Biomedical Engineering Reference
In-Depth Information
examination of the biopsy is used to assign a Gleason score to the tumor, which
is based upon the architecture of the glands and is predictive of patient prog-
nosis (Gleason 1977). Gleason score ranges from 2 to 10, with a 2 representing
small closely packed glands and a good prognosis and 10 representing barely
discernable glands with sheets of cells throughout the surrounding tissue and
has the worst prognosis (Gleason 1977).
Localized disease is usually treated with surgery (radical prostatectomy) or with
radiation therapy or is followed by active surveillance (reviewed in Walsh et al.
2007). A number of minimally invasive options are also under investigation for the
treatment of localized prostate cancer, such as high-intensity focused ultrasound,
interstitial prostate brachytherapy, and cryotherapy (Barqawi and Crawford
2007). For patients with metastatic disease, the frontline therapy is androgen
deprivation therapy (ADT) with chemical or surgical castration (reviewed in
Sharifi et al. 2005). The majority of patients in the United States who are treated
with ADT undergo chemical castration with gonadotropin-releasing hormone
agonists (GnRH-A). Endogenous GnRH is secreted from the hypothalamus
which acts on the anterior pituitary resulting in the secretion of luteinizing hormone
(LH) into the general circulation. LH acts on the testes to secrete testosterone. The
secretion of LH from the anterior pituitary is dependent on the cyclic nature of
GnRH action. Constant stimulation of the anterior pituitary with GnRH-A down-
regulates LH release and hence testosterone release.
Unfortunately, therapy with ADT in the metastatic setting almost always
gives rise to castrate-resistant prostate cancer (CRPC). However, this ''androgen-
independent'' prostate cancer is still dependent on the androgen receptor (AR)
(reviewed in Sharifi et al. 2006) that has undergone gain-of-function changes
resulting in the activation of androgen-responsive genes. These gain-of-function
changes in AR are mediated by gene amplification, mutations in the AR, ligand-
sensitization of the AR by various growth factors and receptors, as well as by the
local conversion of precursors to testosterone and dihydrotestosterone (Scher and
Sawyers 2005; Stanbrough et al. 2006).
1.2 The Prostate Gland Architecture and Morphogenesis
The prostate is a small glandular organ that secretes a component of the seminal
fluid (Fig. 1). It is composed of three major glandular zones (reviewed in Joshua
et al. 2008). The peripheral zone (PZ) surrounds the distal urethra and is the
major component of a normal prostate. The central zone (CZ) constitutes about
25% of the prostate and surrounds the ejaculatory ducts. The transition zone
(TZ) surrounds the proximal urethra. The supporting stroma is comprised of
smooth muscle, fibroblasts, lymphocytes, and neurovascular tissue. Most pros-
tate tumors arise within the PZ with less than 30% arising in the TZ (McNeal
et al. 1988). Furthermore, TZ tumors are less aggressive and have lower recur-
rence rates than PZ tumors.
