Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, ...tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Here, we present a review of recent discoveries in the field of platelet biology and the role of platelets in cancer progression as well as challenges in targeting platelets for cancer treatment.
Besides their function in limiting blood loss and promoting wound healing, experimental evidence has highlighted platelets as active players in all steps of tumorigenesis including tumor growth, tumor cell extravasation, and metastasis. Additionally, thrombocytosis in cancer patients is associated with adverse patient survival. Due to the secretion of large amounts of microparticles and exosomes, platelets are well positioned to coordinate both local and distant tumor-host crosstalk. Here, we present a review of recent discoveries in the field of platelet biology and the role of platelets in cancer progression as well as challenges in targeting platelets for cancer treatment.
miRNAs are a key component of the noncoding RNA family. The underlying mechanisms involved in the interplay between the tumor microenvironment and cancer cells involve highly dynamic factors such as ...hypoxia and cell types such as cancer-associated fibroblasts and macrophages. Although miRNA levels are known to be altered in cancer cells, recent evidence suggests a critical role for the tumor microenvironment in regulating miRNA biogenesis, methylation, and transcriptional changes. Here, we discuss the complex protumorigenic symbiotic role between tumor cells, the tumor microenvironment, and miRNA deregulation.
miRNAs play a central role in cell signaling and homeostasis. In this article, we provide insights into the regulatory mechanisms involved in the deregulation of miRNAs in cancer cells and the tumor microenvironment and discuss therapeutic intervention strategies to overcome this deregulation.
Beta-adrenergic signaling has been found to regulate multiple cellular processes that contribute to the initiation and progression of cancer, including inflammation, angiogenesis, apoptosis/anoikis, ...cell motility and trafficking, activation of tumor-associated viruses, DNA damage repair, cellular immune response, and epithelial-mesenchymal transition. In several experimental cancer models, activation of the sympathetic nervous system promotes the metastasis of solid epithelial tumors and the dissemination of hematopoietic malignancies via β-adrenoreceptor-mediated activation of protein kinase A and exchange protein activated by adenylyl cyclase signaling pathways. Within the tumor microenvironment, β-adrenergic receptors on tumor and stromal cells are activated by catecholamines from local sympathetic nerve fibers (norepinephrine) and circulating blood (epinephrine). Tumor-associated macrophages are emerging as key targets of β-adrenergic regulation in several cancer contexts. Sympathetic nervous system regulation of cancer cell biology and the tumor microenvironment has clarified the molecular basis for long-suspected relationships between stress and cancer progression, and now suggests a highly leveraged target for therapeutic intervention. Epidemiologic studies have linked the use of β-blockers to reduced rates of progression for several solid tumors, and preclinical pharmacologic and biomarker studies are now laying the groundwork for translation of β-blockade as a novel adjuvant to existing therapeutic strategies in clinical oncology.
Circular RNAs in Cancer Bach, Duc-Hiep; Lee, Sang Kook; Sood, Anil K.
Molecular therapy. Nucleic acids,
06/2019, Letnik:
16
Journal Article
Recenzirano
Odprti dostop
Circular RNAs (circRNAs) are a class of single-stranded closed RNA molecules that are formed by precursor mRNA back-splicing or skipping events of thousands of genes in eukaryotes as covalently ...closed continuous loops. High-throughput sequencing and bioinformatics approaches have uncovered the broad expression of circRNAs across species. Their high stability, abundance, and evolutionary conservation among species points to their distinct properties and diverse cellular functions as efficient microRNAs and protein sponges; they also play important roles in modulating transcription and splicing. Additionally, most circRNAs are aberrantly expressed in pathological conditions and in a tissue-specific manner such as development and progression of cancer. Herein, we highlight the characteristics, functions, and mechanisms of action of circRNAs in cancer; we also provide an overview of recent progress in the circRNA field and future application of circRNAs as cancer biomarkers and novel therapeutic targets.
Translation of nanoparticles (NPs) into clinical practice has been limited by toxic effects induced by nonspecific accumulation of NPs in healthy organs after systemic administration. The ideal NPs ...should accumulate in the target site, carry out their function, and then ultimately be eliminated from the body. Here, we show a single-compartment, multifunctional ultrasmall copper sulfide nanodot (CuS ND) that is rapidly cleared from the body. These CuS NDs have a hydrodynamic diameter of <6 nm, can efficiently absorb near-infrared light for photothermal ablation therapy, and stably incorporate the copper-64 radioisotope for noninvasive positron emission tomography (PET). Importantly, ∼95% of CuS NDs are excreted intact through the renal–urinary system within 24 h with minimal retention in the liver and the spleen. The ultrasmall CuS NDs accumulate in 4T1 tumors in Balb/c mice, as monitored by PET imaging, and mediate tumor ablation when combined with near-infrared light irradiation. As a first example of PET-visible, renal-clearable inorganic nanomaterials with peak absorption in the near-infrared region, CuS NDs represent a robust platform for cancer imaging and therapy.
