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Philosophical Transactions of the Royal... Feb 2019In tumour cells, macropinocytosis functions as an amino acid supply route and supports cancer cell survival and proliferation. Initially demonstrated in oncogenic... (Review)
Review
In tumour cells, macropinocytosis functions as an amino acid supply route and supports cancer cell survival and proliferation. Initially demonstrated in oncogenic KRAS-driven models of pancreatic cancer, macropinocytosis triggers the internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids. These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools, as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel amino acid supply route that tumour cells use to survive the nutrient-poor conditions of the tumour microenvironment. Macropinocytosis has also emerged as an entry mechanism for a variety of nanomedicines, suggesting that macropinocytosis regulation in the tumour setting can be harnessed for the delivery of anti-cancer therapeutics. A slew of recent studies point to the possibility that macropinocytosis is a pervasive feature of many different tumour types. In this review, we focus on the role of this important uptake mechanism in a variety of cancers and highlight the main molecular drivers of macropinocytosis in these malignancies. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Topics: Humans; Neoplasms; Pinocytosis; Tumor Microenvironment
PubMed: 30967003
DOI: 10.1098/rstb.2018.0153 -
Sub-cellular Biochemistry 2022The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions...
The distinct movements of macropinosome formation and maturation have corresponding biochemical activities which occur in a defined sequence of stages and transitions between those stages. Each stage in the process is regulated by variously phosphorylated derivatives of phosphatidylinositol (PtdIns) which reside in the cytoplasmic face of the membrane lipid bilayer. PtdIns derivatives phosphorylated at the 3' position of the inositol moiety, called 3' phosphoinositides (3'PIs), regulate different stages of the sequence. 3'PIs are synthesized by numerous phosphoinositide 3'-kinases (PI3K) and other lipid kinases and phosphatases, which are themselves regulated by small GTPases of the Ras superfamily. The combined actions of these enzymes localize four principal species of 3'PI to distinct domains of the plasma membrane or to discrete organelles, with distinct biochemical activities confined to those domains. Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P) and phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P) regulate the early stages of macropinosome formation, which include cell surface ruffling and constrictions of circular ruffles which close into macropinosomes. Phosphatidylinositol 3-phosphate (PtdIns3P) regulates macropinosome fusion with other macropinosomes and early endocytic organelles. Phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P) mediates macropinosome maturation and shrinkage, through loss of ions and water, and subsequent traffic to lysosomes. The different characteristic rates of macropinocytosis in different cell types indicate levels of regulation which may be governed by the cell's capacity to generate 3'PIs.
Topics: Cell Membrane; Endosomes; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Pinocytosis
PubMed: 35378706
DOI: 10.1007/978-3-030-94004-1_7 -
Endocrine-related Cancer Dec 2019Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves... (Review)
Review
Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.
Topics: Animals; Cancer-Associated Fibroblasts; Cell Differentiation; Chromatin; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms; Pinocytosis
PubMed: 31627186
DOI: 10.1530/ERC-19-0347 -
Cells Aug 2020Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and... (Review)
Review
Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules, and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; Antineoplastic Agents; Cell Proliferation; Humans; Molecular Targeted Therapy; Neoplasms; Oxidative Stress; Pinocytosis; Reactive Oxygen Species; Signal Transduction
PubMed: 32824193
DOI: 10.3390/cells9081904 -
Proceedings of the National Academy of... Dec 2021In fast-moving cells such as amoeba and immune cells, dendritic actin filaments are spatiotemporally regulated to shape large-scale plasma membrane protrusions. Despite...
In fast-moving cells such as amoeba and immune cells, dendritic actin filaments are spatiotemporally regulated to shape large-scale plasma membrane protrusions. Despite their importance in migration, as well as in particle and liquid ingestion, how their dynamics are affected by micrometer-scale features of the contact surface is still poorly understood. Here, through quantitative image analysis of on microfabricated surfaces, we show that there is a distinct mode of topographical guidance directed by the macropinocytic membrane cup. Unlike other topographical guidance known to date that depends on nanometer-scale curvature sensing protein or stress fibers, the macropinocytic membrane cup is driven by the Ras/PI3K/F-actin signaling patch and its dependency on the micrometer-scale topographical features, namely PI3K/F-actin-independent accumulation of Ras-GTP at the convex curved surface, PI3K-dependent patch propagation along the convex edge, and its actomyosin-dependent constriction at the concave edge. Mathematical model simulations demonstrate that the topographically dependent initiation, in combination with the mutually defining patch patterning and the membrane deformation, gives rise to the topographical guidance. Our results suggest that the macropinocytic cup is a self-enclosing structure that can support liquid ingestion by default; however, in the presence of structured surfaces, it is directed to faithfully trace bent and bifurcating ridges for particle ingestion and cell guidance.
