Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids.
An epithelial-mesenchymal transition (EMT) characterizes the progression of many carcinomas and it is linked to the acquisition of an invasive phenotype. Given that the tumor microenvironment is an active participant in tumor progression, an important issue is whether a reactive stroma can modulate this process. Using a novel EMT model of colon carcinoma spheroids, we demonstrate that their transforming-growth factor-beta1 (TGF-beta)-induced EMT is accelerated dramatically by the presence of activated macrophages, and we identify tumor necrosis factor-alpha (TNF-alpha) as the critical factor produced by macrophages that accelerates the EMT. A synergy of TNF-alpha and TGF-beta signaling promotes a rapid morphological conversion of the highly organized colonic epithelium to dispersed cells with a mesenchymal phenotype, and this process is dependent on enhanced p38 MAPK activity. Moreover, exposure to TNF-alpha stimulates a rapid burst of ERK activation that results in the autocrine production of this cytokine by the tumor cells themselves. These results establish a novel role for the stroma in influencing EMT in colon carcinoma, and they identify a selective advantage to the stromal presence of infiltrating leukocytes in regulating malignant tumor progression.
Bates
Richard C
RC
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. rbates@caregroup.harvard.edu
Mercurio
Arthur M
AM
D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009940:Organoids / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases