Knowledge regarding cell biologic characteristics of small solid glandular buds in the prostate and their relationship with branching activity in the human prostate is still fragmentary. Our object was to demonstrate, on the basis of immunophenotype, loci that harbor the potential for branching activity within the adult human prostate.
Semiserial sectioning was performed on 13 adult prostates in an effort to identify structures in the prostate that could be considered foci of growth. Selected slides were stained with biomarkers for basal/luminal cells (keratins), proliferation (MIB-1), apoptosis inhibitor (bcl-2), intercellular adhesion (E-cadherin), and stromal-epithelial interactions (tenascin-C). Results were compared with fetal and prepubertal human prostates and microdissected rat prostates.
Five histologic epithelial structures were identified in 19 paraffin blocks, which on serial sectioning showed morphologic transitions with a common pattern, consisting of reduction in number and caliber of acini until small solid buds of epithelial cells were reached. Immunophenotypically, the small solid glandular buds had a basal-cell keratin phenotype, expression of bcl-2 in virtually all cells, high proliferative activity, prominent intracellular localization of E-cadherin, and enhanced periglandular tenascin-C immunoreactivity. The budding tips in fetal and prepubertal prostates revealed an immunostaining pattern identical to the small solid glandular buds in the adult, but different to the rat prostate.
Our data suggest that dispersed small solid glandular buds have a capacity for growth, and as such may be considered foci of resumed reawakening branching activity with in the adult human prostate.
"(J Histochem Cytochem 55:885–890, 2007) K E Y W O R D S development differentiation human prostate immunohistochemistry tissue array analysis THE ADULT PROSTATE EPITHELIUM is composed of basal and luminal compartments distinguished by localization and immunophenotypic characteristics that reflect their differentiation. Basal cells specifically display a high expression of p63, cytokeratin (CK)5/6 and 14, antiapoptotic factor Bcl2, and epidermal growth factor receptor (EGFR) (McDonnell et al. 1992; De Marzo et al. 1998; Xue et al. 2001a). The basal layer is the proliferative compartment in the normal adult prostate. "
[Show abstract][Hide abstract] ABSTRACT: An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.
Journal of Histochemistry and Cytochemistry 10/2007; 55(9):885-90. DOI:10.1369/jhc.7A7192.2007 · 1.96 Impact Factor
"HGF encounters the Met receptor in the basal cells of the prostatic ducts and acini, and in low numbers on the luminal cells of the prostatic ducts and stromal smooth muscle cells [27-29]. During puberty, developing branches within the prostate show high concentrations of Met in ductal tips and respond to stromal stimulation [30,31], a hallmark for HGF/Met-mediated activity. Met signaling is also critical for ductal system formation in kidney, mammary gland, liver, pancreas and lung [32-35]. "
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF), was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells.
We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF) were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models.
We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM) and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM) or nucleolin (on the cell surfaces) eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of laminin-binding integrins, nor can they be linked to expression of the known HGF receptor Met, as neither LNCaP nor clonally-derived C4-2 sub-line contain any detectable Met protein. Even in the absence of Met, small GTPases are activated, linking HGF stimulation to membrane protrusion and integrin activation. Membrane-localized nucelolin levels increase during cancer progression, as modeled by both the PC3 and LNCaP prostate cancer progression cell lines.
We propose that cell surface localized nucleolin protein may function in these cells as a novel HGF receptor. Membrane localized nucleolin binds heparin-bound growth factors (including HGF) and appears upregulated during prostate cancer progression. Antibodies against nucleolin are able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. HGF-nucleolin interactions could be partially responsible for the complexity of HGF responses and met expression reported in the literature.
BMC Cancer 02/2006; 6(1):197. DOI:10.1186/1471-2407-6-197 · 3.36 Impact Factor
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