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Exosome-orchestrated hypoxic tumor microenvironment. ​

Literature Information ​

DOI10.1186/s12943-019-0982-6
PMID30925935
JournalMolecular cancer
Impact Factor33.9
JCR QuartileQ1
Publication Year2019
Times Cited158
KeywordsExosome, Extracellular vesicle, Hypoxia, Non-coding RNA, Tumor microenvironment
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1476-4598
Pages57
Issue18(1)
AuthorsWanrong Meng, Yaying Hao, Chuanshi He, Ling Li, Guiquan Zhu

TL;DR ​

This review highlights the critical role of exosomes in the hypoxic tumor microenvironment, where their interactions between cancer and stromal cells contribute to tumor aggressiveness and treatment resistance. By facilitating multi-directional signaling, exosomes aid in hypoxia adaptation and the remodeling of the tumor microenvironment, emphasizing their potential as targets for therapeutic intervention.

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Exosome · Extracellular vesicle · Hypoxia · Non-coding RNA · Tumor microenvironment

Abstract ​

Hypoxic tumor microenvironment is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. A continuous interference between cancer cells and stromal cells within the hypoxic microenvironment has been uncovered for its importance in cancer development and treatment responsiveness. Exosomes, initially considered as "garbage bins" for unwanted material from cells, are now elucidated to perform a variety of functions that involve interactions within the cellular microenvironment due to their ability to carry numerous cargoes, including lipids, proteins, nucleic acids, and metabolites. Exosome-mediated continuous interference between cancer cells and stroma are believed to regulate hypoxia-adaptation and to rebuild the microenvironment in return. In this review, we will discuss the knowledge in literature with respect to the exosome-mediated multi-directional and mutual signal transmission among the variety of cell types within hypoxic cancer microenvironment.

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Primary Questions Addressed ​

  1. How do exosomes contribute to the communication between cancer cells and stromal cells in a hypoxic tumor microenvironment?
  2. What specific cargoes carried by exosomes are most influential in mediating hypoxia-adaptation in cancer cells?
  3. In what ways can targeting exosome signaling pathways improve treatment outcomes for patients with solid tumors in hypoxic conditions?
  4. How does the composition of exosomes change in response to different levels of hypoxia within the tumor microenvironment?
  5. What are the potential therapeutic applications of manipulating exosome interactions in the context of hypoxic tumors?

Key Findings ​

Background and Objectives ​

The review by Meng et al. (2019) focuses on the role of the hypoxic tumor microenvironment (TME) in cancer progression and treatment resistance. It highlights how exosomes, which were previously thought to be mere cellular waste, are now recognized as crucial mediators of intercellular communication within the TME, particularly under hypoxic conditions. The objective is to explore exosome-mediated signaling between cancer cells and stromal cells in hypoxic environments and its implications for cancer biology.

Main Methods/Materials/Experimental Design ​

The review synthesizes findings from various studies to illustrate the biogenesis, composition, and functions of exosomes in the context of hypoxia. Key aspects include:

  1. Exosome Characteristics:

    • Defined as extracellular vesicles (30-100 nm) formed from the inward budding of endosomal membranes.
    • Carry diverse cargo, including proteins, lipids, nucleic acids, and metabolites.

  2. Hypoxia-Induced Exosome Production:

    • Increased exosome production is linked to hypoxic conditions, mediated by hypoxia-inducible factors (HIFs) such as HIF-1α.
    • Mechanisms include the activation of RHO-associated protein kinase (ROCK) and calpain.

  3. Exosomal Cargo:

    • Proteins and non-coding RNAs (ncRNAs) are critical in mediating responses to hypoxia.
    • Specific exosomal markers and cargo are identified as potential non-invasive biomarkers for tumor hypoxia.

  4. Exosome Functionality:

    • Exosomes facilitate crosstalk between tumor cells and stromal cells, influencing processes like angiogenesis, immune evasion, and metastasis.
Mermaid diagram

Key Results and Findings ​

  1. Exosome Composition: Hypoxia alters the proteomic and RNA profiles of exosomes, which reflect the hypoxic status of tumor cells and can be used as biomarkers.
  2. Tumor-Derived Exosomes (TDEs): TDEs play significant roles in promoting tumor aggressiveness, including:
    • Enhancing invasion and metastasis through the delivery of proteins like MMPs and HIF-1α.
    • Inducing angiogenesis via pro-angiogenic factors.
  3. Stromal Cell Interactions: TDEs influence the behavior of stromal cells (e.g., macrophages, fibroblasts) by modulating their functions and phenotypes, which can lead to a more supportive environment for tumor growth.

Main Conclusions/Significance/Innovation ​

The review underscores the importance of exosomes in mediating complex signaling networks within the hypoxic TME, which contribute to cancer progression and treatment resistance. The insights provided could lead to novel therapeutic strategies targeting exosome pathways for improved cancer management. The identification of hypoxic exosomal biomarkers also presents a promising avenue for non-invasive cancer diagnostics.

