The tumor microenvironment (TME) is the environment between malignant and non-transformed cells, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM) [1] [2] [3] [4]. Cancers are not just masses of malignant cells but complex 'rogue' organs, to which many other cells are recruited and can be corrupted by the transformed cells [5]. The non-malignant cells of the TME have a dynamic and often tumor-promoting function at all stages of carcinogenesis [6].
In addition to malignant cells, adipocytes, fibroblasts, tumor vasculature, lymphocytes, dendritic cells, and cancer-associated fibroblasts are present in the tumor microenvironment. Each of these cell types has unique immunological capabilities that determine whether the tumor will survive and affect neighboring cells [7].
Figure 1. Schematic overview about the most important mechanisms and interactions of the tumor microenvironment (TME)
Figure 1 shows the most important mechanisms and interactions of the TME. Green arrows indicate antitumor activities of the immune system and red arrows indicate inhibitions of antitumor activity of the immune system. Of course, tumors have strong positive tumor growing effects by themselves (loop in the middle).
Angiogenesis Inhibitor in Cancer | |||||||
ANGPT2 | CALR | CHGA | COL1A1 | PF4 | TSP1 | THBS2 | TIMP-1 |
Angiogenic Activator in Cancer | |||||||
G-CSF | CXCL8 | EGF | FGF2 | HGF | PDGFA | PDGF-B | PDGF-C |
PDGF-D | PLGF/PGF | TGF-alpha | TGF beta 1 | TNF-alpha | VEGFA | ||
ECM and ECM Regulators | |||||||
COL10A1 | COL11A1 | COL1A1 | COL22A1 | COL2A1 | COL3A1 | COL4A1 | COL4A2 |
COL4A3 | COL4A4 | COL4A5 | COL4A6 | COL6A2 | COL6A3 | COL6A5 | COL9A1 |
COL9A2 | CTSB | LOX | PLOD2 | ||||
MDSC Cytokines and Growth Factors | |||||||
M-CSF | GM-CSF | IFN Gamma | IL10 | IL12A | IL13 | IL6 | PTGES2 |
S100A8 | S100A9 | TGF beta 1 | TGF beta 2 | TGF-beta 3 | VEGFA | ||
MDS Intracellular Signaling Factors | |||||||
NOS2 | STAT1 | STAT3 | STAT6 | ||||
MDSC Phenotyping-Negative/Positive Markers | |||||||
CD14 | CD34 | CD40 | CD35 | CD21 | CD23 | CD11c | C5AR1 |
CCR2 | CD1D | CD2 | CD274 | CD33 | CD44 | FLT1 | ICAM1 |
IL1R1 | IL4R | IL-6R | ITGA4 | ITGB2 | TFRC |
* MDSC refers to Myeloid-derived Suppressor Cells
References
[1] Alfarouk KO, Muddathir AK, Shayoub ME. Tumor acidity as evolutionary spite [J]. Cancers. 2011, 3 (1): 408–14.
[2] NCI Dictionary of Cancer Terms. National Cancer Institute. 2011-02-02.
[3] Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment [J]. Science. 2015, 348 (6230): 74–80.
[4] Spill F, Reynolds DS, Kamm RD, Zaman MH. Impact of the physical microenvironment on tumor progression and metastasis [J]. Current Opinion in Biotechnology. 2016, 40: 41–48.
[5] Frances R. Balkwill, Melania Capasso and Thorsten Hagemann. The tumor microenvironment at a glance [J]. Journal of Cell Science. 2012, 125, 5591–5596.
[6] Hanahan, D. and Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment [J]. Cancer Cell. 2012, 21, 309-322.
[7] Arneth B. Tumor Microenvironment [J]. Medicina (Kaunas). 2019, 56 (1): 15.
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