卵巢癌肿瘤干细胞耐药性及其治疗的研究进展

肿瘤干细胞是肿瘤组织内具有自我更新能力及无限增殖潜能的一群细胞,对外源细胞毒性药物耐受。卵巢癌肿瘤干细胞在卵巢癌发生、化疗耐药和复发过程中起重要作用。传统治疗对减小肿瘤体积有效,但是治疗后残留的卵巢癌干细胞成为卵巢癌复发和难治的根源,针对卵巢癌肿瘤干细胞的靶向治疗可能在抗卵巢癌治疗中具有重要作用,为临床彻底治愈卵巢癌带来希望。     

CD133与肿瘤干细胞研究进展

越来越多的证据表明肿瘤中存在肿瘤干细胞(cancer stem cells),并且其与肿瘤的增殖、转移、复发和对放化疗不敏感关系密切.因此,肿瘤治疗应当针对肿瘤干细胞,通过特异表面标记分选肿瘤干细胞是研究其生长特点的前提.近年来,CD133为研究最多的在于细胞(stem cell)和多种组织肿瘤干细胞表面独立表达的特异标记分子.通过CD133可以分选干细胞、前体细胞和肿瘤干细胞.众多研究表明,CD133~+肿瘤细胞与肿瘤的自我更新、分化潜能、信号传导调控、药物耐受、复发和预后等均有相关性.CD133~+细胞有望在干细胞相关疾病的治疗和肿瘤靶向治疗中发挥巨大作用.     

肝癌干细胞表面标记物及靶向治疗的研究进展

肝癌是一种常常致命的恶性肿瘤,具有较高的复发率和化疗耐药性。 癌症的主要恶性表现包括复发、转移和化疗耐药性,且都与肿瘤干细胞（cancer stem cells,CSCs）的存在有关。 在过去的几十年中,CSCs已经在包括肝癌在内的许多肿瘤中被鉴定和确定。 越来越多的证据揭示了许多肝癌干细胞（liver cancer stem cells,LCSCs）的生物学行为及其调控的机制。 基于这些研究结果,LCSCs的根除是靶向治疗的目标之一。 本综述重点介绍LCSCs表面标记物最新进展及其靶向治疗策略的发展。     

卵巢癌干细胞标记物的研究进展

卵巢癌是致命的妇科癌症之一。虽然目前的治疗策略相对有效,但存在易复发及化疗耐药,其与卵巢癌干细胞有着密切的联系。肿瘤干细胞（CSC）是肿瘤内罕见的化疗耐药性细胞,其可以用更多分化的子细胞填充大部分肿瘤,并可能导致复发性疾病。目前,对卵巢癌干细胞的分离与鉴定已经开展了很多研究,并分析了卵巢癌干细胞特异性标记物的特性。本文旨在对卵巢癌干细胞标记物的相关研究以及其作为治疗靶点的潜力进行综述。     

肿瘤干细胞的研究进展

肿瘤干细胞(cancer stem cell)是存在于肿瘤组织中的一小部分具有干细胞性质的细胞群体.近年来,越来越多的学者认为肿瘤干细胞的残存是恶性肿瘤复发的根源.随着研究的深入,肿瘤干细胞的靶向治疗为恶性肿瘤的治疗带来了新的希望.     

肿瘤干细胞与肿瘤的诊断、转归和预后的关系

肿瘤干细胞(cancer stem cells,CSCs)是近年来干细胞研究和肿瘤研究的热点之一,它具有强大的自我更新和致瘤能力以及不断分化的潜能。目前研究发现肿瘤治疗后易复发、预后差、具有强耐药性与肿瘤中存在肿瘤干细胞有密切的关系。且肿瘤干细胞学说认为,肿瘤很可能是肿瘤干细胞产生的,并且已有学者和专家在造血系统肿瘤和多种实体瘤中分离并鉴定出肿瘤干细胞。对肿瘤干细胞、肿瘤干细胞与肿瘤的发生、发展、诊断、治疗及预后之间的关系作一综述。     

