Elevated hyaluronan and hyaluronan‐mediated motility receptor are associated with biochemical failure in patients with intermediate‐grade prostate tumors

Abstract

Background The clinical course of prostate cancer (PCa) measured by biochemical failure (BF) after prostatectomy remains unpredictable in many patients, particularly in intermediate Gleason score (GS) 7 tumors, suggesting that identification of molecular mechanisms associated with aggressive PCa biology may be exploited for improved prognostication or therapy. Hyaluronan (HA) is a high molecular weight polyanionic carbohydrate produced by synthases (HAS1-3) and fragmented by oxidative/nitrosative stress and hyaluronidases (HYAL1-4, SPAM1) common in PCa microenvironments. HA and HA fragments interact with receptors CD44 and HMMR resulting in increased tumor aggressiveness in experimental PCa models. We evaluated the association of HA-related molecules with BF after prostatectomy in GS7 tumors. Methods Tissue microarrays were constructed from a 96-patient cohort. HA histochemistry and HAS2, HYAL1, CD44, CD44v6, and HMMR immunohistochemistry were quantified using digital pathology techniques. Results HA in tumor-associated stroma and HMMR in malignant epithelium were significantly and marginally significantly associated with time to BF in univariate analysis, respectively. After adjusting for clinicopathologic features, both HA in tumor-associated stroma and HMMR in malignant epithelium were significantly associated with time to BF. Although not significantly associated with BF, HAS2 and HYAL1 positively correlated with HMMR in malignant epithelium. Cell culture assays demonstrated that HMMR bound native and fragmented HA, promoted HA uptake, and was required for a pro-migratory response to fragmented HA. Conclusions HA and HMMR are factors associated with time to BF in GS7 tumors, suggesting that increased HA synthesis and fragmentation within the tumor microenvironment stimulates aggressive PCa behavior through HA-HMMR signaling.

RB Loss Promotes Prostate Cancer Metastasis

“…2E). Furthermore, as previously demonstrated (19), RHAMM expression is highly elevated in prostate cancer compared with normal prostate tissue. E2F1, CCNA1 , and MKI67 were utilized as controls and demonstrated similar trends (Fig.…”

“…4F; refs. 12, 19, 23). Thus, RHAMM overexpression mimics the RB-loss metastatic phenotype and is a clinically meaningful marker of metastatic disease.…”

“…42). Furthermore, high RHAMM expression is associated with biochemical failure in Gleason score 7 disease (19). It is also one of the three-protein signatures in a multi-biomarker predictive model that best predicts biochemical failure at 3 and 5 years (19).…”

Hyaluronan as a therapeutic target in human diseases

“…The peptide was also able to prevent nuclear accumulation of HA [158] and to inhibit prostate tumor cell migration toward to fragmented HA [304]. …”

Carcinoma Cell Hyaluronan as a “Portable” Cancerized Prometastatic Microenvironment

“…RHAMM is considered to be a tumor marker for leukemia [44] and colorectal subtypes [42]. Elevated RHAMM expression is associated with castration resistant disease in patients harboring prostatic metastases [36] and elevated levels of RHAMM and HA area associated with a likelihood of biochemical failure in at-risk (Gleason 7) prostatectomized patients [45]. RHAMM hyperexpression in breast primary tumor cell subpopulations is linked to increased peripheral metastases [46] while increased RHAMM expression in colorectal tumor budding cells at the invasive front of primary tumors is linked to frequent lymphatic invasion, high tumor grade and nodal metastasis [47].…”