Plexin-B3 expression stimulates MET signaling,breast cancer stem cell specification,and lung metastasis

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Human breast cancer histoid: an in vitro 3-dimensional co-culture model that mimics breast cancer tissue

Progress in our understanding of heterotypic cellular interaction in the tumor microenvironment, which is recognized to play major roles in cancer progression, has been hampered due to unavailability of an appropriate in vitro co-culture model. The aim of this study was to generate an in vitro 3-dimensional human breast cancer model, which consists of cancer cells and fibroblasts. Breast cancer cells (UACC-893) and fibroblasts at various densities were co-cultured in a rotating suspension culture system to establish co-culture parameters. Subsequently, UACC-893, BT.20, or MDA.MB.453 were co-cultured with fibroblasts for 9 days. Co-cultures resulted in the generation of breast cancer histoid (BCH) with cancer cells showing the invasion of fibroblast spheroids, which were visualized by immunohistochemical (IHC) staining of sections (4 μm thick) of BCH. A reproducible quantitative expression of C-erbB.2 was detected in UACC-893 cancer cells in BCH sections by IHC staining and the Automated Cellular Imaging System. BCH sections also consistently exhibited qualitative expression of pancytokeratins, p53, Ki-67, or E-cadherin in cancer cells and that of vimentin or GSTPi in fibroblasts, fibronectin in the basement membrane and collagen IV in the extracellular matrix. The expression of the protein analytes and cellular architecture of BCH were markedly similar to those of breast cancer tissue.     

单细胞测序技术及其在乳腺癌研究中的应用

乳腺癌是起源于乳腺各级导管和乳腺上皮细胞,由增生到不典型增生而逐步发展成原位癌、早期浸润癌至浸润性癌的一种恶性肿瘤。传统高通量测序技术对乳腺癌的研究主要是鉴定与乳腺癌发生发展相关的"驱动基因",但是对于乳腺癌基因组结构变化以及亚克隆的鉴定等存在一定的局限性,并且忽略了乳腺癌肿瘤细胞之间的异质性。近年来兴起的单细胞测序技术是以单个细胞为研究对象,对基因拷贝和基因表达等数据进行分析,探究乳腺癌的细胞组成、细胞状态和细胞命运,绘制乳腺癌生态系统图谱,对临床患者进行精准分层,为实现个体化治疗提供支持。同时,还可以揭示乳腺癌与T细胞、巨噬细胞等免疫细胞间的相关性,为发现乳腺癌新的治疗靶点、免疫检查点等提供参考。本文对单细胞测序技术及其在乳腺癌研究中的应用和研究进展进行了综述,以期为单细胞测序技术的进一步发展提供参考,同时为理解乳腺癌的发病机制和免疫治疗提供基础支持。     

Influence of adjuvant radiotherapy on circulating epithelial tumor cells and circulating cancer stem cells in primary non-metastatic breast cancer

Background: There is an unmet need to identify biomarkers that directly reflect response to adjuvant radiotherapy (RT). Circulating epithelial tumor cells (CETCs) represent the liquid component of solid tumors and are responsible for metastatic relapse. CETC subsets with cancer stem cell characteristics, circulating cancer stem cells (cCSCs), play a pivotal role in the metastatic cascade. Monitoring the most aggressive subpopulation of CETCs could reflect the aggressiveness of the remaining tumor burden. There is limited data on the detection and monitoring changes in CETC and cCSC numbers during RT in early breast cancer.Methods: CETC numbers were analyzed prior to, at midterm and at the end of RT in 52 primary non-metastatic breast cancer patients. Hormone receptor status was determined in CETCs prior to and at the end of RT. For the identification of cCSCs cell suspensions from the peripheral blood of patients were cultured in vitro under conditions favoring growth of tumorspheres.Results: Hormone receptor status in CETCs before RT was comparable to that in primary tumor tissue. Prior to RT numbers of CETCs correlated with aggressiveness of primary tumors. cCSCs could be successfully identified and monitored during RT. Prior to RT patients treated with neoadjuvant chemotherapy had significantly higher numbers of CETCs and tumorspheres compared to patients after adjuvant chemotherapy. During RT, the number of CETCs decreased continuously in patients after neoadjuvant chemotherapy but not after adjuvant chemotherapy.Conclusion: Monitoring the number of CETCs and the CETC subset with cancer stem cell properties during RT may provide additional clinically useful prognostic information.     

Circulating myeloid-derived suppressor cells: An independent prognostic factor in patients with breast cancer

Evading immune destruction is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid immune cells, are thought to foster the establishment of an immunosuppressive tumor microenvironment, but it remains unclear how. This study aims to determine the levels of circulating MDSCs and their subpopulations and test their immunosuppressive functions in patients with breast cancer (BC). We analyzed the fractions of MDSCs in freshly isolated peripheral blood mononuclear cells of patients with BC and healthy donors using flow cytometry. Circulating MDSCs were further phenotyped using fluorescently labeled antihuman monoclonal antibodies. Coculture experiments revealed the effects of MDSCs on CD3⁺ T cell response. Moreover, we correlated circulating MDSC levels with clinicopathological features of patients with BC. We show that the fraction of HLA-DR ^– CD33 ⁺ MDSCs in peripheral blood is about 10-fold higher in patients with BC than in healthy control individuals. The levels of all MDSC subpopulations, including monocytic and granulocytic MDSCs, are significantly elevated. Coculture experiments of purified HLA-DR ^– CD33 ⁺ MDSCs and CD3 ⁺ T cells demonstrate that T cell proliferation is more effectively inhibited by BC patient-derived MDSCs than by healthy control MDSCs. Moreover, increased circulating MDSC levels robustly associate with advanced BC stage and positive lymph node status. By being more abundant and more effective T cell suppressors, BC patient-derived circulating MDSCs exert a dual immunosuppressive effect. Our findings pave the way to develop novel diagnostic and immunotherapeutic strategies, aimed at detecting and inhibiting MDSCs in patients with BC.     

