Gamma- 突触核蛋白与肿瘤关系的研究进展

Synucleins家族是一种主要在神经元内表达的高度可溶性的蛋白家族。已知synucleins家族有3个成员α-synuclein(SNCA),β-synuclein(SNCB)和γ-synuclein(SNCG)。其中SNCA与SNCB参与神经递质释放过程,被认为与神经退行性变疾病密切相关,特别是在阿尔茨海默病与帕金森病中常有异常表达。近年来研究表明,SNCG在人类许多肿瘤中过表达,如乳腺癌、结直肠癌、女性生殖系统肿瘤、前列腺癌、膀胱癌等。通过研究表明γ-Synucleins异常表达机制目前包括DNA甲基化、激动蛋白-1激活、对转录因子SP1结合位点、有丝分裂检验点基因、雌激素受体影响。通过以上机制,SNCG促进上述肿瘤细胞的增殖、抑制肿瘤细胞的凋亡以及促进肿瘤细胞的转移。根据文献分析,我们提出SNCG可作为多种肿瘤预后的潜在指标的可能,同时以SNCG为切入点,探讨神经系统是否可以对肿瘤发生、发展的影响作用。     

Tumor-suppressive Function of Protein-tyrosine Phosphatase Non-receptor Type 23 in Testicular Germ Cell Tumors Is Lost upon Overexpression of miR142–3p microRNA

Protein-tyrosine phosphatase non-receptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. However, its physiological role(s) and detailed expression profile(s) have not yet been elucidated. We investigated the function and regulation of PTPN23 in the formation of testicular germ cell tumors (TGCTs). Expression of PTPN23 in human TGCT cell lines was significantly lower than that in spermatogonial stem cells in mice. Overexpression of PTPN23 in NEC8, a human TGCT cell line, suppressed soft agar colony formation in vitro and tumor formation in nude mice in vivo. These data indicate that PTPN23 functions as a tumor suppressor in TGCTs. Multiple computational algorithms predicted that the 3′ UTR of human PTPN23 is a target for miR-142-3p. A luciferase reporter assay confirmed that miR-142-3p bound directly to the 3′ UTR of PTPN23. Introduction of pre-miR-142 in the PTPN23 transfectant of NEC8 led to suppressed expression of PTPN23 and increased soft agar colony formation. Quantitative RT-PCR data revealed a significantly higher expression of miR-142-3p in human seminomas compared with normal testes. No difference in mRNA expression between seminoma and non-seminoma samples was detected by in situ hybridization. Both quantitative RT-PCR and immunohistochemical analyses revealed that PTPN23 expression was significantly lower in TGCTs than in normal testicular tissues. Finally, a lack of PTPN23 protein expression in human TGCTs correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCTs.     

胃癌的肿瘤微环境研究进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素,有别于正常细胞与其周围组织所形成的微环境,组织缺氧和酸中毒、间质高压形成、大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征,这种特性在肿瘤的发生、进展、转移中扮演重要的角色。胃癌早期症状不典型、转移迅速、死亡率高,是消化系统最常见的恶性肿瘤,目前,关于肿瘤微环境的研究尚处于起步阶段,对胃癌肿瘤微环境的研究有助于我们进一步认识胃癌发生发展的机制,并为临床诊断、治疗胃癌提供依据。因此,本文就近年来在胃癌肿瘤微环境方面的研究进展作一综述。     

Aberrant leukocyte infiltration: a direct trigger for breast tumor invasion and metastasis

Our previous studies revealed that leukocyte infiltration could trigger breast and prostate tumor invasion through physical disruption of tumor capsules. Our current study, involving multiple types of human tumors, further suggests that leukocyte infiltration also triggers metastasis through the following pathways : 1) the physical movement into the epithelium disrupts inter-cellular junctions and surface adhesion molecules, which cause the disassociation of tumor cells from tumor cores, 2) some of these tumor cells subsequently form tight junctions with the plasma membranes of leukocytes creating tumor cell-leukocyte chimeras (TLCs), and 3) the leukocytes of TLCs impart migratory capacity to associated tumor cell partners. Our findings suggest a novel pathway for tumor cell dissemination from primary sites and journey to new sites.     

