Tissue Microarray Analysis of Prostate Cancer Specimens Supports a Positive Feedback Loop among Molecules Involved in Hyaluronan Synthesis, Degradation, and Signaling
Vishnu Ganta, Anthony Rizzardi, Lauren Marston, Jessica Tiffany, Rachel Vogel, Nick Rosener, Greg Metzger, James McCarthy, Eva Turley, Stephen Schmechel. University of Minnesota, Minneapolis, MN
Background: Hyaluronan (HA) has been implicated in the biology of prostate cancer (PCa). Hyaluronan synthase 2 (HAS2), Hyaluronidase 1 (Hyal1), and HA receptors including RHAMM and CD44 comprise the hyaluronome, which regulates HA metabolism and function. HA signaling is implicated in regulation of tumor cell proliferation, angiogenesis, inflammation, and metastasis. We sought to investigate the role of these factors in PCa aggressiveness by analyzing their expression in patients with PSA failure.
Design: We built tissue microarrays (TMAs) from tumor present in prostatectomy specimens from a cohort of 161 patients for which PSA follow-up data was available. We used IHC stains directed against HAS2, Hyal1, RHAMM and CD44, and a biotinylated HA binding protein directed against HA, on TMA sections. From whole slide images of stained TMA sections, we used a software algorithm (Genie Histology Pattern Recognition, Aperio, Vista, CA) to automate tissue annotation into several image classes (tumor, stroma, and empty glass). We performed stain intensity analysis separately in tumor and stromal channels (Color Deconvolution, Aperio).
Results: Established pathologic parameters (tumor stage, nodal status, margin status and preoperative PSA) were each separately associated with time to PSA failure. In tumor areas, HAS2, Hyal1 and RHAMM were significantly and positively correlated with each other. Stromal HA levels were significantly associated with time to PSA failure, with patients having higher HA levels being more likely to fail. This relationship held in both univariate and multivariate models (adjusting for established pathologic parameters) (p=0.02 and 0.03 respectively).
Conclusions: There is substantial evidence indicating that malignant progression of prostate tumors is related to increases in the synthesis and degradation of HA and to alterations in RHAMM expression and function. Our data are consistent with this evidence and suggest a model of prostate tumor progression in which increased synthesis and degradation of HA could activate RHAMM function and increase tumor cell proliferation, angiogenesis, inflammation, and metastasis. These data further emphasize the importance of the tumor microenvironment in tumor progression and they suggest it may be possible to better manage PCa patients by using therapeutics that inhibit the interaction of tumor associated RHAMM with fragmented HA.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 124, Monday Morning