摘要
肿瘤的生长和发展有赖于体内促肿瘤和抗肿瘤效应的精确平衡,这除了与肿瘤细胞本身有关外,还涉及到肿瘤细胞所处的微环境。肿瘤微环境是肿瘤在发生和发展的过程中所处的内环境,是一个复杂的体内系统,它除了包括细胞成分外,还包括细胞外基质、细胞因子及其它一些蛋白质。肿瘤微环境中的细胞包括肿瘤细胞、内皮细胞、成纤维细胞、脂肪细胞、神经胶质细胞、免疫和炎症细胞等。肿瘤微环境中的分子,既有肿瘤细胞产生的,也有非肿瘤细胞产生的。肿瘤细胞与肿瘤微环境中其它成分之间的相互作用是肿瘤发展的决定因素,决定了肿瘤是发生转移还是消失,或者成为良性肿瘤。因此在进行肿瘤研究时,关于肿瘤微环境问题的探讨显得尤为重要。
越来越多的证据表明,浸润到肿瘤微环境中的髓源性细胞对肿瘤的生长和血管形成等起到重要作用,这其中包括肥大细胞。肥大细胞是较为古老的免疫细胞,早在1871年,就被免疫学者们所认识。肥大细胞起源于骨髓中的造血干细胞,发育成熟在外周组织。通常人们认为肥大细胞主要在抗寄生虫感染和变态反应中起到重要作用,而关于其在肿瘤中作用的研究较少,并且存在争议。肥大细胞是炎性细胞,活化后可释放多种生物活性物质,包括：肝素、IL-8、VEGF、PDGF、NGF、SCF和组胺等,这类介质被认为可产生促肿瘤生长特性；肥大细胞活化后释放的另一类介质如IL-1、IL-6、TNF-α、纤维蛋白溶酶等则被认为具有抗肿瘤生长特性。现代免疫学研究认为,肥大细胞可以做为免疫调节细胞,一方面它可以通过递呈抗原、促进T细胞激活等效应上调免疫应答,另一方面它也可以通过产生IL-10介导负向免疫调节作用。肥大细胞特性和功能的复杂性可能正是当前肿瘤中肥大细胞究竟是什么作用存在争议的原因。本课题旨在探讨肥大细胞在肿瘤发生、发展中的真正作用,并对其部分机制进行初步的探讨。本研究分为以下三部分：
第一部分：肥大细胞对肿瘤生长的影响在这一部分的研究中,我们建立了两种动物模型,第一种是指把H22细胞接种到小鼠右大腿肌肉后形成刚触摸到肿瘤结节的动物模型(肌肉接种2×105个H22后10-12天)；第二种是指H22细胞肌肉接种形成1×1cm2大小肿瘤(肌肉接种2×105个H22后26-28天)的动物模型。前者称为肿瘤初期模型,而后者则称为肿瘤后期模型。在本研究中,我们把从H22(2×105个)接种到接种后12天这一段时间称为肿瘤发展的初期,H22接种形成l×1cm2大小肿瘤以后的时间称为肿瘤发展的后期(在这里只是特指而已,与临床诊断上所指概念并不完全相同)。我们通过两种策略观察肥大细胞在肿瘤中的作用,一种策略是阻断体内肥大细胞的功能,另一种则是把体外培养的肥大细胞与肿瘤细胞共注射的策略。研究发现,在肿瘤发展的初期,肥大细胞表现出抑制肿瘤生长的特性,这种特性与其趋化CD8+T细胞有关；而随着肿瘤进一步发展到后期,肥大细胞却又呈现出促进肿瘤生长的特点,这与其产生IL-10增多及趋化Treg细胞浸润到肿瘤局部有关,也可能涉及其促血管生成的特性。究竟是什么原因使肥大细胞产生了两种截然相反的功能?肿瘤在发展过程中会因为应激、缺氧、炎症等因素发生肿瘤细胞坏死,因此产生大量的内源性DAMP分子。本课题组前期的研究即发现,肿瘤直径越大释放到组织中的DAMP分子越多。本实验进一步的研究发现,后期肿瘤中的肥大细胞其模式识别受体(TLR2)、协同刺激受体(4-1BB、B7-H1)及IL-10的表达均明显升高,这些说明可能是大量存在的内源性DAMP分子使肥大细胞的功能发生了改变。本部分的另一组实验也证明当肥大细胞经高浓度肿瘤细胞坏死源性分子作用后再与H22细胞共接种小鼠即产生了促瘤生长的特性。由于肿瘤组织内肥大细胞数量较少,限制了进一步的研究,因此我们用体外系统模拟体内进行了第二部分的研究。
第二部分：肿瘤细胞坏死源性分子对肥大细胞生物学特点的影响在本课题组前期的研究中,肿瘤细胞坏死源性分子已被证实含有HMGB1、HSP70等DAMP分子的代表性物质,可以模拟体内肿瘤细胞坏死环境。因此在本部分研究中,我们用高浓度肿瘤细胞坏死源性分子刺激BMMCs来模拟体内肥大细胞发生的部分变化,以进一步探讨肥大细胞与肿瘤的关系。BMMCs受高浓度肿瘤细胞坏死源性分子刺激后,其与血管生成(VEGF、PDGF)、组织重塑(MMP9)和负调节免疫应答(IL-10、TGF-β)相关基因的表达上调,且模式识别受体(TLR4、2)和协同刺激受体分子(CD80、CD86、4-1BB、CTLA-4)的表达也均上调；进一步研究发现肿瘤细胞坏死源性分子刺激肥大细胞所引起的IL-10表达增加涉及TLR4-PI3K-GSK3β-NF-κB信号途径。当肥大细胞TLR4和GSK3β分子功能被阻断后,其促瘤生长的特性则消失。因此当我们用肿瘤细胞坏死源性分子刺激体外培养的BMMCs,发现其从表面分子到胞内信号的转导都发生了有利于促瘤生长特性的变化。
第三部分：肿瘤对小鼠肥大细胞前体数量和表型的影响通过第一和第二部分的研究,我们发现肥大细胞对肿瘤的生长产生了影响,而肿瘤反过来对肥大细胞也产生了作用。除了这些,肿瘤对肥大细胞前体是否也产生了影响呢?因此我们进行了第三部分的研究。研究表明荷瘤小鼠中肥大细胞的动员明显增加,表现为骨髓中粒-单核细胞前体(GMP)、脾脏中肥大细胞和嗜碱性粒细胞共同前体(BMCP)、瘤周肌肉组织中肥大细胞前体(MCP)和肥大细胞的比例均明显增高,但有趣的是髓外器官阶段肥大细胞前体识别内源性DAMPs分子的模式识别受体(如TLR2)的表达并无明显变化,但瘤周肌肉组织MC和MCP中此类受体阳性的细胞比例却明显增高。这说明肿瘤对肥大细胞的影响从产生前体的骨髓阶段即开始,首先引起肥大细胞前体数量的增加,增多的肥大细胞在外周组织肿瘤微环境中受到足够强危险信号的刺激后,其表面相应受体的表达上调,这种驯化的结果最终使肥大细胞发生了从抑瘤生长到促瘤生长特性的转变。
本研究证明在肿瘤发展的初期,肥大细胞通过趋化CD8+T细胞抑制了肿瘤的生长；随着肿瘤的进一步发展,肿瘤微环境中出现的大量内源性DAMP分子改变了肥大细胞的特性,肥大细胞一方面IL-10表达上调,另一方面趋化Treg细胞浸润到肿瘤局部,从而促进了肿瘤的生长。因此肥大细胞在肿瘤中的作用具有可塑性,准确把握肥大细胞这种特性对深刻理解这一古老而又年轻的免疫细胞意义重大,而且也为临床上开展以肥大细胞为靶点的抗肿瘤治疗提供了科学依据。
