肿瘤干细胞糖代谢的研究进展

正常干细胞与缺氧关系密切,在不同阶段有不同的糖代谢特点,主要以糖酵解为主,既可以快速产生ATP,又可以减少ROS产生,以保证干细胞的稳态。肿瘤干细胞线粒体功能障碍,决定了它也是以糖酵解代谢为主。微环境中的氧和葡萄糖浓度都影响着肿瘤干细胞的干性变化,并且糖酵解抑制剂显示了显著的杀伤肿瘤干细胞的能力,这是提高肿瘤疗效的方向之一。     

乳腺癌干细胞的研究进展

乳腺癌是对广大女性威胁最大、最为常见的恶性肿瘤,其高度的异质性使乳腺癌患者的临床表现、形态学特征以及分子生物学表达均呈现出明显的不一致性,给诊断和治疗带来了很大的困难,这使得人们开始探寻导致乳腺癌高度异质性的原因,多方面的研究探索将人们的注意力引入乳腺癌的起源问题。近年的文献相继报道了有关乳腺癌干细胞的研究,文章对此作一综述。     

Basal-like乳腺癌与干细胞的研究进展

0引言目前基于基因谱将乳腺癌划分为5个分子亚型[1-2],其中Basa1-1ike乳腺癌具有独特的基因表型和形态特点,其恶性程度高,侵袭性强,临床预后差,引起了国内外肿瘤学家的高度关注.肿瘤干细胞是最近几年来肿瘤发生机制研究领域的热点,笔者就Basa1-1ike乳腺癌及其与乳腺癌干细胞相关性作一综述.     

Genomic Profiling Shows Increased Glucose Metabolism in Luminal B Breast Cancer

We had previously reported a close association between pathological response and the maximum tumor standardized uptake value (SUVmax) measured by ¹⁸F-fluorodeoxyglucose positron emission tomography prior to chemotherapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that glucose hypermetabolism by luminal B tumors may result in chemotherapy responsiveness. Using a single-gene expression assay, TargetPrint® (Agendia) and a 70-gene expression classifier, MammaPrint® (Agendia), we divided 20 patients with ER-positive primary breast cancer into luminal A and luminal B subtypes and compared the tumor SUVmax value between the two groups. A significantly higher SUVmax was measured for luminal B tumors (n=10; mean±SD, 7.6±5.6) than for luminal A tumors (n=10; mean±SD, 2.6±1.2; p=0.01). Glucose hypermetabolism could help predict intrinsic subtyping and chemotherapy responsiveness as a supplement to ER, progesterone receptor, HER2, and Ki-67 histochemical scores.     

乳腺干细胞和乳腺癌

乳腺干细胞是一种未分化的细胞，具有永远增殖和自我更新能力。乳腺癌中的癌症干细胞可能起源于正常干细胞，以细胞表面标志CD44^＋/CD24^-/low识别。癌症干细胞可能为肿瘤转移和复发的原因。识别乳腺癌干细胞和普通癌症细胞之间的差异，可以发展更有效的诊断和治疗方法。     

Ampelopsin Inhibits Breast Cancer Glucose Metabolism Reprogramming Based on Network Pharmacology and Molecular Docking

Background: Breast cancer (BC) is the most frequent type of gynecology tumors with high morbidity and mortality. Ampelopsin, the main active compound of Ampelopsis grossedentata, exerts an anti-tumor effect on a variety of cancers. However, the anti-cancer role of ampelopsin in BC remains unclear. The aim of this study is toexplore the mechanism of ampelopsin against breast cancer. Materials and Methods: The target genes of ampelopsin in the treatment of breast cancer were determined and analyzed by network pharmacology and moleculardocking. Cytoscape software was used to identify the core target genes and construct a protein–protein interaction(PPI) network. Discovery Studio software was used to perform the molecular docking of ampelopsin and coregenes and glycolytic metabolic enzymes. Results: In total, 25 potential target genes of ampelopsin were screenedout. The core target genes of ampelopsin against breast cancer were AKT1, ESR1, ESR2, NCOA1, HSP90AA1,NCOA2, BECN1, COMT, HMOX1, and CDK6, with AKT1, ESR1 and ESR2 considered as the key target proteins.Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that ampelopsin inhibited breast cancer viamodulating the estrogen signaling pathway, apoptosis regulation, carbohydrate metabolism, and inflammation.Molecular docking analysis showed that ampelopsin possessed a stable binding ability to regulate the three targetproteins and glycolytic metabolic enzymes such as ALDOA and LDHA. Conclusions: Ampelopsin may inhibitthe proliferation of breast cancer cells by acting on AKT and estrogen-related glucose metabolic pathways andinhibiting the enzymes involved in glycolysis and oxidative phosphorylation.     