Research Limitations and Future Directions ​

  1. Limitations: The review acknowledges the need for more comprehensive studies to elucidate the exact mechanisms by which hypoxia influences exosome production and cargo composition.
  2. Future Directions:
    • Further exploration of stromal cell-derived exosomes in the hypoxic TME.
    • Development of exosome-based therapies and diagnostic tools to target hypoxic tumors effectively.
    • Investigation of the role of specific exosomal ncRNAs and proteins in modulating tumor behavior and immune responses.

References ​

  1. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. - H F Heijnen;A E Schiel;R Fijnheer;H J Geuze;J J Sixma - Blood (1999)
  2. Bone marrow stromal cells: characterization and clinical application. - P H Krebsbach;S A Kuznetsov;P Bianco;P G Robey - Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists (1999)
  3. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. - J Wolfers;A Lozier;G Raposo;A Regnault;C Théry;C Masurier;C Flament;S Pouzieux;F Faure;T Tursz;E Angevin;S Amigorena;L Zitvogel - Nature medicine (2001)
  4. Hypoxia induces heat shock protein expression in human coronary artery bypass grafts. - A Hammerer-Lercher;J Mair;J Bonatti;S B Watzka;B Puschendorf;S Dirnhofer - Cardiovascular research (2001)
  5. Intestinal epithelial cells secrete exosome-like vesicles. - G van Niel;G Raposo;C Candalh;M Boussac;R Hershberg;N Cerf-Bensussan;M Heyman - Gastroenterology (2001)
  6. Rho-kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. - Z Wang;N Jin;S Ganguli;D R Swartz;L Li;R A Rhoades - American journal of respiratory cell and molecular biology (2001)
  7. Hypoxia--a key regulatory factor in tumour growth. - Adrian L Harris - Nature reviews. Cancer (2002)
  8. Exosomes: composition, biogenesis and function. - Clotilde Théry;Laurence Zitvogel;Sebastian Amigorena - Nature reviews. Immunology (2002)
  9. Cleavage of L1 in exosomes and apoptotic membrane vesicles released from ovarian carcinoma cells. - Paul Gutwein;Alexander Stoeck;Svenja Riedle;Daniela Gast;Steffen Runz;Thomas P Condon;Alexander Marmé;Minh-Chau Phong;Otwin Linderkamp;Alexander Skorokhod;Peter Altevogt - Clinical cancer research : an official journal of the American Association for Cancer Research (2005)
  10. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. - John Condeelis;Jeffrey W Pollard - Cell (2006)

Literatures Citing This Work ​

  1. Role of the Exosome in Ovarian Cancer Progression and Its Potential as a Therapeutic Target. - Koji Nakamura;Kenjiro Sawada;Masaki Kobayashi;Mayuko Miyamoto;Aasa Shimizu;Misa Yamamoto;Yasuto Kinose;Tadashi Kimura - Cancers (2019)
  2. Recent advances of exosomes in immune-mediated eye diseases. - Na Li;Lu Zhao;Yankai Wei;Vicki L Ea;Hong Nian;Ruihua Wei - Stem cell research & therapy (2019)
  3. Cardiomyocyte-Derived Exosomes: Biological Functions and Potential Therapeutic Implications. - Hui Yu;Zhanli Wang - Frontiers in physiology (2019)
  4. Exosomal miRNA-1231 derived from bone marrow mesenchymal stem cells inhibits the activity of pancreatic cancer. - Song Shang;Jinfeng Wang;Shilin Chen;Renyun Tian;Hui Zeng;Liang Wang;Man Xia;Haizhen Zhu;Chaohui Zuo - Cancer medicine (2019)
  5. Extracellular Vesicles in Modifying the Effects of Ionizing Radiation. - Tünde Szatmári;Rita Hargitai;Géza Sáfrány;Katalin Lumniczky - International journal of molecular sciences (2019)
  6. Overexpression of MALAT1 Relates to Lung Injury through Sponging miR-425 and Promoting Cell Apoptosis during ARDS. - Lu Wang;Jiao Liu;Wenjie Xie;Guang Li;Lan Yao;Rui Zhang;Bin Xu - Canadian respiratory journal (2019)
  7. Role of Matrix Metalloproteinases in Angiogenesis and Cancer. - Saray Quintero-Fabián;Rodrigo Arreola;Enrique Becerril-Villanueva;Julio César Torres-Romero;Victor Arana-Argáez;Julio Lara-Riegos;Mario Alberto Ramírez-Camacho;María Elizbeth Alvarez-Sánchez - Frontiers in oncology (2019)
  8. Advances of Zinc Signaling Studies in Prostate Cancer. - Dangdang Li;Daniel B Stovall;Wenmeng Wang;Guangchao Sui - International journal of molecular sciences (2020)
  9. Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression. - Hongxia Li;Li Tong;Hong Tao;Zhe Liu - Bioscience reports (2020)
  10. Oxidative stress-induced RAC autophagy can improve the HUVEC functions by releasing exosomes. - Linxin Zhu;Jiankun Zang;Bing Liu;Guocheng Yu;Lili Hao;Lian Liu;Jingxiang Zhong - Journal of cellular physiology (2020)

... (148 more literatures)

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