptake. Exosomes are lipid bilayer-enclosed EVs of 30–150 nm in diameter, which can transfer RNA, functional proteins, lipids, and metabolites to recipient cells in vivo. Most cell types, including immune cells, can secrete and uptake exosomes. Biogenesis, secretion, and uptake of immune cell-derived exosomes are regulated by intracellular proteins and extracellular stimuli. Immune cell-derived exosomes can mediate crosstalk between innate and adaptive immunity and regulate cancer progression and metastasis. The dichotomous roles of immune cell-derived exosomes towards tumor cells can induce suppressive or active immune responses. Hence, immune cell-secreted exosomes may have applications in cancer diagnosis and immunotherapy and could potentially be developed for vaccination and chemotherapy drug transportation.

Tumor Plasticity and Resistance to Immunotherapy.

Abstract: Tumor cell plasticity exhibited as an epithelial–mesenchymal transition (EMT) has been identified as a major obstacle for the effective treatment of many cancers. This process, which involves the dedifferentiation of epithelial tumor cells towards a motile, metastatic, and mesenchymal tumor phenotype, mediates resistance to conventional therapies and small-molecule targeted therapies. In this review, we highlight current research correlating the role of tumor plasticity with resistance to current immunotherapy approaches and discuss future and ongoing combination immunotherapy strategies to reduce tumor cell plasticity-driven resistance in cancer.

Molecular Tumor Boards in Clinical Practice.

Abstract: Next-generation sequencing (NGS) application in clinical practice requires the implementation of molecular tumor boards (MTBs). Starting from a systematic review of literature, we discuss the MTB-related key points: MTB aims and composition, types of tumors to discuss, types of molecular analyses, methods for classifying actionability, appropriate turnaround time, and cost management.

Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?

Abstract: Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed 'hyperprogressive disease' (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy.

Abstract: The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited durable success in clinical cases despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy. In this Opinion article, we discuss our claim that endogenous tumor exosomal PD-L1 and tumor-derived exosome-induced PD-L1 are two of the most notable mechanisms of exosome-mediated resistance against antitumor immunity and we discuss how this resistance could directly influence immune checkpoint therapy failure.

Mutant p53 on the Path to Metastasis.

Abstract: Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.

Metabolic Fitness and Plasticity in Cancer Progression

Abstract: Cancer cells have enhanced metabolic needs due to their rapid proliferation. Moreover, throughout their progression from tumor precursors to metastases, cancer cells face challenging physiological conditions, including hypoxia, low nutrient availability, and exposure to therapeutic drugs. The ability of cancer cells to tailor their metabolic activities to support their energy demand and biosynthetic needs throughout disease progression is key for their survival. Here, we review the metabolic adaptations of cancer cells, from primary tumors to therapy resistant cancers, and the mechanisms underpinning their metabolic plasticity. We also discuss the metabolic coupling that can develop between tumors and the tumor microenvironment. Finally, we consider potential metabolic interventions that could be used in combination with standard therapeutic approaches to improve clinical outcome.

TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines.

Abstract: TP53 is the most frequently mutated gene in breast cancer, but its role in survival is confounded by different studies concluding that TP53 mutations are associated with negative, neutral, or positive outcomes. Closer examination showed that many studies were limited by factors such as imprecise methods to detect TP53 mutations and small cohorts that combined patients treated with drugs having very different mechanisms of action. When only studies of patients receiving the same treatment(s) were compared, they tended to agree. These analyses reveal a role for TP53 in response to different treatments as complex as its different biological activities. We discuss studies that have assessed the role of TP53 mutations in breast cancer treatment and limitations in interpreting reported results.

Zebrafish Xenografts for Drug Discovery and Personalized Medicine.

Abstract: Cancer is the second leading cause of death in the world. Given that cancer is a highly individualized disease, predicting the best chemotherapeutic treatment for individual patients can be difficult. Ex vivo models such as mouse patient-derived xenografts (PDX) and organoids are being developed to predict patient-specific chemosensitivity profiles before treatment in the clinic. Although promising, these models have significant disadvantages including long growth times that introduce genetic and epigenetic changes to the tumor. The zebrafish xenograft assay is ideal for personalized medicine. Imaging of the small, transparent fry is unparalleled among vertebrate organisms. In addition, the speed (5–7 days) and small patient tissue requirements (100–200 cells per animal) are unique features of the zebrafish xenograft model that enable patient-specific chemosensitivity analyses.

TRAIL of Hope Meeting Resistance in Cancer.

Abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis selectively via its interaction with the death receptors TRAILR1/DR4 and TRAILR2/DR5 in a wide range of cancers, while sparing normal cells. Despite its tremendous potential for cancer therapeutics, the translation of TRAIL into the clinic has been confounded by TRAIL-resistant cancer populations. We discuss different molecular mechanisms underlying TRAIL-mediated apoptosis and resistance to TRAIL. We also discuss the successes and failures of recent preclinical and clinical studies of TRAIL-induced apoptosis, and current attempts to overcome TRAIL resistance, and we provide a perspective for improving the prospects of future clinical implementation.

Tunneling Nanotubes: The Fuel of Tumor Progression?

Abstract: Tunneling nanotubes (TNTs) are thin membrane tubes connecting remote cells and allowing the transfer of cellular content. TNTs have been reported in several cancer in vitro, ex vivo, and in vivo models. Cancer cells exploit TNT-like connections to exchange material between themselves or with the tumoral microenvironment. Cells acquire new abilities (e.g., enhanced metabolic plasticity, migratory phenotypes, angiogenic ability, and therapy resistance) via these exchanges, contributing to cancer aggressiveness. Here, we review the morphological and functional features of TNT-like structures and their impact on cancer progression and resistance to therapies. Finally, we discuss the case of glioblastoma (GBM), in which a functional and resistant network between cancer cells in an in vivo model has been described for the first time.

Diagnostic Power of DNA Methylation Classifiers for Early Detection of Cancer

Abstract: DNA methylation-based epigenetic signatures have become valuable cancer biomarkers. We highlight the advantages of liquid biopsy based DNA-methylation profiling for noninvasive diagnosis of early stage cancers and discuss the advanced analytical approaches developed by commercial and academic partnerships.