高透明质酸和透明质酸介导的运动受体与中等级别前列腺肿瘤患者的生化失败相关。
Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors.
机构信息
Department of Pathology, University of Washington, Seattle, Washington; Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
出版信息
Cancer. 2014 Jun 15;120(12):1800-9. doi: 10.1002/cncr.28646. Epub 2014 Mar 25.
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 through HAS3) and fragmented by oxidative/nitrosative stress and hyaluronidases (HYAL1 through HYAL4, SPAM1) common in PCa microenvironments. HA and HA fragments interact with receptors CD44 and hyaluronan-mediated motility receptor (HMMR), resulting in increased tumor aggressiveness in experimental PCa models. This study 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 promigratory 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.
背景
前列腺癌（PCa）患者经前列腺切除术治疗后，生化复发（BF）所反映的临床病程仍具有不可预测性，尤其是在中等级别（GS）7 的肿瘤患者中，这表明识别与侵袭性 PCa 生物学相关的分子机制可能有助于改善预后或治疗效果。透明质酸（HA）是一种高分子量多糖，由合成酶（HAS1 到 HAS3）合成，并通过氧化/硝化应激和透明质酸酶（HYAL1 到 HYAL4、SPAM1）分解，这些酶在 PCa 微环境中普遍存在。HA 及其片段与受体 CD44 和透明质酸介导的运动受体（HMMR）相互作用，导致实验性 PCa 模型中的肿瘤侵袭性增加。本研究评估了 HA 相关分子与 GS7 肿瘤前列腺切除术后 BF 的相关性。
方法
从 96 例患者队列中构建组织微阵列。使用数字病理学技术对肿瘤相关基质中的 HA 组织化学染色和 HAS2、HYAL1、CD44、CD44v6 和 HMMR 免疫组化进行定量分析。
结果
在单变量分析中，肿瘤相关基质中的 HA 和恶性上皮中的 HMMR 分别与 BF 时间呈显著和边缘显著相关。在调整了临床病理特征后，肿瘤相关基质中的 HA 和恶性上皮中的 HMMR 与 BF 时间均呈显著相关。尽管与 BF 无显著相关性，但 HAS2 和 HYAL1 与恶性上皮中的 HMMR 呈正相关。细胞培养实验表明，HMMR 结合天然和片段化的 HA，促进 HA 的摄取，并且是对片段化 HA 产生促迁移反应所必需的。
结论
HA 和 HMMR 是 GS7 肿瘤与 BF 时间相关的因素，这表明肿瘤微环境中 HA 合成和片段化的增加通过 HA-HMMR 信号刺激侵袭性 PCa 行为。
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