低氧微环境与卵巢癌转移相关性研究进展

肿瘤微环境是肿瘤细胞、内皮细胞、免疫细胞、成纤维细胞及细胞外基质等共同构成的肿瘤的局部病理环境。大量研究结果显示,肿瘤转移与肿瘤微环境中的多种因素密切相关。低氧是恶性肿瘤微环境的特征之一,低氧微环境在肿瘤组织的生长、代谢、转移及耐药过程中发挥着重要的作用,尤其是与肿瘤转移密切相关。卵巢恶性肿瘤死亡率居妇科肿瘤首位,卵巢癌缺乏早期诊断的指标,易早期转移、浸润以及其对化疗药物的耐受,是造成其高死亡率、影响预后的关键因素。因此,深入探讨卵巢癌转移与低氧微环境的关系,寻求有效抑制转移的新靶点,对于肿瘤的诊断及治疗具有重要的作用。     

妇科肿瘤与炎症

证据表明,炎症在恶性肿瘤的发生、发展等方面发挥着重要作用,同时固有免疫的某些信号分子,如选择素、趋化因子及其受体能促进肿瘤细胞侵袭、迁移和转移,从而促进肿瘤转移.肿瘤细胞、周围正常的宿主基质细胞和浸润的炎性细胞共同组成一个整体--肿瘤微环境,这一微环境包含各类炎性细胞和炎性分子,是肿瘤细胞持续增殖的基础.研究炎症与妇科...     

肿瘤间质在卵巢癌中的研究进展

肿瘤间质包括间质肌纤维母细胞、上皮细胞、粒细胞等。大量研究表明,肿瘤间质可产生诸如蛋白酶、生长因子、免疫调节因子等大量分子,通过影响肿瘤微环境中细胞内外双向的信号交换网络,参与肿瘤细胞的增殖分化、细胞凋亡、黏附及迁移等过程,与多种肿瘤的发生发展密切相关。近年研究表明,肿瘤间质在卵巢癌的发生发展、侵袭转移等过程中扮演重要角色,其与卵巢癌临床病理特征及预后有关,已成为当前卵巢癌生物学干预治疗的热门靶点。     

卵巢癌转移前微环境免疫抑制的形成及其机制

腹膜广泛转移是导致卵巢癌患者手术难以切净、反复复发以及生存预后差的主要原因之一。研究发现，卵巢癌转移前通过肿瘤细胞、免疫抑制细胞和间质细胞的相互作用在腹膜特定部位形成免疫抑制的转移前微环境，包括肿瘤细胞自身特性改变、免疫细胞募集及功能异常、间质细胞分布及调控能力异常等。本文就卵巢癌转移前微环境免疫抑制的形成及其机制进行综述，以期探寻卵巢癌转移中关键分子，明确免疫逃逸关键机制，为临床卵巢癌的治疗提供新的思路。     

免疫检查点PD-1/PD-L1在卵巢癌诊治及预后方面的应用进展

卵巢癌是死亡率最高的妇科恶性肿瘤。因其起病隐匿,不易早期诊断,并具有易转移、易复发,且易耐药等特性,卵巢癌患者死亡率居高不下。免疫治疗在卵巢癌中的应用是近年来的研究热点,其通过增强患者自身免疫细胞功能或解除肿瘤局部免疫抑制微环境,起到杀伤肿瘤细胞的作用。程序性细胞死亡蛋白1（PD-1）及其配体PD-L1是重要的免疫调控信号分子,PD-1/PD-L1信号通路可影响T淋巴细胞浸润及功能,在肿瘤局部抑制性免疫微环境的形成中发挥重要作用。研究表明,阻断PD-1/PD-L1信号通路可以促进微环境中免疫细胞发挥原有抗肿瘤功能。现就PD-1/PD-L1分子在卵巢癌诊治、预后判断及该分子通路阻断在疾病临床治疗的应用方面进行综述。     

明胶酶与卵巢癌侵袭转移关系的研究

卵巢癌目前仍是病死率最高的妇科恶性肿瘤 ,肿瘤的局部侵袭和弥漫的腹腔内转移是卵巢癌患者治疗失败和死亡的直接原因。肿瘤的侵袭转移是一复杂的、多步骤的肿瘤细胞与宿主细胞及基质间相互作用的过程 ,但肿瘤细胞对细胞外基质的破坏是肿瘤细胞侵袭转移的基本模式。在卵巢癌侵袭转移中 ,肿瘤细胞降解细胞外基质造成局部侵袭、腹腔种植、穿透血管壁 ,实现远处转移[1] 。大量实验表明 ,明胶酶介导的基质降解对肿瘤的侵袭和转移起着极为重要的作用 ,也是目前研究肿瘤侵袭和转移的热点。1　明胶酶的结构明胶酶 (ｇｅｌａｔｉｎａｓｅ)有Ａ、Ｂ两…     

外泌体参与重塑卵巢上皮性癌微环境的研究进展

卵巢上皮性癌（卵巢癌）是死亡率最高的妇科恶性肿瘤,腹腔内播撒是其主要的生物学特征之一,究其原因可能与腹腔局部微环境有关。近年的研究发现,外泌体参与了卵巢癌细胞及其微环境之间信息的传递,对卵巢癌微环境的重塑起着尤为重要的作用,进而影响肿瘤的生长、转移及耐药等各种恶性生物学行为。本文就外泌体参与重塑卵巢癌微环境的研究进展进...     