Spatial and single-cell transcriptomics decipher the cellular environment containing HLA-G+ cancer cells and SPP1+ macrophages in colorectal cancer

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Annexin A1 in inflammation and breast cancer: a new axis in the tumor microenvironment

ABSTRACT

Targeting inflammation in cancer has shown promise to improve and complement current therapies. The tumor microenvironment plays an important role in cancer growth and metastasis and -tumor associated macrophages possess pro-tumoral and pro-metastatic properties. Annexin A1 (ANXA1) is an immune-modulating protein with diverse functions in the immune system and in cancer. In breast cancer, high ANXA1 expression leads to poor prognosis and increased metastasis. Here, we will review ANXA1 as a modulator of inflammation, and discuss its importance in breast cancer and highlight its new role in alternative macrophage activation in the tumor microenvironment. This review may provide an updated understanding into the various roles of ANXA1 which may enable future therapeutic developments for the treatment of breast cancer.     

MicroRNAs and breast cancer stem cells: Potential role in breast cancer therapy

MicroRNAs (miRNAs) can control cancer and cancer stem cells (CSCs), and this topic has drawn immense attention recently. Stem cells are a tiny population of a bulk of tumor cells that have enormous potential in expansion and metastasis of the tumor. miRNA have a crucial role in the management of the function of stem cells. This role is to either promote or suppress the tumor. In this review, we investigated the function and different characteristics of CSCs and function of the miRNAs that are related to them. We also demonstrated the role and efficacy of these miRNAs in breast cancer and breast cancer stem cells (BCSC). Eventually, we revealed the metastasis, tumor formation, and their role in the apoptosis process. Also, the therapeutic potential of miRNA as an effective method for the treatment of BCSC was described. Extensive research is required to investigate the employment or suppression of these miRNAs for therapeutics approached in different cancers in the future.     

Acid-adapted cancer cells alkalinize their cytoplasm by degrading the acid-loading membrane transporter anion exchanger 2, SLC4A2

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Normal breast epithelial cells induce apoptosis of breast cancer cells via Fas signaling

Fas/Fas ligand (Fas L) death pathway is an important mediator of apoptosis. Deregulation of Fas pathway is reported to be involved in the immune escape of breast cancer and the resistance to anti-cancer drugs. In this study, we demonstrated that conditioned medium by normal breast epithelial cells (NBEC-CM) induced apoptosis of MCF-7 and T-47D Fas-sensitive cells but had no effect on MDA-MB-231 Fas-resistant cells. Inhibition of PI3 kinase or NF-kappaB by specific inhibitors or transient transfections restored the sensitivity of MDA-MB-231 cells to NBEC-induced apoptosis. Moreover, the constitutive activation of NF-kappaB was controlled by PI3 kinase because inhibition of PI3 kinase reduced NF-kappaB activity. Inducible activation of NF-kappaB rendered MCF-7 cells resistant to NBEC-CM- and Fas agonist antibody-triggered apoptosis. Therefore, constitutive or inducible activation of PI3 kinase and/or NF-kappaB in breast cancer cells rendered them resistant to NBEC-triggered apoptosis. In addition, Fas neutralizing antibody and dominant negative Fas abolished NBEC-triggered apoptosis. Western blot and confocal microscopy analysis showed an increase of membrane Fas/Fas L when cells were induced into apoptotis by NBEC-CM. Taken together, these data show that NBEC induced apoptosis in breast cancer cells via Fas signaling.     

Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer

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Autocrine activation of MAPK signaling mediates intrinsic tolerance to androgen deprivation in LY6D prostate cancer cells

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CD73; a key ectonucleotidase in the development of breast cancer: Recent advances and perspectives

Tumor cell invasion and metastasis are the definitive cause of mortality in breast cancer (BC). Hypoxia and pro-inflammatory cytokines upregulate the CD73 gene in the tumor microenvironment. Subsequently, CD73 triggers molecular and cellular signaling pathways by both enzymatic and nonenzymatic pathways, which finally leads to breast tumor progression and development. In this paper, we summarize current advances in the understanding of CD73-driven mechanisms that promote BC development and mortality. Furthermore, we evaluate the therapeutic potential of CD73 targeting in BC.     

Resistance to mesenchymal reprogramming sustains clonal propagation in metastatic breast cancer

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Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche

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乳腺癌干细胞分选及相关信号通路研究进展

肿瘤干细胞是指存在于肿瘤组织中的具有干细胞特性,即能够多向分化和自我更新的一类细胞群。随着肿瘤干细胞概念的提出,乳腺癌干细胞成为当今科研领域的一个研究热点。因此,了解如何分选乳腺癌干细胞及如何维持其"干性"对治疗及预防乳腺癌具有至关重要的意义。主要从乳腺癌干细胞分选、相关信号通路、上皮-间充质转换(EMT)等方面进行综述。