Differential mast cell phenotypes in benign versus cancer tissues and prostate cancer oncologic outcomes.

We reported previously that high numbers of mast cells in benign (extra-tumoral) regions of the prostate are associated with worse outcomes after radical prostatectomy including biochemical recurrence and the development of metastases. Herein, with a cohort of 384 men, we performed mast cell subtyping and report that higher minimum number of the tryptase-only (MCT ) subset of extra-tumoral mast cells is associated with increased risk of biochemical recurrence (comparing highest to lowest tertiles: HR 2.32, 95% CI 1.37-3.93; P-trend = 0.002), metastases (HR 3.62, 95% CI 1.75-7.47; P-trend 0.001), and death from prostate cancer (HR 2.87, 95% CI 1.19-6.95; P-trend = 0.02). Preliminary RNA sequencing and comparison of benign versus cancer tissue mast cells revealed differential expression of additional site-specific genes. We further demonstrate that the genes CXCR4 and TFE3 are more highly expressed in tumor-infiltrating mast cells as well as other tumor-infiltrating immune cells and in tumor cells, respectively, and represent an altered tumor microenvironment. KIT variants were also differentially expressed in benign versus cancer tissue mast cells, with KIT variant 1 (GNNK+ ) mast cells identified as more prevalent in extra-tumoral regions of the prostate. Finally, using an established mouse model, we found that mast cells do not infiltrate Hi-Myc tumors, providing a model to specifically examine the role of extra-tumoral mast cells in tumorigenesis. Hi-Myc mice crossed to mast cell knockout (Wsh) mice and aged to 1 year revealed a higher degree of pre-invasive lesions and invasive cancer in wild-type mice versus heterozygous and knockout mice. This suggests a dosage effect where higher numbers of extra-tumoral mast cells resulted in higher cancer invasion. Overall, our studies provide further evidence for a role of extra-tumoral mast cells in driving adverse prostate cancer outcomes. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

High Extratumoral Mast Cell Counts Are Associated with a Higher Risk of Adverse Prostate Cancer Outcomes.

BACKGROUND: Given our previous findings that low intratumoral and high extratumoral mast cell numbers are associated with higher risk of biochemical recurrence after radical prostatectomy, we now assessed this relationship with race and the development of metastases. METHODS: We stained for mast cell tryptase via IHC and fluorescent immunolabeling in 885 men across multiple tissue microarray sets designed to assess biomarkers in association with race and prostate cancer outcomes (median follow-up, 7.0 years). RESULTS: Intratumoral and extratumoral mast cell counts were significantly lower in tissues from African-American compared with European-American men, but not within strata of cancer grade. There was no association between mast cell counts and ERG positivity, PTEN loss, or TP53 missense mutation. Higher minimum extratumoral mast cells were associated with an increased risk of biochemical recurrence [comparing highest with lowest tertiles: HR, 1.61; 95% confidence interval (CI), 1.12-2.29; P trend = 0.01]; this pattern was similar among European-American and African-American men and by grade of disease. There was no significant association between minimum intratumoral mast cell count and biochemical recurrence, overall or within strata of race and grade. Finally, high minimum number of extratumoral mast cells was associated with prostate cancer metastases (comparing highest with lowest tertiles: HR, 2.12; 95% CI, 1.24-3.63; P trend = 0.01). CONCLUSIONS: High extratumoral mast cell numbers are associated with biochemical recurrence and the development of metastases after radical prostatectomy. IMPACT: Higher numbers of benign tissue mast cells are associated with a higher risk of adverse outcomes after radical prostatectomy, including metastatic prostate cancer.