免疫检查点PD-1/PD-L1在卵巢癌诊治及预后方面的应用进展

卵巢癌是死亡率最高的妇科恶性肿瘤。因其起病隐匿,不易早期诊断,并具有易转移、易复发,且易耐药等特性,卵巢癌患者死亡率居高不下。免疫治疗在卵巢癌中的应用是近年来的研究热点,其通过增强患者自身免疫细胞功能或解除肿瘤局部免疫抑制微环境,起到杀伤肿瘤细胞的作用。程序性细胞死亡蛋白1(PD-1)及其配体PD-L1是重要的免疫调控信号分子,PD-1/PD-L1信号通路可影响T淋巴细胞浸润及功能,在肿瘤局部抑制性免疫微环境的形成中发挥重要作用。研究表明,阻断PD-1/PD-L1信号通路可以促进微环境中免疫细胞发挥原有抗肿瘤功能。现就PD-1/PD-L1分子在卵巢癌诊治、预后判断及该分子通路阻断在疾病临床治疗的应用方面进行综述。     

肿瘤细胞与淋巴管内皮细胞的交互作用及转移

肿瘤淋巴转移是医学界亟待解决的难题之一,以往研究多集中在肿瘤细胞本身,难以全面阐释淋巴转移的发病机制。近年研究发现,肿瘤细胞能与肿瘤微环境中其他细胞发生交互作用,淋巴管内皮细胞（lymphatic endothelial cell,LEC）是肿瘤微环境中的重要一员,与肿瘤的淋巴转移密切相关。鉴于此,深入研究肿瘤细胞与LEC的交互作用可能会为肿瘤淋巴转移的病因研究及传统抗癌治疗带来新的曙光。     

鞘氨醇-1-磷酸与卵巢癌的研究进展

鞘氨醇-1-磷酸（S1P）是鞘磷脂代谢产生的一种生物活性脂类,在多种癌症中对肿瘤具有促进作用。细胞内S1P生成由鞘氨醇激酶（SphKs）等调控,与相应受体（S1PR）结合发挥生物学效应。近年来涉及S1P与卵巢癌相关的研究提示卵巢癌患者中S1P呈高表达状态,其可以通过参与促进卵巢癌细胞的增殖和转移、抑制肿瘤细胞凋亡、诱导新生血管形成以及改变肿瘤免疫微环境状态等多种方式调节肿瘤细胞生物学行为,促进卵巢癌的发生和发展。阻断S1P信号传导途径中关键蛋白（包括S1P、SphK1、S1PR等）的相关药物能够抑制卵巢癌细胞生长及诱导细胞凋亡。因此,S1P相关途径可能成为卵巢癌治疗的潜在分子目标。本文简要综述了S1P信号通路在卵巢癌中的生理功能及相关药物研究进展。     

Manipulating the Wnt/β-catenin signaling pathway to promote anti-tumor immune infiltration into the TME to sensitize ovarian cancer to ICB therapy

ObjectiveImmune checkpoint blockade (ICB) therapy shows limited efficacy in ovarian cancers due to the “cold” immune phenotype surrounding these tumors. Previous studies have shown that in ovarian cancer Wnt/β-catenin pathway activation contributes to this immune phenotype. Here, we evaluated the anti-tumor and immune-enhancing properties of the Wnt inhibitor, CGX-1321, used alone or in combination with either DKN-01 or anti-PD-1 therapy, in pre-clinical ovarian cancer models.MethodsThe parental ID8 murine ovarian cancer model harboring a knock-out of p53 (ID8p53^?/?) and MISIIR-Tag spontaneous ovarian cancer models were used to test the effects of CGX-1321 alone or in combination therapies on tumor burden and immune cell landscape in the tumor microenvironment (TME). Flow cytometry and NanoString analyses were used to characterize the changes in tumor-intrinsic signaling and immune-related profiles in the TME of ovarian cancer in response to treatments.ResultsCGX-1321 significantly reduced tumor burden and constrained tumor progression in the ID8p53^?/? and MISIIR-Tag models. Furthermore, CGX-1321 increased infiltrating CD8+ T cells in the TME. Combining CGX-1321 with either DKN-01 or anti-PD-1 therapy also decreased tumor burden and increased CD8+ T cell infiltration in the omentum TME but did not do so to a greater extent that CGX-1321 monotherapy.ConclusionsCGX-1321 significantly reduced tumor burden and enhanced CD8+ T cell levels in ovarian cancer, nevertheless the addition of DKN-01 or anti-PD-1 therapies did not enhance these effects of CGX-1321. Further investigation is needed to determine if CGX-1321 + DKN-01 combination treatment sensitizes pre-clinical ovarian cancer to ICB therapy.     