以肿瘤干细胞为靶点的肿瘤治疗新策略

肿瘤干细胞(cancer stem cells,CSCs)是存在于肿瘤组织中具有干细胞性质的细胞亚群,目前在脑肿瘤、乳腺癌、前列腺癌和结肠癌等实体瘤中均获得鉴定.CSCs具有自我更新的能力,被认为是肿瘤的起源.近年来,以CSCs为治疗靶点的研究已成为肿瘤治疗的新研究领域.     

超大剂量化疗在治疗卵巢癌中的应用

目前 ,卵巢癌仍然是妇科恶性肿瘤中死亡率最高的肿瘤 ,耐药和复发是治疗失败的主要原因 ,妇科肿瘤学者在不断地寻求新的治疗方法 ,以改善卵巢癌患者的生存率。在造血干细胞移植的支持下 ,超大剂量化疗治疗血液系统疾病和淋巴瘤、乳腺癌等实体瘤已经取得了较好的疗效 ,对卵巢癌的治疗也显示出了较好的应用前景。一、超大剂量化疗和造血干细胞移植临床实践证明 ,增加化疗药物剂量可显著提高对肿瘤细胞的杀伤作用。但化疗药物对正常骨髓细胞的抑制作用严重限制了其剂量的增加 ,并影响到实体瘤的治疗效果。造血干细胞移植是在患者接受化疗之前 ,…     

肿瘤微环境中间充质干细胞与癌症干细胞的关系及其在乳腺癌进展中的作用

乳腺癌是女性最高发的恶性肿瘤,在治疗过程中复发、转移、耐药等将显著降低患者的疗效,因此解决复发转移和耐药问题成为研究者关注的方向。近年来,癌症干细胞（cancer stem cells,CSCs）和间充质干细胞（mesenchymal stem cells,MSCs）在肿瘤微环境中调控癌症发生和发展的作用被广泛研究。本文就MSCs和CSCs在乳腺癌进展中的作用以及两者的潜在联系进行阐述,为后续开发新的治疗方案以改善乳腺癌患者预后提供方向和借鉴。     

肿瘤干细胞相关机制及靶向肿瘤干细胞治疗研究进展

肿瘤干细胞(cancer stem cells,CSCs)是肿瘤细胞中存在的小部分具有无限自我更新和多向分化潜能的细胞亚群,是肿瘤形成、复发、恶性转移和耐受放化疗性的细胞学根源.肿瘤干细胞的相关研究为肿瘤的治疗提供了新的思路,肿瘤干细胞靶向治疗可能成为肿瘤根治的希望.然而,目前对肿瘤干细胞的调控机制还不甚清楚,基于调控肿瘤干细胞的抗肿瘤治疗还有待成熟.本综述旨在总结近年来有关调控肿瘤干细胞及相关肿瘤治疗的主要研究进展,并对基于肿瘤干细胞调控的抗肿瘤治疗进行讨论和展望.     

SPOC1, a novel PHD-finger protein: association with residual disease and survival in ovarian cancer

We report the identification of a novel human gene (SPOC1) which encodes a protein with a PHD-finger domain. The gene is located in chromosomal region 1p36.23, a region implicated in tumor development and progression. RNA in situ hybridization experiments showed strong SPOC1 expression in some rapidly proliferating cell types, such as spermatogonia, but not in nonproliferating mature spermatocytes. In addition, high SPOC1 mRNA expression was observed in several ovarian cancer cell lines. This prompted us to systematically examine SPOC1 expression in ovarian cancer in relation to prognosis. SPOC1 mRNA expression was quantified in tumor tissue of 103 patients with epithelial ovarian cancer. Interestingly, SPOC1 was associated with residual disease, whereby patients with unresectable tumors showed higher levels compared to patients without residual tumor tissue after surgery (p = 0.029). The univariable proportional hazards model showed an association between SPOC1 expression and survival (p = 0.043, relative risk = 1.535). Median survival time was 1,596 days for patients with low SPOC1 expression vs. only 347 days for patients with high expression, using Kaplan-Meier analysis. However, SPOC1 was not associated with survival when multivariable analysis was adjusted for residual disease. This can be explained by the correlation between residual disease and SPOC1 expression. In conclusion, SPOC1 is a novel PHD-finger protein showing strong expression in spermatogonia and ovarian cancer cells. SPOC1 overexpression was associated with unresectable carcinomas and shorter survival in ovarian cancer.     

