MSC-L的抗肿瘤基质细胞作用及其抑癌功效的研究

Tumor stromal cells play an important role in tumor development. For instance, tumor stromal cells constitute the tumor microenvironment, which largely contribute to tumor proliferation, and usually induce tumor cells resistance to clinic treatments. It is already known that mesenchymal stem cells (MSCs) may be an important source of tumor stromal cells. Reports showed that MSCs could specifically migrate into tumor tissues. After incorporating into tumor stroma, MSCs even can translate into cancer associated fibroblasts and pericytes, thereby further provide suitable niche for tumor growth. LIGHT, an acronym for homologous to lymphotoxin, which shows inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes, is a member of TNF superfamily. LIGHT is a potent immune stimulating factor and may prime strong anti-tumor immunity. Our recent report showed that, after LIGHT transfection into MSCs (MSC-L), MSC-L may target delivering LIGHT into tumor tissues and prime anti-tumor immunity to control tumors(Cancer Research, 72:3980-3989, 2012). Further, we observed that, compared with MSCs, MSC-L can form bone-like structure in nude mice but can not form resembled structure in synergistic immune competent BALB/c mice, which indicate that MSC-L may induce anti-MSCs or its progeny immunity. Thus, based on the role of MSCs in tumor disturbing stroma formation and the potent role of MSC-L in anti-tumor immunity, the MSC-L might be potentially used as a novel strategy for cancer biotherapy. In this proposed study, we will further investigate whether, besides directly priming anti-tumor cells immunity, MSC-L could control tumor growth via destruction of tumor stromal cells by priming anti-MSCs and tumor stromal cells immunity. Through this proposed study, we wish that MSC-L might be valuable as a biotherapeutic agent for cancer treatment in the near future.

肿瘤基质细胞在肿瘤发生发展中起重要作用，其可为肿瘤提供合适的微环境。已知间充质干细胞可特异趋化到肿瘤组织，转化为肿瘤相关成纤维细胞及血管周细胞（pericyte），从而成为肿瘤基质细胞的重要来源。LIGHT是肿瘤坏死因子TNF家族成员之一，有很强的免疫刺激作用。我们先前已证明将LIGHT转入MSCs(MSCs-LIGHT,简称MSC-L）能有效抑制肿瘤生长。进一步研究发现相对于MSCs，MSC-L在裸鼠体内可形成骨样组织，而在免疫功能正常的同系小鼠却未见类似结构，提示MSC-L可能通过LIGHT产生抗MSCs的免疫效应而干扰肿瘤生长。因此，我们将结合MSC-L的抗肿瘤效应和MSCs在肿瘤基质形成中所起的重要作用，探讨并证明MSC-L除了可以通过介导抗肿瘤细胞的免疫外，MSC-L也可能通过破坏肿瘤基质细胞而控制肿瘤。这提示了MSC-L具有潜在的肿瘤生物治疗作用，并为临床肿瘤治疗提供新思路。

间充质干细胞(MSCs)作为骨髓中两大主要的干细胞类群之一，能够积极参与造血调控，并具有很强的自我增殖和多分化潜能。最初发现MSCs可向炎症组织特异性趋化，而肿瘤组织则被认为是一种无法痊愈的慢性炎症，因此有研究提示MSCs可大量向肿瘤组织特异性趋化, 甚至可转变成为肿瘤相关成纤维细胞而促进肿瘤发展。.本项目前期研究将具有很强的免疫刺激作用的肿瘤坏死因子超家族成员LIGHT基因转入MSCs，成功观察到MSC-LIGHT可以将LIGHT输送到肿瘤组织，通过逆转免疫抑制性肿瘤微环境而打破宿主对肿瘤免疫耐受。MSCs超强的肿瘤趋化能力和LIGHT的免疫刺激作用相结合，不仅可以激活宿主对肿瘤细胞的免疫，还可以激活对肿瘤间质细胞的免疫反应，以预防性和治疗性两种途径有效控制肿瘤发展，其中CD4+ T细胞在诱导阶段起重要作用，而CD8+ T细胞在效应阶段很关键。在前期研究的基础上，后期研究发现不需要依赖外源性引进LIGHT基因对MSCs进行改造，MSCs自身远距离输体也能够起到有效的抑制肿瘤的效果，改变了MSCs被认为是促进肿瘤的生长和转移的传统理论，在应用上可以有效避开导入外源基因而带来的临床不安全性和不确定性，使MSCs自身的抗肿瘤的效应得到开发和应用得到更好的优化。该部分研究以小鼠乳腺癌细胞4T1为肿瘤模型，共同注射MSCs和4T1能够促进4T1的生长，远距离注射MSCs却可以抑制4T1的生长。研究发现远距离注射MSCs能够减少小鼠体内的髓性来源的免疫抑制细胞的积累，增加机体促炎细胞因子的分泌，如干扰素，肿瘤坏死因子，toll样受体TLR-3和TLR-4。这些因素的增加，导致了机体T淋巴细胞的积累和活化，从而加强了机体对于肿瘤的免疫，抑制肿瘤的生长。本研究首次在免疫正常的BALB/c小鼠背景下，以鼠源乳腺癌4T1细胞和大肠癌CT26.WT细胞发现了MSCs的抑瘤现象，又通过无胸腺免疫缺陷裸鼠的免疫重建模型，以人源乳腺癌BCap37细胞验证了T淋巴细胞的积累和活化是该现象的重要机制。.本研究的发现能够更加清晰地阐释MSCs的生物免疫调节机制，有利于MSCs的临床转化和肿瘤治疗。