Immunobiology of gestational trophoblastic diseases

Gestational trophoblastic diseases (GTDs) comprise a group of interrelated diseases characterized by development after gestation, widespread metastases, and high curability with chemotherapy. The good prognosis of GTDs is considered partly a result of the host immune response to paternal antigens expressed on trophoblastic cells. In this study, we review current understanding of the immunobiology of GTDs. First of all, we describe the microenvironment between trophoblastic cells and subpopulation of immune cells. Second, immunogenetics, immune microenvironment around abnormal trophoblast, and mechanism of GTDs escaping from maternal immune system surveillance were also discussed. Third, we propose the possible immunotherapy for persistent GTDs, particularly the vaccine designed on human chorionic gonadotrophin, which is generally accepted as a tumor marker for GTDs diagnosis. Due to the low incidence of GTDs and high response to chemotherapy, there have been few literatures about immunobiologic characteristics of GTDs compared with the other gynecologic malignancies, such as ovarian cancer, but the immunologic behavior of GTDs should be explored for further understanding of the etiology of these diseases and to help designing immunotherapeutic strategies for persistent GTDs.     

Stromal POSTN induced by TGF-β1 facilitates the migration and invasion of ovarian cancer

ObjectivePeriostin (POSTN) overexpression observed in various cancer types is correlated with metastasis and tumor progression. However, its effect on the crosstalk between ovarian cancer cells and cancer-associated fibroblasts (CAFs) remains elusive. This study aims to ascertain the role of CAF-derived POSTN in the ovarian cancer microenvironment.MethodsPOSTN expression in high-grade serous ovarian cancer (HGSC) was detected through immunochemistry. Transwell assay was conducted to determine cell migration and invasion. POSTN was knocked down or overexpressed using lentiviral vectors. The potential downstream effects of POSTN were explored and verified by RNA sequencing and western blotting, respectively. In vitro metastatic capability of ovarian cancer cells regulated by POSTN was determined by indirect co-culture.ResultsPOSTN was highly enriched in HGSC stromal components, particularly in fibroblasts, while its overexpression was correlated with reduced overall survival (OS). CAF-derived POSTN functioned as a ligand for integrin αvβ3, fueling the migration and invasion of ovarian cancer cells by activating the PI3K/Akt pathway and inducing the epithelial-mesenchymal transition (EMT). Additionally, the pro-metastatic properties and the activation of fibroblasts induced by TGF-β1 partly relied on POSTN.ConclusionsStromal-derived POSTN drives the remodeling of the pro-metastatic microenvironment, which might be as a potential therapeutic target in patients with ovarian cancer.     

树突状细胞体外诱导抗卵巢癌免疫的实验研究

目的 观察人外周血树突状细胞(Dendritic cells,DC),体外能否诱导抗卵巢癌免疫应答。方法 用粒细胞-巨噬细胞集落刺激因子(GM-CSF)、白介素-4(IL-4)和肿瘤坏死因子α(TNF-α)从健康女性外周血分化诱导DC,以源于人卵巢癌细胞系HO-8910的肿瘤抗原粗提物冲击致敏DC,将致敏DC、同源淋巴细胞和卵巢癌细胞共育,观察负载抗原DC体外诱导淋巴细胞对HO-8910细胞的杀伤作用,同时设不同类型肿瘤细胞(Eca-109和PC-12)作为对照。MTT法测定细胞杀伤活性。结果 经卵巢癌细胞HO-8910肿瘤抗原脉冲致敏的DC能诱导淋巴细胞特异性地杀伤卵巢癌细胞。结论 用GM-CSF、IL-4和TNF-α从人外周血诱生的DC能从卵巢癌细胞HO-8910冻融物有效递呈抗原并诱导出高效而特异的抗卵巢癌免疫反应。     