Biochemical Analysis of Metastasis-Related Ax Actin in B16 Mouse Melanoma Cells After Chemical Reversional Modulation and of Tumor Progression-Related A′ Actin in the Ontogeny of Human Malignant Melanoma

To examine the correlation between tumor metastasis and A^x actin in mouse melanoma and between tumor progression and A′, actin in human melanoma and further to investigate whether or not it is a generally existing principle, we studied the effects of reversion agents, which distinctly decrease metastatic ability of melanoma cells, on the appearance of A^x actin. Will an induced decrease in metasasis of established highly metastatic B16-F10 mouse melanoma cells cause the appearance of A^x actin? We also examined the appearance of A′ actin in eight human benign pigment cell tumors and nine human malignant melanoma tissues or cells in relation to tumor progression. In vitro treatment of B16-F10 cells with each of these agents suppressed metastatic ability of the cells injected intravenously into syngenic mice; however, none of the treated cells represented A^x actin in vitro. These results suggest that the appearance of A^x actin may be a result of long-term tumor cell progression leading to changes in gene level, but because the treatments with these agents were only carried out over a short period, they could not effect changes in gene level; thus, A^x actin appearance remained unchanged. Appearance of A′ actin was detected only in human benign pigment cell tumors such as nevus cell nevi, but not in malignant melanomas, which were also formed in a long period of tumor progression in vivo. These results suggest that A′ actin is a clinically useful marker to determine the prognosis and level of tumor progression of human pigment cell tumors.     

Effect of cisplatin upon expression of in vivo immune tumor resistance

The major intent of cancer treatment with cytotoxic drugs is direct tumor cell damage, but some of these drugs have been shown to be immunomodulatory. Cisplatin is a widely used cytotoxic drug that has been combined with biological response modifiers in recent clinical trials. To evaluate further whether cisplatin may independently alter the level of host resistance against tumor growth, the drug was tested in the Mc7 sarcoma rat tumor model. The expression of in vivo tumor resistance against Mc7 sarcoma in syngeneic Wistar rats is mediated by circulating non-cytotoxic T lymphocytes. These cells interact specifically with tumor cells to generate cytotoxic effectors locally at the site of a tumor challenge. Activities of these components of expression of tumor resistance were measured in vivo after administration of cisplatin and dose-dependent effects were found. Low-dose cisplatin (0.3 mg/kg) increased the activity of the circulating lymphocytes that mediate tumor resistance, and high-dose cisplatin (9 mg/kg) suppressed both mediator lymphocyte activity and the generation of antitumor effector mechanisms. These studies suggest that low-dose cisplatin may be immunomodulatory and combining it with biological response modifiers might be a useful strategy. However, high-dose cisplatin given with biological response modifiers may negate potential immunomodulatory activities of such agents.     

Allogeneic gastric cancer cell-dendritic cell hybrids induce tumor antigen (carcinoembryonic antigen) specific CD8+ T cells

The development of protocols for the ex vivo generation of dendritic cells (DCs) has led to intensive research of their potential use in immunotherapy. Accumulating results show the efficacy of this treatment on melanomas which are highly immunogenic. However, its efficacy remains unclear in other tumors. In this study, allogeneic gastric cancer cell–DC hybrids were used to determine the efficacy of this type of immunotherapy in gastric cancer. Fusion cells of DC and allogeneic gastric cancer cells were generated by polyethylene glycol (PEG) and electrofusion. These hybrids were used to induce tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTLs). The DCs were successfully fused with the allogeneic gastric cancer cells resulting in hybrid cells. These hybrid cells were functional as antigen-presenting cell because they induced allogeneic CD4+ T cells proliferation. CD8+ T cells stimulated by the MKN-45-DC hybrid cells were able to kill MKN-45 when used for immunization. The CTLs killed another gastric cancer cell line, MKN-1, as well as a melanoma cell line, 888mel, suggesting the recognition of a shared tumor antigen. MKN-45 specific CTLs can recognize carcinoembryonic antigen (CEA), indicating that the killing is due to tumor antigens as well as alloantigens. This approach suggests the possible use of allogeneic gastric cancer cell–DC hybrids in DC based immunotherapy for gastric cancer treatment.     

