Roles of hyaluronic acid in cancer stem cell niche

摘要 乳腺癌如果在早期被诊断出来，已经成为一种可以治愈的疾病；然而，超过90%的 乳腺癌的死亡仍然归因于转移，而骨是转移的乳房的主要远处器官。 肿瘤生长。因此，阐明骨骼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。最新的癌症干细胞 该理论仍然是一种假设，它预测有一组不同的转移细胞 具有类似茎的特征以及侵袭能力。我们的初步数据表明：(I)癌症干状 高转移细胞系的细胞(CSCs)高水平表达透明质酸合成酶基因2(HAS2) 与患者无转移生存期显著相关，(Ii)CSCs中HAS2显著激活 透明质酸作用下肿瘤相关巨噬细胞中血小板衍生生长因子-BB的表达 (HA)在的CSCs和CD44中，继而激活骨龛细胞中FGF7和FGF9的表达 其次是刺激CSCs的自我更新；(Iii)HAS2的抑制剂4MU可以阻断这一恶性循环 并在体外和体内显著抑制骨转移。在目前的拨款申请中， 我们提出了我们的新假设：(I)HA在CSCs中的高表达促进了Pre-Pre-Pre的“接管”。 骨骼中存在的造血干细胞生态位激活和动员 骨巢，进而促进CSC的自我更新和(Ii)HAS2的前体药物抑制剂可以 用于转移性疾病的预防和治疗干预。为了检验这些假设，我们将 首次研究了CSCs的HAS2在体内骨转移中的作用，并测试了一种新的“PRO-2”的疗效。 HAS2抑制剂药物在我们的骨转移动物模型中的作用(目标1)。我们还将阐明其机制 HAS2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HAS2在乳腺癌转移中的临床相关性，并确定 骨转移的潜在诊断/预后标记物(目标3)。这个项目的最终目标是 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。我们相信，提出的假设，如果被证明是有效的，将提出一种新的 范式理解骨转移的病理机制，这将显著影响 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.