EpCAM在上皮性卵巢癌中的应用与研究进展

上皮性卵巢癌是死亡率最高的妇科恶性肿瘤,由于症状隐匿并缺乏有效的筛选工具,临床早期很难诊断。最近有研究表明上皮细胞黏附分子(epithelial cell adhesion molecule,Ep CAM)可作为早期检测和卵巢癌预后治疗的生物标志物之一。EpCAM是第1个通过单克隆抗体识别的人类肿瘤特异性抗原,在上皮性卵巢癌中高表达。其能够调节上皮细胞完整性,介导卵巢癌细胞间黏附、迁移作用,同时在卵巢癌细胞侵袭中发挥重要作用,其表达与卵巢癌患者预后密切相关。目前作为一种重要的肿瘤标志物,EpCAM成为卵巢肿瘤免疫治疗的新靶点及评价患者预后的重要指标。EpCAM在上皮性卵巢癌中的高表达对于肿瘤的治疗、预后有重要意义。现对Ep CAM在上皮性卵巢癌中的应用与研究进展进行综述。     

间皮素在卵巢癌肿瘤微环境中作用的研究

卵巢癌死亡率高，早期诊断困难，而提高早期诊断率至关重要。间皮素（mesothelin，MSLN）与卵巢癌的发生、发展密切相关，在卵巢癌肿瘤微环境中起到重要作用。MSLN是一种糖蛋白，在许多癌症（包括卵巢癌和间皮瘤）中过表达，在细胞存活、增殖和肿瘤进展、黏附中起作用。CA125是MSLN的配体，两者相互结合成为MSLN:CA125复合体，介导卵巢癌细胞腹膜种植。MSLN的肿瘤特异性表达可用于癌症早期诊断，评估卵巢癌的治疗效果，检测原发肿瘤和转移病灶的分布，成为新治疗靶点并进行肿瘤免疫靶向治疗。尽管已开展的MSLN靶向免疫毒素、抗MSLN嵌合抗体等药物和肿瘤疫苗的临床试验提示MSLN可作为潜在肿瘤治疗靶点，改善肿瘤治疗的临床效果，但还需要更多的研究证实MSLN在肿瘤转移中的作用及其治疗方案。     

MUC16在卵巢癌发生发展中的研究进展

MUC16,又名CA125,是一种表达于各类上皮细胞表面的高分子量糖蛋白,主要发挥保护和修复上皮的作用。MUC16是早期诊断上皮性卵巢癌的重要肿瘤指标,广泛应用于临床。近来研究发现,MUC16的异常表达与卵巢癌的不良预后和发生发展密切相关。MUC16可以通过与间皮素结合促进卵巢癌远处转移,可以通过抑制肿瘤细胞和免疫细胞形成免疫突触帮助卵巢癌细胞实现免疫逃逸。MUC16还可以通过在卵巢癌中的过表达来影响肿瘤细胞的上皮间质转化（EMT）、增殖、迁移和转移,促进卵巢癌的发生发展。尽管有关MUC16与卵巢癌的研究逐渐取得进展,但MUC16的生化结构及其在卵巢癌中具体作用机制仍处于研究阶段。综述MUC16的生化结构及其在卵巢癌细胞的免疫逃逸和卵巢癌增殖、迁移、侵袭和转移中的研究进展,旨在为卵巢癌的治疗提供新的靶点。     

Translocation of Fas by LPA prevents ovarian cancer cells from anti-Fas-induced apoptosis

OBJECTIVES: Alterations in the expression of Fas have been demonstrated in various cancers as a mechanism for tumor cells to escape from immune surveillance. In this study, we observed the effect of lysophosphatidic acid (LPA) on Fas expression and function in ovarian cancer cells. METHODS: Ovarian cancer cell lines were incubated with or without LPA and Fas cell surface presentations were detected by flow cytometry. Anti-Fas IgM was added for induction and analysis of apoptosis by flow cytometry. Cell lysis and subcellular fractions were probed for protein expression by Western blot. Cells were also stained with human anti-Fas Ab, followed with Rhodamine red-X-conjugated goat anti-mouse IgG, and immunofluorescence images were acquired on a Nikon digital camera. RESULTS: Following treatment with LPA, ovarian cancer cells showed significant rapid reduction of Fas presentation on the cell surface. LPA protected ovarian cancer cells from anti-Fas-induced apoptosis. Cell lysis and subcellular fractionations proved that LPA treatment induced a translocation of Fas receptors, along with phosphorylated ezrin, from the membrane anchored to the actin cytoskeleton, to the cytosol. Translocation of the Fas receptor reduced Fas concentration in the membrane and may inhibit its clustering and internalization during early apoptosis induced by anti-Fas. DISC staining proved that LPA inhibited Fas receptor aggregation and caspase-8 activation at the membrane, which further inhibited caspase-3 and 7 activation in the cytosol. CONCLUSIONS: Our studies suggest that LPA induces translocation of Fas from the cell membrane to the cytosol, which may provide a mechanism by which ovarian cancer cells evade FasL-bearing immune cells.