Roles of hyaluronic acid in cancer stem cell niche

总结 乳腺癌已经成为一种可治愈的疾病，如果它是在早期诊断;然而，超过90%的人， 乳腺癌死亡仍归因于转移，骨是转移性乳腺癌的主要远端器官。 肿瘤生长因此，阐明骨的确切病理机制至关重要 转移，以确定这种毁灭性疾病的特定治疗靶点。最近的癌症干细胞 仍然作为一种假设的理论预测，存在一种独特的转移细胞群， 具有茎状特征和入侵能力。我们的初步数据表明，（i）癌症干细胞样 来自高转移性细胞系的细胞（CSC）表达高水平的透明质酸合酶基因2（HAS 2） 这与患者的无转移生存率显著相关，（ii）CSC中的HAS 2显著激活 透明质酸对肿瘤相关巨噬细胞PDGF-BB表达的影响 (HA)在CSC和TAM中的CD 44，然后激活骨龛细胞中FGF 7和FGF 9的表达 随后刺激CSC的自我更新，和（iii）HAS 2的抑制剂，4 MU，可以阻断这种恶性循环， 在体内外均能显著抑制骨转移。在目前的拨款申请中， 我们提出了我们的新假设，即（i）CSC中HA的高表达有助于“接管”前 造血干细胞（HSC）在骨骼中的现有生态位，并激活TAM和动员 骨龛，其进而促进CSC的自我更新，和（ii）HAS 2的前药抑制剂， 用于转移性疾病的预防和治疗干预。为了验证这些假设，我们将 首先检查CSC的HAS 2在体内骨转移中的作用，并且还测试了新的“前- HAS 2抑制剂在我们的骨转移动物模型中的“药物”作用（目的1）。我们还将阐明 HAS 2通过动员体外骨微环境促进CSC的自我更新（目的2）。 此外，我们将直接研究HAS 2在乳腺癌转移中的临床相关性，并确定HAS 2在乳腺癌转移中的作用。 骨转移的潜在诊断/预后标志物（目的3）。该项目的最终目标是 明确骨转移的病理过程，并确定特定的治疗和预防目标， 这种毁灭性的疾病。我们确实相信，所提出的假设，如果被证明是有效的，将提出一个新的 范式，以了解骨转移的病理机制，这将显着影响 乳腺癌的治疗

Summary Breast cancer has become a curable disease if it is diagnosed at an early stage; however, more than 90% of breast cancer deaths are still attributed to metastases and bone is the major distant organ of metastatic breast tumor growth. Therefore, it is of paramount importance to elucidate the exact pathological mechanism of bone metastasis to identify a specific therapeutic target for this devastating disease. The recent cancer stem cell theory, which still remains as a hypothesis, predicts that there is a distinct population of metastatic cells that have stem-like characteristics as well as invasive ability. Our preliminary data indicate that (i) cancer stem-like cells (CSCs) from highly metastatic cell lines express a high level of hyaluronan synthase gene 2 (HAS2) which is significantly correlated with patient metastasis-free survival, (ii) HAS2 in CSCs significantly activates the expression of PDGF-BB in tumor associated macrophage (TAM) through interaction of hyaluronic acid (HA) in CSCs and CD44 in TAM, which then activates the expression of FGF7 and FGF9 in bone niche cells followed by stimulating self-renewal of CSCs and (iii) the inhibitor of HAS2, 4MU, can block this vicious cycle in the bone niche and significantly suppress bone metastasis in vitro and in vivo. In the current grant application, we propose our novel hypotheses that (i) high expression of HA in CSCs facilitates a "take-over" of pre- existing niche of hematopoietic stem cells (HSC) in the bone and activates TAM and mobilizes the bone niche, which in turn promotes self-renewal of CSC and (ii) a prodrug inhibitor for HAS2 can be used for preventive and therapeutic intervention of metastatic disease. To test these hypotheses, we will first examine the role of HAS2 of CSCs in bone metastasis in vivo and also test the efficacy of a novel "pro- drug" of HAS2 inhibitor in our animal model of bone metastasis (Aim 1). We will also elucidate the mechanism by which HAS2 promotes self-renewal of CSC by mobilizing bone microenvironment in vitro (Aim 2). Furthermore, we will directly examine the clinical relevance of HAS2 in breast cancer metastasis and identify potential diagnostic/prognostic markers for bone metastasis (Aim 3). The ultimate goal of this project is to define the pathological process of bone metastasis and identify specific therapeutic and preventive targets for this devastating disease. We do believe that the proposed hypothesis, if proven to be valid, will present a novel paradigm to understand the pathological mechanism of bone metastasis which will significantly impact the treatment of breast cancer.