Persistent Inflammation Leads to Proliferative Neoplasia and Loss of Smooth Muscle Cells in a Prostate Tumor Model

Autor: Andreas Birbach, David Eisenbarth, Nicolas Kozakowski, Eva Ladenhauf, Marc Schmidt-Supprian, Johannes A. Schmid
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Zdroj: Neoplasia: An International Journal for Oncology Research, Vol 13, Iss 8, Pp 692-703 (2011)
Druh dokumentu: article
ISSN: 1476-5586
1522-8002
DOI: 10.1593/neo.11524
Popis: In prostate cancers, epidemiological data suggest a link between prostate inflammation and subsequent cancer development, but proof for this concept in a tumor model is lacking. A constitutively active version of IκB kinase 2 (IKK2), which is activated by many inflammatory stimuli, was expressed specifically in the prostate epithelium. Constitutive activation of the IKK2/nuclear factor κB axis was insufficient for prostate transformation. However, in combination with heterozygous loss of phosphatase and tensin homolog, IKK2 activation led to an increase in tumor size, formation of cribriform structures, and increase in fiber in the fibroblastic stroma. This phenotype was coupled with persistent inflammation evoked by chemokine expression in the epithelium and stroma. The hyperplastic and dysplastic epithelia correlated with changes evoked by decreased androgen receptor activation. Conversely, inflammation correlated with stromal changes highlighted by loss of smooth muscle cells around prostate ducts. Despite the loss of the smooth muscle barrier, tumors were rarely invasive in a C57BL/6 background. Data mining revealed that smooth muscle markers are also downregulated in human prostate cancers, and loss of these markers in primary tumors is associated with subsequent metastasis. In conclusion, our data show that loss of smooth muscle and invasiveness of the tumor are not coupled in our model, with inflammation leading to increased tumor size and a dedifferentiated stroma.
Databáze: Directory of Open Access Journals
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