Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines

Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47–62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets.     

记忆抑制基因

长期记忆贮存分子基础研究最重要的进展之一是揭示了记忆的巩固涉及基因表达的改变。与肿瘤发生和形成的早期研究集中在生长的正向调节基因 (即显性活跃的致癌基因 )相似 ,既往关于长期记忆和突触可塑性分子水平的研究也主要集中于正向调节基因上。近几年提出了关于突触变化启动核内变化导致基因表达过程的多种分子模型 [1 ] ,这些模型受肿瘤发生和发展的信号转导理论启示 ,其中最引人注目的发现之一是揭示长期持续的突触可塑性变化不但需要有利于记忆贮存的正向调节机制的激活 ,同时也需要清除阻止记忆贮存的抑制性因素。正如正常状况下肿…     

转移抑制基因KAI1与骨肉瘤侵袭转移特性的关系

目的：探讨骨肉瘤组织和骨肉瘤细胞系中转移抑制基因KAI1 mRNA的表达与骨肉瘤侵袭转移特性的关系。方法:采用RT-PCR法研究18例手术切除新鲜骨肉瘤组织和3株培养骨肉瘤细胞系中KAI1 mRNA的表达，并同时研究3株培养骨肉瘤细胞系的增殖、侵袭和转移等生物学特性，利用全自动图像分析系统进行半定量分析。结果:KAI1 mRNA的表达量在伴有肺转移的骨肉瘤组织中为0.80±0.50，显著低于在不伴有肺转移的骨肉瘤组织中的1.48±0.64，前者显著低于后者（P＜0.05），KAI1 mRNA的表达与骨肉瘤的肺转移显著相关；3株骨肉瘤细胞系中U2-OS的增殖、粘附和侵袭力最低（均P＜0.01），而KAI 1 mRNA在骨肉瘤细胞系U2-OS中显著高表达（P＜0.05） 。结论：转移抑制基因KAI1可能通过抑制骨肉瘤细胞的增殖、粘附和侵袭而参与抑制骨肉瘤的肺转移。     

Influence of diet on metastasis and tumor dormancy

Tumor metastasis is responsible for most cancer deaths, and can occur after long periods of tumor dormancy. Information learned from experimental studies on tumor metastasis and dormancy is shedding light on mechanisms responsible and possible therapeutic approaches. ‘Seed’ (the cancer cell) and ‘soil’ (the microenvironment of the secondary organ) factors contribute to metastatic outcome. This review considers the possibility that various dietary components may affect both ‘seed’ and ‘soil’ compartments, thereby influencing the growth of metastases, and discusses an experimental study on dietary genistein that illustrates this concept. While studies on human diet are complex, the possibility that relatively non-toxic dietary intervention strategies could impact on metastasis and patient survival is attractive and worthy of further study in appropriate experimental models of metastasis and tumor dormancy.     

The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis

Myeloid-derived suppressor cells (MDSC) are important to the tumour microenvironment as they actively suppress the immune system and promote tumour progression and metastasis. These cells block T-cell activation in the tumour microenvironment, preventing anti-tumour immune activity. The ability of a treatment to alter the suppressive function of these cells and promote an immune response is essential to enhancing overall therapeutic efficacy. Interleukin-12 (IL-12) has the potential not only to promote anti-tumour immune responses but also to block the activity of cells capable of immune suppression. This paper identifies a novel role for IL-12 as a modulator of MDSC activity, with implications for IL-12 as a therapeutic agent. Treatment with IL-12 was found to alter the suppressive function of MDSC by fundamentally altering the cells. Interleukin-12-treated MDSC exhibited up-regulation of surface markers indicative of mature cells as well as decreases in nitric oxide synthase and interferon-γ mRNA both in vitro and in vivo. Treatment with IL-12 was also found to have significant therapeutic benefit by decreasing the percentage of MDSC in the tumour microenvironment and increasing the percentage of active CD8(+) T cells. Treatment with IL-12 resulted in an increase in overall survival accompanied by a reduction in metastasis. The findings in this paper identify IL-12 as a modulator of immune suppression with significant potential as a therapeutic agent for metastatic breast cancer.     

The role of plasminogen activators in metastasis

It is proposed the tumour plasminogen activators play an essential role in the invasive and metastic process of malignancy.     

Myeloid derived suppressor cells and the release of micro-metastases from dormancy

Clinical & Experimental Metastasis - Metastasis is the primary cause of cancer mortality and an improved understanding of its pathology is critical to the development of novel therapeutic...     