The growth and development of tumors is regulated by a precise balance between pro-and anti-tumorigenic effects, stimulated by the tumor cells themselves, as well as theirs microenvironment. Tumor microenvironment provides an internal milieu in which tumor cell proliferation and survival and tumor growth and development happen. This microenvironment is a complex system, including different cell types, extracellular matrix (ECM), cytokines and other stromal elements. Cellular components of tumor microenvironment is composed of tumor cells, fibroblasts, smooth muscle cells, endothelial cells, adipocytes, glial cells, and resident and recruited immune and inflammatory cells. The molecular composition of the tumor microenvironment is established jointly by tumor cells as well as non-tumor cells. Interaction of tumor cells with other components of tumor microenvironment are crucial factor determining if tumor cells will progress towards metastasis, if they will stay dormant or if they will disappear. The role of the microenvironment during the study of carcinogenesis is now realized to be of critical importance.
There is a growing acceptance that bone marrow-derived myeloid cells can play an active role in tumor growth and angiogenesis. Infiltrating myeloid cells populations include mast cells. Mast cells were first described in 1878, which originate from hematopoietic stem cells in the bone marrow, and they mature in the tissues. They are commonly known for their role in allergic and parasites defense reactions, but the function of mast cells in tumor remains to be characterized in detail. Inflammatory stimuli can activate mast cells to release a diverse array of biologically active products, many of which can benefit the tumor including heparin, IL-8, VEGF, PDGF, NGF and SCF. However, mast cells also release molecules that could be considered detrimental to the tumor include IL-1, IL-6, TNF-αand tryptase. Recently, Mast cells are considered as immunoregulatory cells. They can exert positive immunoregulatory effects on immune cells by presenting antigens to T cells and prompting T cells activation. In addition, Mast cells can mediate negative immunomodulatory functions by producing IL-10. Thus, the prognostic significance of mast cells infiltration into tumors is controversial now. The true role of mast cells in tumor remains to be elucidated. Our experiment is aim to reveal whether mast cells have regulatory role on tumor growth. This experiment is subdivided into three parts.
