Introduction: We constructed a phylogenic tree of TME based on the transcriptomes from melanoma biopsy samples. From these data, we developed a model that fits the clinical observations in various solid cancer. However, clinical data on the development of TME are like snapshots of cancer at discrete points and thus represent partial views of a dynamic process. It is a model based on an inductive argument. To make the argument more deductive, we examined whether the model fits observations of murine cancer progression. There are only a few dozen mouse cancers in which cancer development takes place reliably and reproducibly in mice with intact immune system. These cancer models in mice augmented the developmental model of TME based on the clinical data.

Summary: The tumor development is initiated by a slowly growing, nearly homogeneous colony of cancer cells that can evade detection by the cells’ innate mechanism of immunity such as natural killer (NK) cells (1st Stage; Colonization). Subsequently, the colony develops into a tumor filled with lymphocytes and stromal cells, releasing proinflammatory cytokines, growth factors, and chemokines (2nd Stage; Lymphocyte Infiltration). Cancer progression proceeds to a well-vesiculated silent tumor releasing no inflammatory signal, being nearly devoid of lymphocytes (3rd Stage; Silenced). Eventually some cancer cells within a tumor undertake epithelial-to-mesenchymal transition (EMT), which leads to cancer metastasis (4th 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 (5th 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.

Conclusion: There seem to be aspects of cancer development that are independent of cell types and DNA mutations. The hypothesis is that the aspects that are governed solely by the TME can be discovered. Therefore, a productive approach would be to study a particular solid cancer and learn when and how a tumor recruits lymphocytes, fibroblasts, and macrophages to build a Stage 2 environment, and when and how the environment is changed into Stage 3 and Stage 4, and then test how chemotherapeutics and immunotherapies would affect these environments. It is anticipated that most of the knowledge gained would be applicable to essentially any other solid cancer.

Citation Format: Ryuji Yamaguchi, Guy Perkins. An emerging model for cancer development from a tumor microenvironment perspective in mice and humans [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B100.