Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.     

肿瘤干细胞与肿瘤转移

肿瘤干细胞和其微环境住肿瘤形成、浸润性生长和转移灶形成等各步骤均具有关键性作用。阐明其相互作用的分子机制，可为肿瘤转移的诊断、治疗和预后，提供可靠的分子标志和靶点：文章主要就以上进行综述。     

肿瘤干细胞与肿瘤转移

肿瘤干细胞（TSCs）在肿瘤启动作用中的重要性已在造血系统肿瘤中得到证实，最近亦有在实体瘤中的相关报道。TSCs与正常干细胞具相似的生物学特性，这对研究TSCs与肿瘤转移的关系有非常重要意义？文章简要论述TSCs研究现状及TSCs与肿瘤转移两者可能存在的相关性。     

Enhanced Tumorigenicity of Rat Bladder Squamous Cell Carcinoma Cells after Abrogation of Gap Junctional Intercellular Communication

We previously demonstrated a clear tendency for actively communicating rat bladder carcinoma cell lines with elevated expression of connexin 43 mRNA to possess strong tumorigenicity. In the present study, immunohistochemical analysis established that normal bladder epithelium did not express connexin 43 protein, but bladder carcinomas often expressed the protein, particularly on the membranes of cells within areas of squamous cell differentiation. To investigate the role of connexin 43 overexpression in rat bladder carcinoma cells, an anti-sense connexin 43 expression vector was transfected into BC31 cells having a high communication capacity. In the resultant transfectants, there was little or no communication capacity and connexin 43 expression. The growth rate in vitro was not changed compared to that of cells treated with the vector alone (without the anti-sense sequence), but tumorigenicity in nude mice was dramatically enhanced. The results indicate that connexin 43 overexpression in rat bladder carcinogenesis is related to squamous cell differentiation, and the protein can have tumor suppressor characteristics, as in other organs.     

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。     

肿瘤转移与肿瘤干细胞

肿瘤转移是恶性肿瘤进展的重要特征,也是导致肿瘤患者治疗失败和死亡（〉90％）的最主要原因。微环境中复杂的信号通路,肿瘤细胞基因表型、上皮表型和表面粘附分子表达的改变,肿瘤转移的器官归巢现象等都将影响肿瘤转移结局。肿瘤转移分子机制迄今尚不清楚。近年来,上皮细胞-间质细胞转化（epithelial—mesenchymal transition,EMT）被认为是肿瘤转移早期的关键步骤。     

IGF-1 from Adipose-Derived Mesenchymal Stem Cells Promotes Radioresistance of Breast Cancer Cells

Purpose: The aim of this study was to investigate effects of adipose-derived mesenchymal stem cells (AMSCs)on radioresistance of breast cancer cells. Materials and Methods: MTT assays were used to detect any influenceof AMSC supernatants on proliferation of breast cancer cells; cell migration assays were used to determine theeffect of breast cancer cells on the recruitment of AMSCs; the cell survival fraction post-irradiation was assessedby clonogenic survival assay; γ-H2AX foci number post-irradiation was determined via fluorescence microscopy;and expression of IGF-1R was detected by Western blotting. Results: AMSC supernatants promoted proliferationand radioresistance of breast cancer cells. Breast cancer cells could recruit AMSCs, especially after irradiation.IGF-1 derived from AMSCs might be responsible for the radioresistance of breast cancer cells. Conclusions:Our results suggest that AMSCs in the tumor microenvironment may affect the outcome of radiotherapy forbreast cancer in vitro.     

