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Curated Papers > High-impact authoritative literature on "tumor microenvironment"

Tumor microenvironment in gastric cancers. ​

Literature Information ​

DOI10.1111/cas.14521
PMID32519436
JournalCancer science
Impact Factor4.3
JCR QuartileQ2
Publication Year2020
Times Cited182
KeywordsCAFs, TAMs, endothelial cells, gastric cancer, gastrin
Literature TypeJournal Article, Review
ISSN1347-9032
Pages2696-2707
Issue111(8)
AuthorsYukiko Oya, Yoku Hayakawa, Kazuhiko Koike

TL;DR ​

This review explores the complex interactions within the tumor microenvironment, highlighting the roles of various stromal cells, including cancer-associated fibroblasts, immune cells, and endothelial cells, particularly in mouse gastric cancer models. The findings underscore the heterogeneous nature of stromal populations and their dual roles in promoting or restraining tumor growth, emphasizing the potential for targeting these interactions to develop new cancer therapies.

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CAFs · TAMs · endothelial cells · gastric cancer · gastrin

Abstract ​

The tumor microenvironment favors the growth and expansion of cancer cells. Many cell types are involved in the tumor microenvironment such as inflammatory cells, fibroblasts, nerves, and vascular endothelial cells. These stromal cells contribute to tumor growth by releasing various molecules to either directly activate the growth signaling in cancer cells or remodel surrounding areas. This review introduces recent advances in findings on the interactions within the tumor microenvironment such as in cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells, in particular those established in mouse gastric cancer models. In mice, myofibroblasts in the gastric stroma secrete R-spondin and support normal gastric stem cells. Most CAFs promote tumor growth in a paracrine manner, but CAF population appears to be heterogeneous in terms of their function and origin, and include both tumor-promoting and tumor-restraining populations. Among immune cell populations, tumor-associated macrophages, including M1 and M2 macrophages, and myeloid-derived suppressor cells (MDSCs), are reported to directly or indirectly promote gastric tumorigenesis by secreting soluble factors or modulating immune responses. Endothelial cells or blood vessels not only fuel tumors with nutrients, but also interact with cancer stem cells and immune cells by secreting chemokines or cytokines, and act as a cancer niche. Understanding these interactions within the tumor microenvironment would contribute to unraveling new therapeutic targets.

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Primary Questions Addressed ​

  1. How do different types of stromal cells interact with gastric cancer cells to influence tumor progression?
  2. What specific roles do cancer-associated fibroblasts (CAFs) play in the heterogeneity of the tumor microenvironment in gastric cancers?
  3. In what ways do immune cell populations, such as M1 and M2 macrophages, differ in their contributions to gastric tumorigenesis?
  4. How might targeting the interactions between endothelial cells and cancer stem cells provide new therapeutic strategies for gastric cancers?
  5. What recent advances have been made in understanding the signaling molecules released by the tumor microenvironment in gastric cancer models?

Key Findings ​

Research Background and Objectives ​

The tumor microenvironment (TME) plays a crucial role in the progression of gastric cancers by supporting the growth and expansion of cancer cells. This review focuses on the complex interactions within the TME, particularly involving cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells, as established in mouse models of gastric cancer. The objective is to elucidate these interactions to identify potential therapeutic targets for gastric cancer treatment.

Main Methods/Materials/Experimental Design ​

The review synthesizes findings from various studies that utilize mouse models of gastric cancer to investigate the roles of different cell types within the TME. The main components examined include:

  • Cancer-Associated Fibroblasts (CAFs): Their heterogeneity and contributions to tumor progression through the secretion of growth factors and cytokines.
  • Immune Cells: The roles of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in promoting or inhibiting tumorigenesis.
  • Endothelial Cells: Their dual role in supplying nutrients to tumors and modulating immune responses.

The following flowchart summarizes the technical approach:

Mermaid diagram

Key Results and Findings ​

  1. CAFs:

    • Identified as a dominant component in the TME, they exhibit heterogeneity, with some promoting and others restraining tumor growth.
    • Secrete various soluble factors (e.g., IL-6, CXCL12) that enhance tumor proliferation, invasion, and metastasis.

  2. Immune Cells:

    • TAMs: M1 macrophages have a pro-inflammatory role, while M2 macrophages contribute to immune suppression and tumor progression.
    • MDSCs: Characterized by dual expression of CD11b and Gr-1, they inhibit T-cell responses and promote tumor growth.

  3. Endothelial Cells:

    • Act as a cancer niche by interacting with both cancer stem cells and immune cells, facilitating tumor growth through angiogenesis and immune modulation.

