UroToday - In the February 15, 2010 issue of Clinical Cancer Research, Drs. Eleni Efstathiou and Christopher Logothetis present their paradigm regarding the prostate cancer (CaP) tumor microenvironment and how it contributes to CaP progression and response to therapy.

They propose that the tumor microenvironment in CaP may account for the stage-dependent chemotherapy-response profile seen in CaP. They discuss how CaP progresses through a microenvironment-dependent state in which initially the prostate epithelial cells interact with the surrounding stromal tissue in a paracrine fashion but eventually advance to a microenvironment-independent or autocrine state. This may in part explain why earlier use of chemotherapy in CaP progression has not shown definitive benefit but there is response in later stages when the tumor is autocrine. Clinical observations support targeting the organ-specific microenvironment to alter disease outcome.

An example of this is the bone environment in which CaP interacts with the surrounding tissue and has served as a unique target for therapies. Stromal androgen receptor signaling in both the prostate gland and the bone functions as a tumor promoter. The importance of androgen signaling as a target is also demonstrated by inhibition of the enzyme CYP-17, a key enzyme in the biosynthesis of androgens in the gonads, adrenals and even during the autocrine state by prostate epithelial cells themselves.

The authors propose that CaP interacts with pathways involved in the development and function of prostate and bone in progression and resistance. The properties of the microenvironment determine features of the clinical disease phenotype via adaptation and selection. As CaP progresses, aberrant paracrine pathways serve tumor growth and assist tumor survival. In these later stages, CaP becomes self-supporting and autocrine. An improved understanding of the stromal-epithelial compartment signaling pathways will lead to more effectively applied combination therapies with specific targets. A therapeutic paradigm can be applied for disease stage-specific therapies. In early disease states, there is rationale for inhibiting progression by maintaining a function barrier of the prostate microenvironment. Examples of this are strategies to altering the ration of E-cadherin to matrix metalloproteinase expression and an increase in the vascular density of the microenvironment. This opportunity exists longer compared with other cancers where the autocrine state is established quicker. A combination of agents could modulate the networks of signaling pathways involved in CaP progression. A final example that the authors provide is combining inhibition of VEGF and Src kinase, both active in advanced disease and the bone microenvironment, which is now in phase III clinical trial.

Efstathiou E, Logothetis CJ
Clin Cancer Res. 2010 Feb 15;16(4):1100-7. doi:10.1158/1078-0432.CCR-09-1215

UroToday Contributing Editor Christopher P. Evans, MD, FACS

UroToday - the only urology website with original content global urology key opinion leaders actively engaged in clinical practice. To access the latest urology news releases from UroToday, go to: www.urotoday

Copyright © 2010 - UroToday

Tag Cloud