乳腺癌干细胞相关信号通路及其抑制剂的研究进展

摘 要：乳腺癌干细胞是乳腺癌组织中少数具备自我更新能力与多向分化潜能的细胞,与乳腺癌的发生发展密切相关。目前,乳腺癌治疗后易转移、易复发与乳腺癌干细胞的存在相关。乳腺癌干细胞信号通路在激活乳腺癌细胞功能、乳腺癌调控细胞分化以及控制乳腺癌细胞分裂方面起着关键作用,打破其平衡状态将导致乳腺癌细胞失控性增长及肿瘤发生。针对相应通路进行阻断性靶向治疗可能成为乳腺癌治疗的新视角。全文主要就乳腺癌干细胞相关信号通路及其抑制剂的研究进展进行阐述,以期为乳腺癌患者获得更加有效的临床治疗提供参考。     

Tumor-Endothelial Interaction Links the CD44+/CD24- Phenotype with Poor Prognosis in Early-Stage Breast Cancer

Materials and Methods

The genomic effects of tumor-endothelial interactions in cancer are not yet well characterized. To study this interaction in breast cancer, we set up an ex vivo coculture model with human benign and malignant breast epithelial cells with endothelial cells to determine the associated gene expression changes using DNA microarrays.

Results

The most prominent response to coculture was the induction of the M-phase cell cycle genes in a subset of breast cancer cocultures that were absent in cocultures with normal breast epithelial cells. In monoculture, tumor cells that contained the stem cell-like CD44⁺/CD24^- signature had a lower expression of the M-phase cell cycle genes than the CD44^-/CD24⁺ cells, and in the CD44⁺/CD24^- cocultures, these genes were induced. Pretreatment gene expression profiles of early-stage breast cancers allowed evaluating in vitro effects in vivo. The expression of the gene set derived from the coculture provided a basis for the segregation of the tumors into two groups. In a univariate analysis, early-stage tumors with high expression levels (n = 137) of the M-phase cell cycle genes had a significantly lower metastasis-free survival rate (P = 1.8e - 5, 50% at 10 years) and overall survival rate (P = 5e - 9, 52% at 10 years) than tumors with low expression (n = 158; metastasis-free survival, 73%; overall survival, 84%).

Conclusions

Our results suggest that the interaction of endothelial cells with tumor cells that express the CD44⁺/CD24^- signature, which indicates a low proliferative potential, might explain the unexpected and paradoxical association of the CD44⁺/CD24^- signature with highly proliferative tumors that have an unfavorable prognosis.     

USP22 Contributes to Chemoresistance,Stemness, and EMT Phenotype of Triple-Negative Breast Cancer Cells by egulating the Warburg Effect via c-Myc Deubiquitination

BackgroundUbiquitin-specific protease 22 (USP22) has been implicated in the progression of breast cancer, while its regulatory functions in triple-negative breast cancer (TNBC) have been rarely reported. This study aimed to elucidate the effect and mechanism of USP22 on the malignant phenotype of TNBC cells.Materials and MethodsThe expression of USP22, stemness genes, and EMT-related markers were analyzed by RT-qPCR and/or Western blotting. Cell stemness was determined by cell spheroid formation, flow cytometry for CD44+/CD24-, and extreme limiting dilution analysis. Cell proliferation and cisplatin (DDP) chemoresistance of TNBC cells were assessed by CCK-8 assay and xenograft model. Glycolysis was measured by Seahorse assay. The mechanism underlying the role of USP22 was explored by Co-immunoprecipitation, ubiquitination assay, and cycloheximide-chase analysis.ResultsUSP22 expression was positively correlated with DDP resistance in TNBC patients and cells. The proliferation, spheroid number, CD44+/CD24- cells, the expression of stemness genes and EMT-related markers in TNBC cells were significantly elevated after USP22 was overexpressed; however, these parameters in DDP-resistant TNBC (TNBC/DDP) cells were significantly reduced after silencing USP22. USP22 overexpression enhanced the extracellular acidification rate, proliferation, spheroid number, CD44+/CD24- cell number, and the expression of stemness genes and EMT-related markers in TNBC/DDP cells, while these effects were restrained by glycolysis inhibitors. Mechanically, USP22 interacted with c-Myc to promote its stabilization by deubiquitination in TNBC cells. Silencing of USP22 increased DDP sensitivity and survival of mice bearing TNBC.ConclusionUSP22 contributes to chemoresistance, stemness, and EMT phenotype of TNBC cells by suppressing the glycolysis via c-Myc deubiquitination.     

Phenotypic Screening Reveals Topoisomerase I as a Breast Cancer Stem Cell Therapeutic Target

Cancer stem cells (CSCs) are a subpopulation generally thought to be responsible for cancer initiation and progression. Because CSCs are often rare in the total tumor cell population and differentiate rapidly when grown in culture, it has been challenging to uncover compounds that selectively target CSCs. We previously described CSC-emulating cells derived from breast cancer cell lines that maintained a stable undifferentiated state. We optimized a phenotypic assay with these cells and screened 1,280-bioactive compounds, identifying five that preferentially inhibited CSC-like cell proliferation. Using a compound-guided target identification approach, we found high topoisomerase I (Topo I) expression levels in breast CSC-like cells and primary breast CSCs. Structurally unrelated small molecules targeting Topo I preferentially inhibited CSC-like cells. These results illustrate the substantial power of this CSC phenotypic screening platform and promote Topo I as a potential molecular therapeutic target for therapies aimed at expunging CSCs.     