The Measure of DAMPs and a role for S100A8 in recruiting suppressor cells in breast cancer lung metastasis

To determine whether there was a relationship between damage associated molecular pattern molecule (DAMP) expression and recruitment of suppressor cells to sites of metastasis we measured relative expression of DAMPs, regulatory T cells (Tregs), and myeloid derived suppressor cells (MDSC) in mice at various stages of breast cancer progression using the 4T1 model. Although S100A8 was expressed at relatively low levels in the tumor cells, expression was 100-fold higher in the lung and liver which are common sites of metastasis for this tumor. Despite the relatively high level of S100A8 expression in the lungs of naïve mice, the level of expression increased further and was significantly elevated after only 7 days of tumor growth. The same pattern was observed for MDSC, and both S100A8 and MDSC expression peaked in the lungs of mice following 21 days of tumor growth. Characterization of MDSC from the lungs revealed expression of RAGE, and the cells were capable of migrating in a dose-dependent manner toward S100A8. In addition, the MDSC expressed low levels of MHC Class I, MHC Class II, CD80, and secreted TGF-β. Taken together, these data suggest that expression of S100A8 in the lungs may facilitate recruitment of MDSC, which may in turn aid in establishing a metastatic niche capable of suppressing a localized immune response.     

Freedom from wholism in multicellular organisms: a possible role of tumor suppressor genes.

Wholism, known as 'homeostasis' in multicellular organisms, is fundamentally expressed in the regulation of cell proliferation and of the metabolism of individual cells. Control mechanisms represent an overriding control of the autonomy of cells in multicellular organisms. Negative regulation by suppressor genes including tumor suppressor genes is essential to maintain homeostasis in these organisms. Without wholistic regulation, the cellular society of multicellular organisms would progress from bad to worse, with eventual destruction of the whole system. The enhancement of division and differentiation of cells transduced by water-soluble factors may be considered as the controlling structure on the tumor suppressor genes. In microevolution, cell killing by the immunosurveillance systems directed at the external environments has been avoided for the 'self' cells in general, since the multicellular organism may not be considered as only a crowd of single cells.     

肿瘤转移抑制基因Kai1的研究状况

随着分子生物学的深入研究 ,人们对肿瘤发生的分子基础有了明确的认识。然而 ,对威胁肿瘤患者生存的主要原因———肿瘤转移的分子基础却了解较少。目前已知 ,肿瘤转移与肿瘤发生一样 ,不仅有促进基因的激活 ,还伴有抑制基因的失活。肿瘤转移抑制基因的存在是在细胞融合实验中证实的。鼠前列腺癌细胞系ＡＴ3.1具有高转移特性 ,ＡＴ2 .1则是非转移的 ,两种细胞融合后 ,得到的细胞仍然保持肿瘤细胞的特点 ,却不具备高转移特性。将人的第 11号染色体转移到鼠高转移的前列腺癌细胞系ＡＴ6 .1中 ,也观察到相同的结果 ,提示有转移抑制基因定位于该…     

Breast cancer metastasis suppressor 1: update

This article reviews information related to the BRMS1 (BReast Metastasis Suppressor 1) metastasis suppressor gene. BRMS1 was identified by differential display comparing metastasis-suppressed chromosome 11 hybrids with metastatic, parental MDA-MB-435 human breast carcinoma cells. BRMS1 has subsequently been shown to suppress metastasis, but not tumorigenicity of human melanoma cells. The murine version, Brms1, also suppresses metastasis and exhibits a high level of homology to the human gene at the structure, nucleotide and amino acid levels. The mechanisms of action remain to be determined; however, BRMS1 transfectant cells have restored gap junctional intercellular communication. Recent data suggest that BRMS1 is part of the mSin3A histone deacetylase complex.     

The role of suppressor cells in congenital influenza infection in mice

Young mice with congenital influenza infection have lower immune responsiveness of lymphocytes to nonspecific mitogens and influenza virus antigens. Lymphocytes of such animals inhibit proliferation of normal lymphoid cells activated with concanavalin A and immune lymphocytes activated with influenza virus antigens. It is assumed that in congenital influenza infection one of the possible mechanisms of immunosuppression in mice is the activation of suppressor T-cells.     

The role of the neural niche in brain metastasis

Cancers with neurologic metastasis are a burdensome affliction. As primary cancer care improves, the incidence of metastatic cancer increases as a result of prolonged survival time. Because of this, advances in the understanding of the mechanisms of metastasis are important for the development of continuing management strategies. Knowing how metastatic tumor cells engage, survive, and proliferate in the central nervous system (CNS) is an important first step in developing treatment paradigms. The neural niche is the soil of the CNS that accommodates tumor cells, is a microenvironment of cell signaling that exists between the tumor cell and the native neural cellular network. Elements of the neural niche have been identified as acquaintances for metastatic tumor growth. As more is known about the neural niche, treatment strategies can be developed to target these networks of metastatic tumor progression.