TNF-a在肿瘤中的作用

肿瘤坏死因子是一个特别的,并具有多重功能的细胞因子,它在免疫调节,炎症反应,机体防御当中起着关键的作用。根据不同的细胞微环境,肿瘤坏死因子可以诱导多种反应,例如凋亡,坏死,血管生成,免疫细胞激活,细胞分化,细胞迁移。TNF在肿瘤当中是一把双刃剑。一方面,TNF是一个内源性的肿瘤促进因素,因为TNF可以刺激肿瘤细胞生长,增殖,侵袭,转移,血管生成。另一方面,TNF具有杀肿瘤细胞的作用。因此,如果可以调控肿瘤坏死因子的功能,将为癌症的治疗提供可能。     

Delineating the longitudinal tumor evolution using organoid models

Cancer is an evolutionary process fueled by genetic or epigenetic alterations in the genome. Understanding the evolutionary dynamics that are operative at different stages of tumor progression might inform effective strategies in early detection, diagnosis, and treatment of cancer. However, our understanding on the dynamics of tumor evolution through time is very limited since it is usually impossible to sample patient tumors repeatedly. The recent advances in in vitro 3D organoid culture technologies have opened new avenues for the development of more realistic human cancer models that mimic many in vivo biological characteristics in human tumors. Here, we review recent progresses and challenges in cancer genomic evolution studies and advantages of using tumor organoids to study cancer evolution. We propose to establish an experimental evolution model based on continuous passages of patient-derived organoids and longitudinal sampling to study clonal dynamics and evolutionary patterns over time. Development and integration of population genetic theories and computational models into time-course genomic data in tumor organoids will help to pinpoint the key cellular mechanisms underlying cancer evolutionary dynamics, thus providing novel insights on therapeutic strategies for highly dynamic and heterogeneous tumors.     

可移植性小鼠组织细胞肉瘤侵袭与转移模型的建立

将小鼠可移植性组织细胞肉瘤ＬⅡ分别接种在近交系６１５小鼠的胁部皮下、后肢肌肉和爪垫皮下组织内,取全肺和各部位淋巴结进行组织学检查,观察肿瘤自发转移率及转移程度。胁部皮下与后肢肌肉移植组待荷瘤小鼠自然死亡,平均存活时间分别为３９．３、２７．９ｄ,淋巴结转移率分别为９５．７％和１００％,肺转移率均为１００％。爪垫皮下移植组在肿瘤接种后１、３、５、１０、２０、３０和４０ｄ处死荷瘤小鼠,早期淋巴结转移出现在肿瘤接种后第１０天,至第３０天时形成肺转移瘤。局部侵袭达Ⅲ～Ⅳ级时才发生肿瘤转移,肺转移出现时间晚于淋巴转移。结果表明,ＬⅡ瘤株具有淋巴道合并血道转移的特性,是研究肿瘤侵袭和转移的理想实验肿瘤模型。     

Functional mechanism of Ginsenosides on tumor growth and metastasis

Ginsengs, has long been used as one medicinal herb in China for more than two thousand years. Many studies have shown that ginsengs have preventive and therapeutic roles for cancer, and play a good complementary role in cancer treatment. Ginsenosides, as most important constituents of ginseng, have been extensively investigated and emphasized in cancer chemoprevention and therapeutics. However, the functional mechanism of Ginsenosides on cancer is not well known. This review will focus on introducing the functional mechanisms of ginsenosides and their metabolites, which regulate signaling pathways related with tumor growth and metastasis. Ginsenosides inhibit tumor growth via upregulating tumor apoptosis, inducing tumor cell differentiation and targeting cancer stem cells. In addition, Ginsenosides regulate tumor microenvironment via suppressing tumor angiogenesis-related proteins and pathways. Structural modification of ginsenosides and their administration alone or combinations with other Chinese medicines or chemical medicines have recently been developed to be a new therapeutic strategy for cancer.     