Hawaii natural compounds are promising to reduce ovarian cancer deaths

The low survival rate of patients with ovarian cancer largely results from the advanced ovarian tumors as well as tumor resistance to chemotherapy, leading to metastasis and recurrence. However, it is missing as to an effective therapeutic approach that focuses on these aspects to prolong progression-free survival and to decrease mortality in ovarian cancer patients. Here, based on our cancer drug discovery studies, we provide prospective insights into the development of a future line of drugs to effectively reduce ovarian cancer deaths. Pathways that increase the probability of cancer, such as the defective Fanconi anemia (FA) pathway, may render cancer cells more sensitive to new drug targeting.     

ATP生物荧光技术在卵巢癌体外药敏检测中的应用

目的 评价ATP生物荧光肿瘤药敏检测与临床疗效的相关性,探讨其临床应用价值。方法 对34例卵巢癌新鲜瘤组织和腹水进行肿瘤细胞分离、原代培养,以ATP生物荧光体外药敏检测技术进行检测。结果ATP生物荧光法测定细胞数量具有相关性好(r=0.9981),量程宽(10-100000个细胞),敏感性高(最小检测10个活细胞)的优点,其检测结果与其他方法相比有较高的相关性。32例卵巢癌病人体外药敏结果表明,其整体预测值为90.6％;其中阳性预测值为94.7％,阴性预测值为84.6％,敏感性90％,特异性91.7％。各种药物体外药敏检测结果与临床资料基本相符。结论 ATP生物荧光肿瘤药敏检测结果与临床疗效具有较好的相关性。该药敏检测方法对于筛选及临床应用新药,研究和确定新的化疗方案和治疗原则,评估联合用药方案,实现肿瘤病人的个体化化疗具有指导作用。     

Hospicells (ascites‐derived stromal cells) promote tumorigenicity and angiogenesis

The microenvironment is known to play a dominant role in cancer progression. Cells closely associated with tumoral cells, named hospicells, have been recently isolated from the ascites of ovarian cancer patients. Whilst these cells present no specific markers from known cell lineages, they do share some homology with bone marrow‐derived or adipose tissue‐derived human mesenchymal stem cells (CD9, CD10, CD29, CD146, CD166, HLA‐1). We studied the role of hospicells in ovarian carcinoma progression. In vitro, these cells had no effect on the growth of human ovarian carcinoma cell lines OVCAR‐3, SKOV‐1 and IGROV‐1. In vivo, their co‐injection with adenocarcinoma cells enhanced tumor growth whatever the tumor model used (subcutaneous and intraperitoneally established xenografts in athymic mice). In addition, their injection increased the development of ascites in tumor‐bearing mice. Fluorescent macroscopy revealed an association between hospicells and ovarian adenocarcinoma cells within the tumor mass. Tumors obtained by coinjection of hospicells and human ovarian adenocarcinoma cells presented an increased microvascularization indicating that the hospicells could promote tumorigenicity of ovarian tumor cells in vivovia their action on angiogenesis. This effect on angiogenesis could be attributed to the increased HIF1α and VEGF expression associated with the presence of the hospicells. Collectively, these data indicate a role for these ascite‐derived stromal cells in promoting tumor growth by increasing angiogenesis.     