Topics: Cell Membrane; Chemotaxis; Computer Simulation; Dictyostelium; Models, Biological; Movement; Phosphatidylinositol 3-Kinases; Pinocytosis; Signal Transduction
PubMed: 34876521
DOI: 10.1073/pnas.2110281118 -
Frontiers in Immunology 2021
Topics: Neoplasms; Phagocytes; Phagocytosis; Pinocytosis; Receptors, IgG
PubMed: 34630442
DOI: 10.3389/fimmu.2021.772256 -
Philosophical Transactions of the Royal... Feb 2019
Topics: Animals; Humans; Macrophages; Pinocytosis
PubMed: 30967000
DOI: 10.1098/rstb.2018.0146 -
ELife Feb 2020Transport of fluids, molecules, nutrients or nanoparticles through coral tissues are poorly documented. Here, we followed the flow of various tracers from the external...
Transport of fluids, molecules, nutrients or nanoparticles through coral tissues are poorly documented. Here, we followed the flow of various tracers from the external seawater to within the cells of all tissues in living animals. After entering the general coelenteric cavity, we show that nanoparticles disperse throughout the tissues via the paracellular pathway. Then, the ubiquitous entry gate to within the cells' cytoplasm is macropinocytosis. Most cells form large vesicles of 350-600 nm in diameter at their apical side, continuously internalizing their surrounding medium. Macropinocytosis was confirmed using specific inhibitors of PI3K and actin polymerization. Nanoparticle internalization dynamics is size dependent and differs between tissues. Furthermore, we reveal that macropinocytosis is likely a major endocytic pathway in other anthozoan species. The fact that nearly all cells of an animal are continuously soaking in the environment challenges many aspects of the classical physiology viewpoints acquired from the study of bilaterians.
Topics: Actins; Animals; Anthozoa; Cytoplasm; Dextrans; Diffusion; Models, Biological; Nanoparticles; Pinocytosis
PubMed: 32039759
DOI: 10.7554/eLife.50022 -
The Journal of Biological Chemistry Nov 2019How cells utilize nutrients to produce the ATP needed for bioenergetic homeostasis has been well-characterized. What is less well-studied is how resting cells... (Review)
Review
How cells utilize nutrients to produce the ATP needed for bioenergetic homeostasis has been well-characterized. What is less well-studied is how resting cells metabolically shift from an ATP-producing catabolic metabolism to a metabolism that supports anabolic growth. In metazoan organisms, the discovery of growth factors and the ability of their receptors to induce new transcription and translation led to the hypothesis that the bioenergetic and synthetic demands of cell growth were primarily met through the replacement of nutrients consumed during net macromolecular synthesis, a demand-based system of nutrient uptake. Recent data have challenged this hypothesis. Instead, there is increasing evidence that cellular nutrient uptake is a push system. Growth factor signaling has been linked to direct stimulation of nutrient uptake. The ability of growth factor signaling to increase the uptake of glucose, lipids, and amino acids to levels that exceed a cell's bioenergetic and synthetic needs has been documented in a wide variety of settings. In some tissues, this leads to the storage of the excess nutrients in the form of glycogen or fat. In others, the excess is secreted as lactate and certain nonessential amino acids. When growth factor signaling stimulates nutrient uptake to levels that exceed a cell's bioenergetic needs, adaptive changes in intermediate metabolism lead to the production of anabolic precursors that fuel the net synthesis of protein, lipids, and nucleic acids. Through the increased production of these precursors, growth factor signaling provides a supply-side stimulation of cell growth and proliferation.
Topics: Animals; Cell Cycle; Glycolysis; Homeostasis; Humans; Intercellular Signaling Peptides and Proteins; Nutrients; Pinocytosis
PubMed: 31628187
DOI: 10.1074/jbc.AW119.008146 -
Cellular and Molecular Life Sciences :... Oct 2010The cardiovascular system developed early in evolution and is pivotal for the transport of oxygen, nutrients, and waste products within the organism. It is composed of... (Review)
Review
The cardiovascular system developed early in evolution and is pivotal for the transport of oxygen, nutrients, and waste products within the organism. It is composed of hollow tubular structures and has a high level of complexity in vertebrates. This complexity is, at least in part, due to the endothelial cell lining of vertebrate blood vessels. However, vascular lumen formation by endothelial cells is still controversially discussed. For example, it has been suggested that the lumen mainly forms via coalescence of large intracellular vacuoles generated by pinocytosis. Alternatively, it was proposed that the vascular lumen initiates extracellularly between adjacent apical endothelial cell surfaces. Here we discuss invertebrate and vertebrate cardiovascular lumen formation and highlight the possible modes of blood vessel formation. Finally, we point to the importance of a better understanding of vascular lumen formation for treating human pathologies, including cancer and coronary heart disease.
Topics: Animals; Blood Vessels; Cardiovascular System; Endothelial Cells; Extracellular Space; Humans; Invertebrates; Morphogenesis; Neoplasms; Pinocytosis; Vacuoles; Vertebrates
PubMed: 20490602
DOI: 10.1007/s00018-010-0400-0