PartⅠEffect of mast cells on tumor growth. In this study, we constructed two related tumor models. First, the mice with tumors approximately 1×1cm2 were referred to late stage model. Next, those whose tumors can be only attached were considered as early stage model. It is notable that the meaning of early or late stage tumor was not totally identical to the conception in clinical research. To investigate the regulatory effect of mast cells on tumor growth, two strategies were adopted, i.e, either mast cells degranulation was inhibited or mice were coinoculated with mast cells and H22 cells. We show that mast cells actively inhibit the growth of tumor by attracting CD8+T cells at early stage in our tumor model. However, the growth of tumor is promted by mast cells at late stage in our tumor model by up-regulatting the expression of IL-10 and migrating Treg cells, which is likely concerned with tumor angiogenesis. What factors induce the dual role of mast cells on tumor growth? A lot of endogenous damage-associated molecular pattern (DAMP) molecules are induced release from necrotic tumor cells derived from abnormal stress, inflammation and hypoxia in tumors. Our previous experimental results show that the more tumor diameter is, the more DAMP molecules are induced in tumor tissues. Furthermore, the expression of IL-10 and surface molecules TLR2,4-1BB and B7-H1 in mast cells are markedly up-regulated at late stage tumor in this experiment. Endogenous DAMP molecules seem to play important role in turning the effect of mast cells on tumor growth. Another experiment in our study shows that the growth of tumor was prompted when mice were coinoculated with H22 cells and mast cells stimulated by high concentration NTC-Ms. There is few mast cells presence in tumor tissures, so it is difficult to discuss the role of mast cells on tumor growth in vivo. We have to investigate the biological behaviours of mast cells in vitro.
Part II Regulatory effect of the molecules derived from necrotic tumor cells on mast cells biological property. Our previous experimental results show that there are DAMP representative molecules HMGB1 and HSP70 in NTC-Ms which may mimic tumor milieu in vivo. NTC-Ms are used to stimulate BMMCs in vitro in order to mimic the changes of mast cells in tumor tissure. Some genes concernd with angiogenesis (VEGF, PDGF), tissue remodeling (MMP9) and immune-modulation (IL-10, TGF-β) were up-regulated after stimulation with high concentration NTC-Ms. Furthermore, NTC-Ms treatment markedly up-regulated the expression of TLR4, TLR2 and costimulatory molecules CD80, CD86,4-1BB and CTLA-4 in BMMCs. IL-10 production in NTC-Ms-stimulated mast cells are dependent on the TLR4-PI3K-GSK3β-NF-κB signal pathway. The effect of promoting tumor growth of NTC-Ms-stimulated mast cells is concerned with TLR4 or GSK30 activity. The surface receptors and signal molecules of mast cells are changed in favor of the growth of tumor when they are stimulated with NTC-Ms in vitro.
PartⅢEffect of tumor on mast cell precursors numbers and phenotype in mice. PartⅠandⅡshow that mast cells have a regulatory effect on tumor growth, vice versa. To investigate whether tumor has an effect of on mast cell precursors numbers and phenotype in mice, partⅢwas carried out. There are significantly higher proportion of mast cell precursors in bone marrow, spleen and peripheral tissures, but no significant changes of the proportion of TLR2 positive cells in BMCP in tumor-bearing mice. It is obviously higher about the proportion of TLR2 positive cells in peripheral tumor tissures in tumor-bearing mice. In tumor-bearing mice, increased mast cell precursors enter peripheral tumor tissures where the expression of Toll-like receptors is up-regulated when they encounter high concentration endogenous DAMP molecules. The inhibitory effect on tumor growth is turned into promotion when mast cells are instructed by endogenous DAMP molecules in tumor microenvironment.
This study shows that mast cells actively inhibit the growth of tumor by attracting CD8+T cells at early stage tumor. With tumor growing, mast cells are impacted by high concentration endogenous DAMP molecules in tumor microenvironment and promot the growth of tumor by up-regulatting the expression of IL-10 and attracting Treg cells into tumor tissues. It is important to grasp this property of mast cells in order to know this older as well as younger immune cell. Furthermore, this study could provide scientific data on the applicability of mast cell-based interventions.
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