Main Conclusions/Significance/Innovation ​

The review highlights the intricate interplay between various cell types within the TME of gastric cancer, emphasizing the potential for targeting these interactions to develop new therapeutic strategies. Understanding the dual roles of CAFs, immune cells, and endothelial cells in tumor promotion and suppression can lead to innovative approaches in gastric cancer treatment.

Research Limitations and Future Directions ​

The authors acknowledge limitations in current mouse models, which often do not replicate invasive or metastatic characteristics of human gastric cancers. Future research should focus on developing models that accurately reflect the complexity of the human TME, including the investigation of novel therapeutic strategies that target the pro-tumorigenic stroma and activate anti-tumor immune responses. Additionally, the heterogeneity of endothelial cells and their specific contributions to tumor progression require further exploration to enhance therapeutic efficacy.

References ​

  1. R-spondin-3 induces secretory, antimicrobial Lgr5+ cells in the stomach. - Michael Sigal;Maria Del Mar Reinés;Stefanie Müllerke;Cornelius Fischer;Marta Kapalczynska;Hilmar Berger;Elvira R M Bakker;Hans-Joachim Mollenkopf;Michael E Rothenberg;Bertram Wiedenmann;Sascha Sauer;Thomas F Meyer - Nature cell biology (2019)
  2. Immunoregulatory Function of Lymphatic Endothelial Cells in Tumor-draining Lymph Nodes of Human Gastric Cancer. - Mao Tokumoto;Hiroaki Tanaka;Yukie Tauchi;Tatsuro Tamura;Takahiro Toyokawa;Kenjiro Kimura;Kazuya Muguruma;Masakazu Yashiro;Kiyoshi Maeda;Kosei Hirakawa;Masaichi Ohira - Anticancer research (2017)
  3. Gastrin and upper GI cancers. - Yoku Hayakawa;Wenju Chang;Guangchun Jin;Timothy C Wang - Current opinion in pharmacology (2016)
  4. CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. - Yoku Hayakawa;Guangchun Jin;Hongshan Wang;Xiaowei Chen;Christoph B Westphalen;Samuel Asfaha;Bernhard W Renz;Hiroshi Ariyama;Zinaida A Dubeykovskaya;Yoshihiro Takemoto;Yoomi Lee;Ashlesha Muley;Yagnesh Tailor;Duan Chen;Sureshkumar Muthupalani;James G Fox;Arthur Shulkes;Daniel L Worthley;Shigeo Takaishi;Timothy C Wang - Gut (2015)
  5. Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing. - Hiroyuki Tomita;Shigeo Takaishi;Trevelyan R Menheniott;Xiangdong Yang;Wataru Shibata;Guangchun Jin;Kelly S Betz;Kazuyuki Kawakami;Toshinari Minamoto;Catherine Tomasetto;Marie-Christine Rio;Nataporn Lerkowit;Andrea Varro;Andrew S Giraud;Timothy C Wang - Gastroenterology (2011)
  6. Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. - Hayato Nakagawa;Nobumi Suzuki;Yoshihiro Hirata;Yohko Hikiba;Yoku Hayakawa;Hiroto Kinoshita;Sozaburo Ihara;Koji Uchino;Yuji Nishikawa;Hideaki Ijichi;Motoyuki Otsuka;Junichi Arita;Yoshihiro Sakamoto;Kiyoshi Hasegawa;Norihiro Kokudo;Keisuke Tateishi;Kazuhiko Koike - Proceedings of the National Academy of Sciences of the United States of America (2017)
  7. Role of the tumor microenvironment in the pathogenesis of gastric carcinoma. - Hye Won Chung;Jong-Baeck Lim - World journal of gastroenterology (2014)
  8. Role of the Microenvironment in Gastrointestinal Tumors. - Nathaniel Weygant;Yang Ge;C Benedikt Westphalen;Wen Wee Ma;Kenneth J Vega - Journal of oncology (2019)
  9. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. - Daniel L Worthley;Michael Churchill;Jocelyn T Compton;Yagnesh Tailor;Meenakshi Rao;Yiling Si;Daniel Levin;Matthew G Schwartz;Aysu Uygur;Yoku Hayakawa;Stefanie Gross;Bernhard W Renz;Wanda Setlik;Ashley N Martinez;Xiaowei Chen;Saqib Nizami;Heon Goo Lee;H Paco Kang;Jon-Michael Caldwell;Samuel Asfaha;C Benedikt Westphalen;Trevor Graham;Guangchun Jin;Karan Nagar;Hongshan Wang;Mazen A Kheirbek;Alka Kolhe;Jared Carpenter;Mark Glaire;Abhinav Nair;Simon Renders;Nicholas Manieri;Sureshkumar Muthupalani;James G Fox;Maximilian Reichert;Andrew S Giraud;Robert F Schwabe;Jean-Phillipe Pradere;Katherine Walton;Ajay Prakash;Deborah Gumucio;Anil K Rustgi;Thaddeus S Stappenbeck;Richard A Friedman;Michael D Gershon;Peter Sims;Tracy Grikscheit;Francis Y Lee;Gerard Karsenty;Siddhartha Mukherjee;Timothy C Wang - Cell (2015)
  10. GPR30-Expressing Gastric Chief Cells Do Not Dedifferentiate But Are Eliminated via PDK-Dependent Cell Competition During Development of Metaplasia. - Masahiro Hata;Hiroto Kinoshita;Yoku Hayakawa;Mitsuru Konishi;Mayo Tsuboi;Yukiko Oya;Ken Kurokawa;Yuki Hayata;Hayato Nakagawa;Keisuke Tateishi;Hiroaki Fujiwara;Yoshihiro Hirata;Daniel L Worthley;Yuki Muranishi;Takahisa Furukawa;Shunsuke Kon;Hiroyuki Tomita;Timothy C Wang;Kazuhiko Koike - Gastroenterology (2020)