Graphene oxide selectively targets cancer stem cells,across multiple tumor types: Implications for non-toxic cancer treatment,via “differentiation-based nano-therapy”

Tumor-initiating cells (TICs), a.k.a. cancer stem cells (CSCs), are difficult to eradicate with conventional approaches to cancer treatment, such as chemo-therapy and radiation. As a consequence, the survival of residual CSCs is thought to drive the onset of tumor recurrence, distant metastasis, and drug-resistance, which is a significant clinical problem for the effective treatment of cancer. Thus, novel approaches to cancer therapy are needed urgently, to address this clinical need. Towards this end, here we have investigated the therapeutic potential of graphene oxide to target cancer stem cells. Graphene and its derivatives are well-known, relatively inert and potentially non-toxic nano-materials that form stable dispersions in a variety of solvents. Here, we show that graphene oxide (of both big and small flake sizes) can be used to selectively inhibit the proliferative expansion of cancer stem cells, across multiple tumor types. For this purpose, we employed the tumor-sphere assay, which functionally measures the clonal expansion of single cancer stem cells under anchorage-independent conditions. More specifically, we show that graphene oxide effectively inhibits tumor-sphere formation in multiple cell lines, across 6 different cancer types, including breast, ovarian, prostate, lung and pancreatic cancers, as well as glioblastoma (brain). In striking contrast, graphene oxide is non-toxic for “bulk” cancer cells (non-stem) and normal fibroblasts. Mechanistically, we present evidence that GO exerts its striking effects on CSCs by inhibiting several key signal transduction pathways (WNT, Notch and STAT-signaling) and thereby inducing CSC differentiation. Thus, graphene oxide may be an effective non-toxic therapeutic strategy for the eradication of cancer stem cells, via differentiation-based nano-therapy.     

Eradication of chemotherapy-resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of Clostridium perfringens enterotoxin

BACKGROUND:

Emerging evidence has suggested that the capability to sustain tumor formation, growth, and chemotherapy resistance in ovarian as well as other human malignancies exclusively resides in a small proportion of tumor cells termed cancer stem cells. During the characterization of CD44⁺ ovarian cancer stem cells, we found a high expression of the genes encoding for claudin‐4. Because this tight junction protein is the natural high‐affinity receptor for Clostridium perfringens enterotoxin (CPE), we have extensively investigated the sensitivity of ovarian cancer stem cells to CPE treatment in vitro and in vivo.

METHODS:

Real‐time polymerase chain reaction and flow cytometry were used to evaluate claudin‐3/‐4 expression in ovarian cancer stem cells. Small interfering RNA knockdown experiments and MTS assays were used to evaluate CPE‐induced cytotoxicity against ovarian cancer stem cell lines in vitro. C.B‐17/SCID mice harboring ovarian cancer stem cell xenografts were used to evaluate CPE therapeutic activity in vivo.

RESULTS:

CD44⁺ ovarian cancer stem cells expressed claudin‐4 gene at significantly higher levels than matched autologous CD44^? ovarian cancer cells, and regardless of their higher resistance to chemotherapeutic agents died within 1 hour after exposure to 1.0 μg/mL of CPE in vitro. Conversely, small‐interfering RNA‐mediated knockdown of claudin‐3/‐4 expression in CD44⁺ cancer stem cells significantly protected cancer stem cells from CPE‐induced cytotoxicity. Importantly, multiple intraperitoneal administrations of sublethal doses of CPE in mice harboring xenografts of chemotherapy‐resistant CD44⁺ ovarian cancer stem cells had a significant inhibitory effect on tumor progression leading to the cure and/or long‐term survival of all treated animals (ie, 100% reduction in tumor burden in 50% of treated mice; P < .0001).

CONCLUSIONS:

CPE may represent an unconventional, potentially highly effective strategy to eradicate chemotherapy‐resistant cancer stem cells. Cancer 2011;. © 2011 American Cancer Society.