How to Estimate Cancer Stem Cell Frequency Correctly

Cancer stem cell research is a focus for more and more cancer biologists and evidence of involvement incancer devleopment is becoming more abundant. Earlier studies indicated cancer stem cells to be rare asdetermined by the standard xenotransplantation assay using SCID mice in vivo. However, recent studies haveshown that syngeneic transplantation of mouse tumors or modifications to the xenotransplantation assay caneffectively improve the accuracy of detection, with stem cells being more abundant than hitherto thought.Furthermore, to estimate frequency correctly, it is necessary to considerate cancer stem cell subsets with differingcapacities for tumorigenesis.     

Endothelial Cells Promote the Colorectal Cancer Stem Cell Phenotype through a Soluble Form of Jagged-1

1. Download : Download high-res image (154KB)
2. Download : Download full-size image

Highlights? ECs secrete soluble Jagged-1 promoting the colon cancer stem cell phenotype ? EC ADAM17 cleaves Jagged-1 to activate Notch in CRC cells via angiocrine signaling ? CD133-positive and NICD-positive CRC cells are located in the perivascular niche     

CK2 Phosphorylates and Inhibits TAp73 Tumor Suppressor Function to Promote Expression of Cancer Stem Cell Genes and Phenotype in Head and Neck Cancer

Cancer stem cells (CSC) and genes have been linked to cancer development and therapeutic resistance, but the signaling mechanisms regulating CSC genes and phenotype are incompletely understood. CK2 has emerged as a key signal serine/threonine kinase that modulates diverse signal cascades regulating cell fate and growth. We previously showed that CK2 is often aberrantly expressed and activated in head and neck squamous cell carcinomas (HNSCC), concomitantly with mutant (mt) tumor suppressor TP53, and inactivation of its family member, TAp73. Unexpectedly, we observed that classical stem cell genes Nanog, Sox2, and Oct4, are overexpressed in HNSCC with inactivated TAp73 and mtTP53. However, the potential relationship between CK2, TAp73 inactivation, and CSC phenotype is unknown. We reveal that inhibition of CK2 by pharmacologic inhibitors or siRNA inhibits the expression of CSC genes and side population (SP), while enhancing TAp73 mRNA and protein expression. Conversely, CK2 inhibitor attenuation of CSC protein expression and the SP by was abrogated by TAp73 siRNA. Bioinformatic analysis uncovered a single predicted CK2 threonine phosphorylation site (T27) within the N-terminal transactivation domain of TAp73. Nuclear CK2 and TAp73 interaction, confirmed by co-immunoprecipitation, was attenuated by CK2 inhibitor, or a T27A point-mutation of this predicted CK2 threonine phospho-acceptor site of TAp73. Further, T27A mutation attenuated phosphorylation, while enhancing TAp73 function in repressing CSC gene expression and SP cells. A new CK2 inhibitor, CX-4945, inhibited CSC related SP cells, clonogenic survival, and spheroid formation. Our study unveils a novel regulatory mechanism whereby aberrant CK2 signaling inhibits TAp73 to promote the expression of CSC genes and phenotype.Abbreviations: CK2, Casein Kinase 2; CSC, Cancer Stem Cells; DMAT, 2-Dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole; HNSCC, Head and neck squamous cell carcinoma; HEKA, Human epidermal keratinocytes; HOK, Human oral keratinocytes; mt, Mutant; SP, Side population; TAp73, Transactivating p73; TP53, Transforming Protein p53; UM-SCC, University of Michigan Squamous Cell Carcinoma; wt, Wild-type     

Stem Cells and Prenatal Origin of Breast Cancer

The hypothesis that in utero exposure to pregnancy hormones, notably estrogens, is related to the occurrence of breast cancer in the offspring has been examined in a number of epidemiological and experimental studies. Many studies have provided direct or indirect evidence that supports the hypothesis of an intrauterine component in the origin of breast cancer. Human studies to examine the underlying biological mechanisms, however, have been limited. We review the likely role of stem cells in hormone-mediated carcinogenic process, particularly as intermediate steps between in utero exposure to hormones and breast cancer. We summarize also studies related to the assumptions of the hypothesis concerning in utero exposure. We propose the use of stem cell potential as a measurable variable of the 'fertile soil', a term that has been used to characterize the consequences of fetal exposure to intrauterine environment. We conclude by outlining a feasible population-based study that measures stem cell potential to explore mechanisms mediating the relation between in utero exposure to pregnancy hormones and breast cancer risk in the offspring.     

乳腺癌干细胞的调控及作用

乳腺癌是威胁妇女健康的重要疾病之一,由于其病因尚不完全清楚,目前还没有确切的预防方法,手术和放化疗是其主要的治疗办法,但其风险大且具有一定不良反应。研究发现,从实体肿瘤中分离出来的具有自我更新和多向分化能力的乳腺癌干细胞,能够介导肿瘤的侵入、转移和复发等过程,并且能够抵抗传统的放化疗,这对研究以乳腺癌干细胞为靶点的治疗方法具有重要的理论价值和实践意义。本文对乳腺癌干细胞的调控及作用的最新进展作一综述。