Literatures Citing This Work ​

  1. Tumor microenvironment in gastric cancers. - Yukiko Oya;Yoku Hayakawa;Kazuhiko Koike - Cancer science (2020)
  2. Stromal Protein-Mediated Immune Regulation in Digestive Cancers. - Pia Gamradt;Christelle De La Fouchardière;Ana Hennino - Cancers (2021)
  3. Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. - Yoku Hayakawa;Yoshihiro Hirata;Masahiro Hata;Mayo Tsuboi;Yukiko Oya;Ken Kurokawa;Sohei Abe;Junya Arai;Nobumi Suzuki;Hayato Nakagawa;Hiroaki Fujiwara;Keisuke Tateishi;Shin Maeda;Kazuhiko Koike - Microorganisms (2020)
  4. Cancer-associated fibroblasts: overview, progress, challenges, and directions. - Qinrong Ping;Ruping Yan;Xin Cheng;Wenju Wang;Yiming Zhong;Zongliu Hou;Yunqiang Shi;Chunhui Wang;Ruhong Li - Cancer gene therapy (2021)
  5. Cancer-associated cells release citrate to support tumour metastatic progression. - Konstantin Drexler;Katharina M Schmidt;Katrin Jordan;Marianne Federlin;Vladimir M Milenkovic;Gerhard Liebisch;Anna Artati;Christian Schmidl;Gregor Madej;Janina Tokarz;Alexander Cecil;Wolfgang Jagla;Silke Haerteis;Thiha Aung;Christine Wagner;Maria Kolodziejczyk;Stefanie Heinke;Evan H Stanton;Barbara Schwertner;Dania Riegel;Christian H Wetzel;Wolfgang Buchalla;Martin Proescholdt;Christoph A Klein;Mark Berneburg;Hans J Schlitt;Thomas Brabletz;Christine Ziegler;Eric K Parkinson;Andreas Gaumann;Edward K Geissler;Jerzy Adamski;Sebastian Haferkamp;Maria E Mycielska - Life science alliance (2021)
  6. Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade. - Yanna Lei;Xiaoying Li;Qian Huang;Xiufeng Zheng;Ming Liu - Frontiers in oncology (2021)
  7. Potential role of mitochondria in gastric cancer detection: Fission and glycolysis. - Hang Yang;Yan Li;Bing Hu - Oncology letters (2021)
  8. Tumor-Associated Macrophages and Inflammatory Microenvironment in Gastric Cancer: Novel Translational Implications. - Karim Rihawi;Angela Dalia Ricci;Alessandro Rizzo;Stefano Brocchi;Giovanni Marasco;Luigi Vincenzo Pastore;Fabiola Lorena Rojas Llimpe;Rita Golfieri;Matteo Renzulli - International journal of molecular sciences (2021)
  9. SAMD9 Is Relating With M2 Macrophage and Remarkable Malignancy Characters in Low-Grade Glioma. - Wenping Ma;Kenan Zhang;Zhaoshi Bao;Tao Jiang;Ying Zhang - Frontiers in immunology (2021)
  10. The Sensitivity Prediction of Neoadjuvant Chemotherapy for Gastric Cancer. - Juan Sun;Xianze Wang;Zimu Zhang;Ziyang Zeng;Siwen Ouyang;Weiming Kang - Frontiers in oncology (2021)

... (172 more literatures)

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