Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome

Abstract

Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.

Figure 1

Tissue samples stained for HA; each tissue core is 0.6 mm in diameter. A: High stroma staining score in normal (TINT) tissue. B: High stroma staining score in tumor tissue. C: Low HA staining score in normal (TINT) tissue stroma (staining of the basal cells is focally present). D: Low stroma staining score in tumor stroma tissue. Inset: Lack of HA staining in a section pretreated with hyaluronidase, as described earlier in more detail.

Figure 2

Kaplan–Meier curves of the analyzed cohort, divided by each variables median (solid line, above median; dashed line, under median). Patients with a Gleason score of 4 to 10 were managed with watchful waiting. Cross: Censored patients are shown. A: HA staining score in tumor stroma (log-rank test, 7.1; P < 0.01). B: HA staining intensity in tumor epithelium (log-rank test, 4.3; P < 0.05). C: HA staining score in nonmalignant stroma (log-rank test, 8.0; P < 0.01).

Figure 3

Kaplan-Meier curves of the analyzed subgroups of patients managed with watchful waiting, divided by median of HA staining score in nonmalignant tissue (solid line, above median; dashed line, under median). A: A total of 184 patients with Gleason score of 6 or less (log-rank test, 4.7; P < 0.05). B: A total of 180 patients with clinical T1 stage, this group also included 30 patients with a Gleason score of 7, and 13 patients with a Gleason score of 8 to 10 (log-rank rest, 13.2; P < 0.001).

Figure 4

Photographs of rat tissues from the ventral prostate (VP), in control (A), the border zone between an AT-1 tumor (left) and adjacent VP tissue (B), and from the border zone between a MatLyLU tumor (top) and adjacent VP tissue (C) stained to visualize HA. Original magnification, ×200. Note the intense staining around the MatLyLu tumor.

Figure 5

Box-plot showing relative HAS-1 mRNA levels in rat prostate tissues. Copenhagen rats were injected with 2000 AT-1 prostate tumor cells or saline into the ventral prostates (VPs) and examined 10 days later. The HAS-1 expression was notably increased in VP tissue adjacent to tumor, whereas the AT-1 tumor tissue showed no difference in HAS-1 expression compared with the normal VP tissue from animals without tumors. Note that HAS-1 mRNA was not expressed in AT-1 cells in vitro.