Differential Expression of Integrins in Intraductal Spread, Cribriform, and Non-Cribriform Patterns of High Grade Untreated and Treated Prostate Cancer
Vassiliki Tzelepi, Maria Karlou, Sijin Wen, Anh Hoang, Chrisoula Scopa, Christopher Logothetis, Eleni Efstathiou, Patricia Troncoso. University of Patras, Patras, Greece; MD Anderson Cancer Center, Houston
Background: The presence of intraductal spread (IDS) or cribriform (CR) morphologic patterns in prostate cancer (PCa) represents an adverse prognostic feature in untreated and treated patients. However, the molecular features of these patterns, in comparison to high grade non-CR pattern have not been studied in detail. IDS and CR patterns are unique in that tumor cell spatial organization results in their minimal contact with the stroma. We have hypothesized that high grade (HG) PCa loses stromal dependence and becomes epitheliocentric accounting for therapy resistance. Integrins (IT) are transmembrane receptors that mediate cell adhesion and activation of intracellular signaling cascades and represent potential candidates for therapeutic targeting in PCa. Aberrations in IT signaling have been associated with the progression, emergence of castration resistance and metastasis of PCa and may be implicated in the phenotype of CR vs. non-CR pattern of HG PCa.
Design: We used PCa xenografts with CR and non-CR morphology as discovery platforms to identify differences in the expression of the mRNA of various IT components (a1-3, a5-8, a10, aE, aX, av, b1-5, b7, b8) with qRT-PCR. Expression of aX, b1 and b3 were validated with immunohistochemistry in tissue microarrays (TMA) that were constructed from the prostatectomy specimens of patients with untreated (N=62) and short term (2-4 months) (N=29) and long term (5-12 months) (N=18) androgen ablation treated HG PCa. IDS, CR and Gleason Grade 4, non-CR (fused glands) patterns were included in the TMA.
Results: Expression of ITb3, b5 and aX was higher (p<0.001, p=0.014 and p=0.03), whereas ITb1 was marginally lower (p=0.09) in the xenograft with non-CR compared to that with CR morphology. Immunohistochemistry in untreated human tumors showed that stromal expression of ITb3 was higher in non-CR compared to IDS and CR (p<0.001). Additionally, epithelial expression of ITb1 in untreated and treated tumors was lower (p<0.001 and p=0.033) and stromal expression in untreated tumors was higher (p<0.001) in non-CR compared to IDS and CR. No difference was noted between IDS and CR patterns in any of the markers tested.
Conclusions: A downregulation of IT expression was frequently noted in IDS/CR pattern of HG PCa. IDS and CR patterns seem to share biologic properties as shown by their similarities in IT expression. The role of IT expression in the pathogenesis and prognosis of the IDS/CR and non-CR patterns in treated and untreated tumors warrants further study.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 1:00 PM
Poster Session II # 192, Monday Afternoon