Pentraxin-3 in the Pathogenesis and Management of Triple-Negative Breast Cancer

摘要 背景资料。三阴性乳腺癌(TNBCs)表现为晚期组织学分级和 具有攻击性的临床行为。他们对常规的全身治疗完全没有反应，而且 难治性疾病患者的复发率和令人沮丧的5年生存率都有所增加。可靠 因此，TNBC的生物标记物和靶向治疗是迫切需要的，但仍有待定义。 初步调查结果。我们发现PTX3在TNBC标本和患者体内尤其丰富。 衍生异种移植物(PDX)，其水平与TNBC不良患者呈正相关和特异性相关 生死存亡。我们发现，PTX3具有肿瘤干细胞(CSC)样特征，它促进了癌细胞 在悬液中生长，并促进TNBC转移成倍增加。此外，我们还演示了 PTX3激活了抗凋亡通路，并使TNBC细胞对化疗脱敏。遗传 抑制PTX3抑制癌基因诱导的细胞生长，抑制TNBC细胞的恶性特征， 如迁徙和锚地独立增长。重要的是，我们发现循环中的PTX3水平， 它是由TNBC细胞分泌的，与临床前模型中的肿瘤负担有关，尤其是 在TNBC患者中升高。最后，我们发现PTX3的抗体中和导致了TNBC细胞的死亡。 假设。我们假设PTX3是TNBC患者风险分层的关键生物标志物，并且 它是恶性肿瘤的决定性功能驱动因素，也是翻译效用的易处理的治疗靶点 TNBC管理。 具体目标和研究设计。我们将建立PTX3作为临床TNBC的预后生物标志物(AIM 1)，确定PTX3如何调节恶性进展(目标2)，并将PTX3确立为TNBC疗法 目标(目标3)。为此，我们将把肿瘤和循环中PTX3的水平与患者的存活率联系起来。 应用聚合酶链式反应、原位和酶联免疫吸附试验对一大批TNBC患者的回顾性分析 (目标1.1和1.2)。然后我们将确定PTX3在调节自我更新和肿瘤启动中的作用 CSCs的功能(Aim 2.1)，识别PTX3促进的转移步骤(Aim 2.2)并评估其 在体外和体内对化疗耐药性的贡献(目标2.3)。最后，我们将确定 PTX3对使用异种移植的已建立转移瘤的起始(目标3.1)、存活和生长(目标3.2)的作用 模型，以及研究抗PTX3中和抗体抑制肿瘤生长的能力 使用患者来源的异种移植和同基因小鼠癌症模型(AIM 3.3)。 冲击力。我们寻求的结果将引入新的理论，潜在的突破性效用在管理 侵袭性和难以治疗的乳腺癌，迫切需要有针对性的治疗。

SUMMARY Background. Triple-negative breast cancers (TNBCs) present with advanced histological grade and aggressive clinical behavior. They are overwhelmingly unresponsive to conventional systemic treatments, and patients with refractory disease have increased recurrence and dismal 5-year survival rates. Reliable biomarkers and targeted therapies for TNBC are therefore critically needed, but remain to be defined. Preliminary findings. We found that PTX3 was particularly abundant in TNBC specimens and in patient- derived xenografts (PDX), and that its levels positively and specifically correlated with adverse TNBC patient survival. We show that PTX3 propagated cancer-stem-cell (CSC) -like traits, that it promoted cancer cell growth in suspension, and that it promoted multifold increase in TNBC metastasis. In addition, we demonstrate that PTX3 activated anti-apoptotic pathways and de-sensitized TNBC cells to chemotherapy. Genetic suppression of PTX3 inhibited oncogene-induced cell growth, and quelled malignant features of TNBC cells, such as migration and anchorage-independent growth. Importantly, we show that circulating levels of PTX3, which is secreted by TNBC cells, associated with tumor burden in preclinical models and were particularly elevated in TNBC patients. Finally, we show that antibody neutralization of PTX3 caused TNBC cell death. Hypotheses. We hypothesize that PTX3 is a critical biomarker for risk stratification of TNBC patients, and that it is a decisive functional driver of malignancy and a tractable therapeutic target of translational utility in TNBC management. Specific aims and study design. We will establish PTX3 as a prognostic biomarker in clinical TNBC (aim 1), determine how PTX3 regulates malignant progression (aim 2), and establish PTX3 as a TNBC therapeutic target (aim 3). To this end, we will correlate tumoral and circulating levels of PTX3 to patient survival in retrospective analyses of a large TNBC patient cohort using PCR-, -in situ, and ELISA-based approaches (aims 1.1 and 1.2). We will then determine the role of PTX3 in regulating self-renewal and tumor-initiating functions of CSCs (aim 2.1), identify the metastatic steps facilitated by PTX3 (aim 2.2) and assess its contributions to chemoresistance in vitro and in vivo (aim 2.3). Finally, we will determine the essentiality of PTX3 to the initiation (aim 3.1), survival, and growth of established metastases (aim 3.2) using xenograft models, as well as investigate the ability of anti-PTX3 neutralizing antibodies to suppress tumorigenic growth using patient-derived xenograft and syngeneic murine cancer models (aim 3.3). Impact. Our sought results will introduce novel theranostics of potential groundbreaking utility in managing aggressive and difficult-to-treat breast cancers for which targeted therapies are sorely needed.