An Emerging Model for Cancer Development from a Tumor Microenvironment Perspective in Mice and Humans

  • Ryuji Yamaguchi
  • Guy Perkins
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1225)


In the past, cancer development was studied in terms of genetic mutations acquired in cancer cells at each stage of the development. We present an emerging model for cancer development in which the tumor microenvironment (TME) plays an integral part. In this model, the tumor development is initiated by a slowly growing nearly homogeneous colony of cancer cells that can evade detection by the cell’s innate mechanism of immunity such as natural killer (NK) cells (first stage; colonization). Subsequently, the colony develops into a tumor filled with lymphocytes and stromal cells, releasing pro-inflammatory cytokines, growth factors, and chemokines (second stage; lymphocyte infiltration). Cancer progression proceeds to a well-vesiculated silent tumor releasing no inflammatory signal, being nearly devoid of lymphocytes (third stage; silenced). Eventually some cancer cells within a tumor undertake epithelial-to-mesenchymal transition (EMT), which leads to cancer metastasis (fourth stage; EMT). If a circulating metastasized cancer cell finds a niche in a new tissue and evades detection by NK cells, it can establish a new colony in which very few stromal cells are present (fifth stage; metastasis), which is much like a colony at the first stage of development. At every stage, cancer cells influence their own TME, and in turn, the TME influences the cancer cells contained within, either by direct interaction between cancer cells and stromal cells or through exchange of cytokines. In this article, we examine clinical findings and animal experiments pertaining to this paradigm-shifting model and consider if, indeed, some aspects of cancer development are governed solely by the TME.


Tumor microenvironment Epithelial-to-mesenchymal transition (EMT) Metastasis Natural killer cell (NK) Cancer development Malignant pleural mesothelioma (MPN) Lymphocytic infiltration Ductal carcinoma in situ (DCIS) Cancer associated fibroblast (CAF) Tumor associated macrophage (TAM) Myeloid-derived suppressor cell (MDSC) Cytokines Chemokines Pleural effusion 



We would like to thank Prof. Courtney Broaddus at the Dept. of Medicine, University of California, San Francisco, for informative discussion on MPM. The project was initiated when R.Y. was at Kansai Medical University, Hirakata, Japan.


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Ryuji Yamaguchi
    • 1
  • Guy Perkins
    • 2
  1. 1.JRC, Medical Research CompanyOsakaJapan
  2. 2.National Center for Microscopy and Imaging ResearchSchool of Medicine, University of CaliforniaSan Diego, La JollaUSA

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