Small interfering RNAs (siRNA) have recently emerged as a new class of therapeutics with a great potential to revolutionize the treatment of cancer and other diseases. A specifically designed siRNA ...binds and induces post-transcriptional silencing of target genes (mRNA). Clinical applications of siRNA-based therapeutics have been limited by their rapid degradation, poor cellular uptake, and rapid renal clearance following systemic administration. A variety of synthetic and natural nanoparticles composed of lipids, polymers, and metals have been developed for siRNA delivery, with different efficacy and safety profiles. Liposomal nanoparticles have proven effective in delivering siRNA into tumor tissues by improving stability and bioavailability. While providing high transfection efficiency and a capacity to form complexes with negatively charged siRNA, cationic lipids/liposomes are highly toxic. Negatively charged liposomes, on the other hand, are rapidly cleared from circulation. To overcome these problems we developed highly safe and effective neutral lipid-based nanoliposomes that provide robust gene silencing in tumors following systemic (intravenous) administration. This delivery system demonstrated remarkable antitumor efficacy in various orthotopic human cancer models in animals. Here, we briefly overview this and other lipid-based approaches with preclinical applications in different tumor models for cancer therapy and potential applications as siRNA-nanotherapeutics in human cancers.
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Sequencing technology has facilitated a new era of cancer research, especially in cancer genomics. Using next-generation sequencing, thousands of long noncoding RNAs (lncRNAs) have been identified as ...abnormally altered in the cancer genome or differentially expressed in tumor tissues. These lncRNAs are associated with imbalanced gene regulation and aberrant biological processes that contribute to malignant transformation. The functions and therapeutic potential of cancer-related lncRNAs have attracted considerable interest in the past few years. Although few lncRNAs have been well-characterized, researchers have recently made impressive progress in understanding lncRNAs and their novel functions, such as regulation of gene expression, metabolism and DNA repair. These latest findings reinforce the crucial roles of lncRNAs in cancer initiation and development, as well as their possible clinical applications.
The discovery of RNA interference, first in plants and Caenorhabditis elegans and later in mammalian cells, led to the emergence of a transformative view in biomedical research. Knowledge of the ...multiple actions of non-coding RNAs has truly allowed viewing DNA, RNA and proteins in novel ways. Small interfering RNAs (siRNAs) can be used as tools to study single gene function both in vitro and in vivo and are an attractive new class of therapeutics, especially against undruggable targets for the treatment of cancer and other diseases. Despite the potential of siRNAs in cancer therapy, many challenges remain, including rapid degradation, poor cellular uptake and off-target effects. Rational design strategies, selection algorithms, chemical modifications and nanocarriers offer significant opportunities to overcome these challenges. Here, we review the development of siRNAs as therapeutic agents from early design to clinical trial, with special emphasis on the development of EphA2-targeting siRNAs for ovarian cancer treatment.
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To understand how malignant tumors develop, we tracked cell membrane, nuclear membrane, spindle, and cell cycle dynamics in polyploid giant cancer cells (PGCCs) during the formation of high-grade ...serous carcinoma organoids using long-term time-lapse imaging. Single cells underwent traditional mitosis to generate tissue with uniform nuclear size, while others formed PGCCs via asymmetric mitosis, endoreplication, multipolar endomitosis, nuclear fusion, and karyokinesis without cytokinesis. PGCCs underwent restitution multipolar endomitosis, nuclear fragmentation, and micronuclei formation to increase nuclear contents and heterogeneity. At the cellular level, the development of PGCCs was associated with forming transient intracellular cells, termed fecundity cells. The fecundity cells can be decellularized to facilitate nuclear fusion and synchronized with other nuclei for subsequent nuclear replication. PGCCs can undergo several rounds of entosis to form complex tissue structures, termed fecundity structures. The formation of PGCCs via multiple modes of nuclear replication in the absence of cytokinesis leads to an increase in the nuclear-to-cytoplasmic (N/C) ratio and intracellular cell reproduction, which is remarkably similar to the mode of nuclear division during pre-embryogenesis. Our data support that PGCCs may represent a central regulator in malignant histogenesis, intratumoral heterogeneity, immune escape, and macroevolution via the de-repression of suppressed pre-embryogenic program in somatic cells.
Reactive stromal cells are an integral part of tumor microenvironment (TME) and interact with cancer cells to regulate their growth. Although targeting stromal cells could be a viable therapy to ...regulate the communication between TME and cancer cells, identification of stromal targets that make cancer cells vulnerable has remained challenging and elusive. Here, we identify a previously unrecognized mechanism whereby metabolism of reactive stromal cells is reprogrammed through an upregulated glutamine anabolic pathway. This dysfunctional stromal metabolism confers atypical metabolic flexibility and adaptive mechanisms in stromal cells, allowing them to harness carbon and nitrogen from noncanonical sources to synthesize glutamine in nutrient-deprived conditions existing in TME. Using an orthotopic mouse model for ovarian carcinoma, we find that co-targeting glutamine synthetase in stroma and glutaminase in cancer cells reduces tumor weight, nodules, and metastasis. We present a synthetic lethal approach to target tumor stroma and cancer cells simultaneously for desirable therapeutic outcomes.
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•CAFs have an upregulated glutamine anabolic pathway compared to NOFs•CAFs harness atypical carbon and nitrogen sources for glutamine synthesis•Crosstalk between stromal-epithelial cells augments dysregulated metabolism in CAFs•Targeting stromal GS in an orthotopic ovarian cancer model induces tumor regression
Yang et al. reveal that cancer-associated fibroblasts boost glutamine production by harnessing carbon and nitrogen from atypical nutrient sources to maintain cancer cell growth when glutamine is scarce. Co-targeting stromal glutamine synthetase and cancer cell glutaminase disrupts this metabolic crosstalk, inducing tumor regression in an ovarian carcinoma mouse model.
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