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
This is a preview of subscription content, log in to check access.
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.
Strachan DC, Ruffell B, Oei Y et al (2013) CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8 T cells CSF1R inhibition delays cervical and mammary tumor growth in murine models by. Oncoimmunology 2(12):e26968. https://doi.org/10.4161/onci.26968CrossRefPubMedPubMedCentralGoogle Scholar
Garcia AJ, Ruscetti M, Arenzana TL, Tran LM, Bianci-frias D, Sybert E (2017) Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor. Mol Cell Biol 34(11):2017–2028. https://doi.org/10.1128/MCB.00090-14CrossRefGoogle Scholar
Pasello G, Zago G, Lunardi F et al (2018) Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical–pathological features and intratumor heterogeneity over time original article. Ann Oncol 29(March):1258–1265. https://doi.org/10.1093/annonc/mdy086CrossRefPubMedGoogle Scholar
Boylan AM, Sanan DA, Sheppard D, Broaddus VC (1995) Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin avfi5. J Cli Invest 96:1987–2001CrossRefGoogle Scholar
Liu W, Ernst JD, Broaddus VC (2000) Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage, and apoptosis in mesothelial cells. Am J Respir Cell Mol Biol 23:371–378CrossRefGoogle Scholar
Serio G, Pagliarulo V, Marzullo A, Punzi A, Pezzuto F (2016) Case report molecular changes of malignant mesothelioma in the testis and their impact on prognosis: analyses of two cases. Int J Clin Exp Pathol 9(7):7658–7667Google Scholar
Marsella JM, Liu BL, Vaslet CA, Kane AB (1997) Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Environ Health Perspect 105(September):1069–1072PubMedPubMedCentralGoogle Scholar
Kundu S, Kolouri S, Erickson KI, Kramer AF, Rohde GK, May CV (2018) Discovery and visualization of structural biomarkers from MRI using transport-based morphometry. Neuroimage 167:256–275. arXiv:170504919v1CrossRefGoogle Scholar
Boutin C, Xey F, Gouvemet J et al (1993) Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients part 2: prognosis and staging. Cancer 72:394–404CrossRefGoogle Scholar