靶向肿瘤微环境的CAR-T治疗研究*

癌症仍然是现阶段威胁人类健康的一大难题,随着医学的发展,癌症治疗方法除传统方法:手术、放疗、化疗,还可以采用免疫疗法。目前,癌症免疫疗法受到广泛关注,但在应用方面具有许多局限性,如 PD-1/PD-L1 抑制剂,在应用的过程中会出现获得性耐药现象,因此细胞免疫疗法(chimeric antigen receptor T cell, CAR-T) 应运而生,成为弥补免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)和单克隆抗体药物缺陷的新兴治疗方式,简要介绍了 CAR-T 免疫疗法的产生、应用及对 TME 相关靶点的研究进展,为后续研究提供一定的思路。     

靶向肿瘤微环境的CAR-T治疗研究*

癌症仍然是现阶段威胁人类健康的一大难题,随着医学的发展,癌症治疗方法除传统方法:手术、放疗、化疗,还可以采用免疫疗法。目前,癌症免疫疗法受到广泛关注,但在应用方面具有许多局限性,如 PD-1/PD-L1 抑制剂,在应用的过程中会出现获得性耐药现象,因此细胞免疫疗法(chimeric antigen receptor T cell, CAR-T) 应运而生,成为弥补免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)和单克隆抗体药物缺陷的新兴治疗方式,简要介绍了 CAR-T 免疫疗法的产生、应用及对 TME 相关靶点的研究进展,为后续研究提供一定的思路。     

A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity

There are many mechanisms that regulate and dampen the immune response to cancers, including several types of regulatory T cells. Besides the T reg cell, we have identified another immunoregulatory circuit initiated by NKT cells that produce IL-13 in response to tumor growth and this IL-13 then induces myeloid cells to make TGF-beta that inhibits cytotoxic T cell-mediated tumor immunosurveillance in several mouse tumor models. This finding created a paradox in the role of NKT cells in tumor immunity, in that they can also contribute to protection. We resolve this paradox by the finding that the suppressive NKT cell is a type II NKT cell that lacks the canonical invariant T cell receptor, whereas the protective cell is a type I NKT cell that expresses the invariant receptor. Further, we see that these two subsets of NKT cells counter-regulate each other, defining a new immunoregulatory axis. The balance along this axis may determine the outcome of tumor immunosurveillance as well as influence the efficacy of anti-cancer vaccines and immunotherapy.     

硫化铜纳米粒子在肿瘤成像与治疗中的功能研究进展

硫化铜是一种二价铜的硫化物,可以作为半导体材料,化学式为CuS,呈黑褐色,溶解度极低。硫化铜纳米粒子(Copper sulfide nanoparticles, CuS NPs)是纳米尺度大小的硫化铜。近年来,CuS NPs因其结构的可塑性,良好的光热稳定性、生物相容性、突出的光热及光声转换性能,成为了当今纳米材料医学领域的研究热点,在肿瘤诊断和治疗领域中引起了广泛关注。CuS NPs本身可通过介质鳌合金属离子合成多功能纳米粒子,实现肿瘤多模式诊断,并且在光热治疗研究中体现出突出的治疗效果。本文综述了近几年CuS NPs在肿瘤诊断与治疗方面的研究进展,总结肿瘤治疗中的应用研究方法,对CuS NPs在生物医学领域应用中存在的问题进行分析,为解决实际操作过程所遇到的问题提供参考。     