Triazine Derivatives Inhibit Rat Hepatocarcinogenesis but Do Not Enhance Gap Junctional Intercellular Communication

We report here novel candidate chemopreventive agents active against experimental hepatocarcino-genesis. The triazine derivatives 6-(2-chlorophenyl)-2,4-diamino-l,3,5-triazine (2CPDAT), 6-(3-chlorophenyl)-2,4-diamino-l,3,5-triazine (3CPDAT), 6-(4-chlorophenyl)-2,4-diamino-l,3,5-triazine (4CPDAT), 6-(4-pyridyl)-2,4-diamino-l,3,5-triazine (PyDAT), and 6-(pyridine JV-oxid-4-yl)-2,4-diamino-l,3,5-triazine (PyNODAT), synthesized in our laboratory, in addition to 6-(2,5-dichloro-phenyl)-2,4-diamino-l,3,5-triazme (DCPDAT), or irsogladine, which is a widely used anti-ulcer drug, were investigated for potential chemopreventive effects in a rat liver medium-term bioassay system. A significant inhibitory influence on enzyme-altered liver foci was found for 2CPDAT, 3CPDAT, 4CPDAT, and PyNODAT, but not for DCPDAT or PyDAT, The involvement of gap jnnctional intercellular communication in the inhibition was studied, but no change in gap Junctional intercellular communication capacity in rat liver cells in vitro or in gap junction protein (connexin 32) expression in rat liver in vivo was noted. These results indicate that, although these irsogladine analogues exert inhibitory effects on rat liver carcinogenesis, their action is independent of modification of gap Junctional intercellular communication.     

间充质干细胞在肿瘤演进中的作用

摘 要：肿瘤细胞与肿瘤微环境之间相互作用持续存在于肿瘤演进的过程中。间充质干细胞是一类具有多向分化潜能的异质型细胞,可向肿瘤局部迁移,是构成肿瘤微环境的重要成分。间充质干细胞通过改造肿瘤微环境,促进肿瘤血管形成,抑制肿瘤局部免疫应答,转变为肿瘤相关成纤维细胞,促进肿瘤上皮间质转化等机制来促进肿瘤的生长和转移。研究间充质干细胞在肿瘤演进中的作用有助于深入了解肿瘤及其微环境的复杂性,并探索靶向间充质干细胞的肿瘤治疗新策略。     

术前化疗对乳腺癌组织激素受体及耐药基因蛋白表达的影响

  目的  探讨术前化疗对乳腺癌组织激素受体及耐药基因蛋白表达的影响。   方法  收集2009年1月至2011年12月在江苏省肿瘤医院行术前化疗并手术治疗的92例乳腺癌患者临床资料,对化疗前B超引导下经皮粗针穿刺活检乳腺癌组织以及手术标本采用免疫组织化学SP法检测ER、PR、P-gp、GST-π、TOPO-Ⅱ的表达,比较化疗前后表达差异。   结果   经术前化疗后,ER、PR的阳性表达分别由65.2%、56.5%降为50.0%、52.2%,其中ER表达差异具有统计学意义（P < 0.05）。P-gp、GST-π的表达分别由54.3%、32.6%增高到82.6%、45.7%,前后比较差异具有统计学意义（P < 0.05）,同时两者共表达的乳腺癌患者由化疗前的22例增加为32例,TOPO-Ⅱ的阳性表达则由化疗前的48.9%降为41.3%,前后差异无统计学意义（P>0.05）。   结论  术前化疗影响乳腺癌组织中激素受体及耐药基因蛋白的表达,监测其表达对于选择药物、判断预后以及指导治疗具有参考价值。      

沙利度胺对前列腺癌PC-3细胞的增殖及细胞缝隙连接通讯的影响

  目的  观察沙利度胺对前列腺癌PC-3细胞增殖和凋亡的作用及对PC-3细胞中Cx43表达水平的影响。   方法  将处于对数生长期的前列腺癌PC-3细胞分别给予递增浓度的沙利度胺(0、12.5、25、50、100μg/mL)处理24 h和48 h。采用CCK-8法检测不同浓度沙利度胺对PC-3细胞的增殖抑制影响, Annexin V-FITC/PI双染色法检测细胞凋亡情况, RT-PCR法检测Cx43mRNA的表达及Westernblot检测Cx43蛋白的表达。   结果   沙利度胺浓度在25~100μg/mL能明显抑制PC-3细胞体外增殖, 随着时间、浓度增加, 抑制率相应升高。不同浓度组沙利度胺处理PC-3细胞24~48 h后, Cx43 mRNA和蛋白有不同程度的升高(P < 0.05)。   结论  沙利度胺可通过抑制人前列腺癌PC-3细胞增殖、诱导其凋亡, 产生抗肿瘤作用。沙利度胺可上调前列腺癌PC-3细胞Cx43mRNA及蛋白的表达水平, 并可能促进前列腺癌PC-3细胞的细胞缝隙连接通讯功能的恢复, 从而抑制肿瘤生长。      

