Comparably to previous findings by Tischler et al. , we have demonstrated that POSTN is far more highly expressed in cancer tissues than in normal tissues. In our study, POSTN appears to be expressed mainly in the stromal compartment, both in normal and in cancerous tissues. In Tischler’s study, epithelial expression was higher in normal tissues, while in cancerous tissues it was higher in the larger test cohort, but it was lower in the smaller training cohort . Tischler's findings on normal prostate gland tissues are comparable with those previously reported by Tsunoda et al.  who also found higher POSTN expression in normal epithelial cells. However, in this study, POSTN expression was also higher in the epithelium than in the stroma of cancerous tissues . It is not easy to explain the differences that were observed in the three studies. Besides the number of patients and disease stage, these studies differ in some methodological aspects. In our own, as well as in Tischler’s study , POSTN detection was performed using the same rabbit polyclonal antibody capable of recognizing all the different POSTN isoforms. A polyclonal anti-POSTN antibody was also used by the Japanese investigators for their IHC determinations . However, there were major differences concerning staining evaluation. In fact, we and Tischler used an immune score (IRS) obtained by multiplying the intensity of staining by the percentage of stained cells. Notably, comparable median IRS values were obtained by us and by the Swiss colleagues. However, the results obtained in our two studies are not comparable since patients were analyzed after arbitrarily grouping them in different manners. In fact, in the Swiss study, median IRS values were used as cut-off points to dichotomize the tumors into a “POSTN low” and “POSTN high” population, while we found that the cut off score that best defined patient risk was the 75th percentile. In Tsunoda's study , IHC analysis only took into consideration the quantitative expression of POSTN (positive: at least >5% of staining cells), without evaluating staining intensity.
The differences in how patients were grouped, i.e. according to their IRS, may have been particularly relevant when POSTN expression was correlated with clinical outcome.
Tischler’s study  evaluated the correlation between POSTN expression and PSA relapse- free survival. They showed that higher stromal POSTN was significantly associated with shorter PSA-free survival both in the training cohort and in the test cohort set. However, the difference between low and high POSTN subgroups was statistically significant only in the training set. This might reflect the different size of the two cohorts and/or the length of follow-up (45 vs 72 months, respectively). However, it might also be associated with the different characteristics of the two study populations. In fact, 46% of the patients making up the training set showed biochemical failure compared with 20% of those forming the validation set. No relationship between PSA-free survival and epithelial POSTN expression was reported in this study. Unfortunately, these investigators did not explain the criteria that were adopted to define PSA progression, nor did they attempt to correlate POSTN expression with patients' survival.
We also observed a direct relationship between stromal POSTN IRS and PSA-free survival, however the difference was not statistically significant, exactly as reported by Tischler et al.  in their validation set which was much larger than our own set but showed a comparable clinical outcome. However, low epithelial POSTN expression was associated with shorter PSA-free survival in our study, and epithelial expression was not predictive of patient survival. By contrast, stromal expression was highly predictive of the risk of death, while it was only a weak predictor of PSA progression. These findings suggest that POSTN might play a different biological role in tumor progression, depending on its compartmentalization. In fact, while POSTN down-regulation in PCa epithelium appears to be correlated with extra-prostatic extension and biochemical failure, both of which represent early events in the natural history of the disease, POSTN overexpression in the stroma appears to be highly predictive of the risk of death, a late event that usually follows distant spreading and the loss of hormone dependency. This differential effect has been confirmed by multivariate analysis and suggests that it may be possible to identify different tumor phenotypes which are characterized by an increasing risk of PSA failure and death. In this regard, it is certainly intriguing that the prognostic value of POSTN overexpression in stroma is especially evident in patients whose tumors down-regulate POSTN expression in the epithelial compartment, but not in those whose tumors also overexpress the protein in the epithelial component (Figure 5). The phenotype characterized by low POSTN expression in the epithelium and high protein expression in the stroma showed a bleak prognosis, both in terms of PSA-free and overall survival.
Moreover, multi-parametric models showed that the proteomic signature based on the epithelial and stromal expression of POSTN indeed added to the prognostic information provided by the currently available variables, including the Gleason score. It should be stated in this regard that the old Gleason grading system was used and that caution is therefore warranted in data interpretation.