肿瘤微环境应激因子乳酸在肿瘤发展中的作用

肿瘤微环境应激主要包括:缺氧、胞外酸环境、葡萄糖缺乏等。乳酸堆积也是肿瘤微环境应激中一个重要特征。长期以来,乳酸一直被认为是代谢废物,但随着研究深入,发现乳酸作为癌代谢物与肿瘤增殖、转移、血管生成、免疫逃逸以及放化疗效果等肿瘤生物学功能密切相关,此外乳酸还可促进缺氧诱导因子稳定、作为"替代燃料"供能等进一步促进肿瘤恶性进展。因此,本文就肿瘤微环境中乳酸代谢与调控、乳酸对肿瘤生物学功能的影响等方面作一综述,旨在为针对乳酸这一异常代谢特征的抗肿瘤药物开发及临床治疗提供必要依据。     

How regulatory CD25(+)CD4(+) T cells impinge on tumor immunobiology? On the existence of two alternative dynamical classes of tumors

Aiming to get a better insight on the impact of regulatory CD25(+)CD4(+) T cells in tumor immunobiology, a simple mathematical model was formulated and studied. This model is an extension of a previous model for the dynamics of autoreactive regulatory cells and effector cells that interact upon their co-localized activation at the antigen presenting cells (APCs). It assumes that tumor growth stimulates the activation and migration to the adjacent lymph node of fresh APCs loaded with tumor antigens. These APCs stimulate the growth of both effector and regulatory T cells, which may then migrate to the tumor site and induce tumor cell destruction. Our results predict the existence of two alternative dynamic modes of unbounded tumor growth. In the first mode, the tumor induces the expansion of effector T cells that outcompete regulatory T cells, but nevertheless fail to control the tumor. In the second mode, the tumor induces a balanced expansion of both effector and regulatory T cells, which prevents the tumor from being destroyed by the immune cells. Tumors characterized by a high specific growth rate, low immunogenicity, and that are relatively resistant to T cell destructive functions, will grow in the first mode; conversely, tumors that have a slow specific growth rate, that are immunogenic, and/or that are more sensitive to destruction by T cells will grow in the second mode. Overall, this result provides a simple explanation to the fact that the development of some tumors expands regulatory T cells while others do not, predicting how some key dynamical properties of the tumor determine either one or the other type of behavior.     

腹腔注射精氨酸对小鼠S_（180）瘤生长的促进作用

尽管大多数动物实验的结果表明通过饮水或饲料补充精氨酸对一些肿瘤的形成、生长及转移均有显著的抑制作用,但也有少数几篇相反结果的报道。我们采用小鼠腹腔注射的方法,观察了不同剂量（０．１、０．０５、０．０２５克／每天）精氨酸对Ｓ１８０瘤生长的影响,结果发现精氨酸对Ｓ１８０瘤的生长具有显著的促进作用,尤其是０．０５克／每天剂量组,文中就其可能机制进行了讨论。     

编者按: 祛邪还需扶正：免疫治疗给肿瘤治疗带来新曙光

祛邪还需扶正：免疫治疗给肿瘤治疗带来新曙光     

Limitations of the cancer stem cell theory

Cancer stem cells (CSCs) can be operationally defined as a subset of neoplastic cells which are responsible for the growth and re-growth of primary and metastatic tumors. Although the existence of perpetually dividing cells is a logical necessity to explain the malignant properties of human tumors, experimental data supporting their existence have only recently been obtained. New knowledge in basic stem cell biology and the availability of several cell surface markers for the definition and isolation of small subsets of immature cells coupled to the use of the classical model of xenotransplantation in immune deficient mice has identified putative CSCs in several solid tumors such as mammary, colon, brain, pancreas, prostate, melanoma and others. However, the theory must be considered as still in its infancy, since tumors grown in mice only partially recapitulate the biology of human cells. In addition, whether the “transformed” cell is the neoplastic counterpart of a normal stem cell or whether complete malignant behaviour can occur in a more differentiated cell has still to be demonstrated. In spite of these difficulties, the CSC hypothesis could be of clinical relevance, especially in the definition of new ways to assay drug sensitivity of primary human tumors.