Stem Cell Implants for Cancer Therapy: TRAIL-Expressing Mesenchymal Stem Cells Target Cancer Cells In Situ

Purpose

Tumor-specific delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an apoptosis-inducing peptide, at effective doses remains challenging. Herein we demonstrate the utility of a scaffold-based delivery system for sustained therapeutic cell release that capitalizes on the tumor-homing properties of mesenchymal stem cells (MSCs) and their ability to express genetically-introduced therapeutic genes.

Methods

Implants were formed from porous, biocompatible silk scaffolds seeded with full length TRAIL-expressing MSCs (FLT-MSCs). under a doxycycline inducible promoter. In vitro studies with FLT-MSCs demonstrated TRAIL expression and antitumor effects on breast cancer cells. Next, FLT-MSCs were administered to mice using three administration routes (mammary fat pad co-injections, tail vein injections, and subcutaneous implantation on scaffolds).

Results

In vitro cell-specific bioluminescent imaging measured tumor cell specific growth in the presence of stromal cells and demonstrated FLT-MSC inhibition of breast cancer growth. FLT-MSC implants successfully decreased bone and lung metastasis, whereas liver metastasis decreased only with tail vein and co-injection administration routes. Average tumor burden was decreased when doxycycline was used to induce TRAIL expression for co-injection and scaffold groups, as compared to controls with no induced TRAIL expression.

Conclusion

This implant-based therapeutic delivery system is an effective and completely novel method of anticancer therapy and holds great potential for clinical applications.     

乳腺癌干细胞研究的新进展

肿瘤是由肿瘤干细胞异常增殖、分化而形成,常规放化疗仅能消灭增殖期的非致瘤性肿瘤细胞,使肿瘤缩小甚至消失。然而,肿瘤干细胞和普通干细胞一样,对放化疗等方法具有较高的抵抗能力,当治疗停止后,肿瘤干细胞可再次增殖形成肿瘤。目前研究已证实乳腺癌中存在乳腺癌干细胞,并且乳腺癌干细胞在乳腺癌的发生、发展中起着关键作用。乳腺癌干细胞不但介导乳腺癌组织对放化疗的抵抗,还关系到乳腺癌的转移和复发,所以有必要针对乳腺癌干细胞进行深入研究。因此,本文就乳腺癌干细胞的分离鉴定、相关信号通路的调控及其治疗方面的新进展作一综述。      

乳腺癌干细胞研究进展

乳腺癌干细胞是乳腺肿瘤细胞中少数具有自我更新和分化潜能,并能维持乳腺肿瘤的生长和异质性的一类细胞。越来越多的证据表明,乳腺癌干细胞在乳腺癌的发生、生长、复发、转移和抗药性等方面起决定性的作用。因此,研究乳腺癌干细胞的调控机理和开发靶向乳腺癌干细胞的新药已经成为乳腺癌研究中的热点。文章简要综述乳腺癌干细胞的概念,分离鉴定及其在乳腺癌转移和治疗中的作用,并对其分子调控进行了探讨。     

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。     

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.     

干细胞、癌症与癌症干细胞

干细胞被认为是一种未分化的细胞,具有永远增殖和自我更新能力.大量研究证明,癌症中存在对化疗更具抵抗性的癌症干细胞.识别癌症干细胞和普通癌症细胞之间的差异,可以发展更有效的癌症分类、诊断和治疗方法.