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Michael Ittmann Lab

Cellular senescence and benign prostatic hyperplasia

Master
Content

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men, occurring in more than 70 percent of men over the age of 60. BPH results in substantial morbidity in this patient population, including complications such as urinary retention, renal impairment and infection.

A major factor in the pathogenesis of prostatic hyperplasia is the continuing growth of the transition zone of the prostate due to both epithelial and stromal proliferation. FGF7 is expressed in normal and hyperplastic prostate by stromal fibroblasts and acts as a potent epithelial growth factor. We have demonstrated that expression of FGF7 is increased in BPH and tissue levels of FGF7 are strongly correlated with epithelial proliferation in this condition. Using primary cultures of prostatic epithelial and stromal cells we have also shown that Il-1α is secreted by prostatic epithelial cells and can act as a paracrine inducer of FGF7 secretion by the stromal cells. Analysis of normal prostatic peripheral zone and BPH tissue reveals that Il-1α is present at increased levels in hyperplastic prostate and levels of Il-1α correlate strongly with tissue FGF7 concentration. Thus, the increased epithelial proliferation seen in BPH is driven by increased expression of Il-1α by prostatic epithelial cells acting on adjacent stromal cells to increase FGF7 expression.

Our recent work indicates that cellular senescence is a major factor driving expression of IL-1α in vitro and in vivo . A similar relationship holds for epithelial derived IL-8 and stromal FGF2. Thus there is a linkage between cellular senescence and one of the most common pathologies of older men. Current efforts seek to determine if senescence increases expression of other cytokines and growth factor and the mechanism of cellular senescence in prostatic epithelial cells.

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Publications

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Castro P, Chen X, Gomez L, Lamb D, and Ittmann M. 2004. Interleukin-8 expression is increased in senescent prostatic epithelial cells and promotes the development of benign prostatic hyperplasia. The Prostate 60:153-159

Castro P, Giri D, Lamb D, and Ittmann M. 2003. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. The Prostate 55: 30-38.

Giri D, and Ittmann M. 2001. IL-8 is a paracrine inducer of FGF2, a stromal and epithelial growth factor in benign prostatic hyperplasia. Am. J. of Path. 159: 139-147.

Giri D and Ittmann M. 2000. Il-1α is a paracrine inducer of FGF-7, a key epithelial growth factor in benign prostatic hyperplasia. Am. J. Pathol. 157: 249-255.

Ropiquet F, Giri D, Lamb D, and Ittmann M. 1999. FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation. J. Urol. 162: 595-599.