摘要
进展期胃癌根治术后腹膜种植转移约占40%-50%,是影响预后的主要因素之一。胃癌腹膜转移的形成是一个复杂的病理生理过程,胃癌腹膜转移与癌细胞活性及腹膜特征有关,并且需要多种黏附分子、蛋白水解酶、细胞因子及血管生成因子的共同参与。
趋化因子是一类具有趋化作用的细胞因子,根据半胱氨酸相对位置不同,可将趋化因子分为C.CC.CXC和CX3C四大类,除参与炎症反应外,趋化因子及其受体在淋巴细胞归巢、免疫应答、感染、自身免疫性疾病、移植免疫排斥及血管生成等众多生理、病理过程中起着非常重要的作用。近年来,越来越多的证据表明,趋化因子与肿瘤的生长、侵袭和转移密切相关趋化因子及其受体的相互作用与胃癌腹膜乳斑转移的关系目前还不完全清楚,但已有研究表明趋化因子家族中的基质细胞衍生因子一1(SDF-1／CXCL 12)及其受体CXCR4可能在胃癌腹膜转移中发挥作用,用CXCR4的特异性阻断剂AMD3100可以抑制胃癌的腹膜转移。已有资料证明进展期胃癌患者腹膜转移初期首先发生在大网膜乳斑区,而非乳斑区很少出现。大网膜乳斑为腹膜上的淋巴样组织,主要由巨噬细胞和淋巴细胞所组成,当乳斑区的巨噬细胞等炎症细胞受到外界因素刺激后分泌巨噬细胞衍生因子(Macrophage-Derived Chemokine,)即MDC／CCL22,CCL22为CC类趋化因子亚家族成员,CCL22的受体为CC类趋化因子受体4(CCR4),
我们此实验的目的是研究趋化因子受体4(CCR4)在胃癌中的表达；分析与临床病理参数的关系；探讨趋化因子与胃癌细胞之间的作用关系；同时建立小鼠胃癌腹膜乳斑转移模型,观察乳斑区结构；验证胃癌腹膜转移首先特异性选择在乳斑区的理论,并进一步检测趋化因子MDC／CCL22及受体CCR4在乳斑区的表达情况,探讨MDC／CCL22一CCR4轴与胃癌腹膜乳斑转移的可能关系,为胃癌腹膜转移的治疗提供新的靶点。
方法：
取大连医科大学附属第一医院外科手术切除的、经病理证实的56例胃癌组织及56例转移淋巴结、12例大网膜转移灶、10例正常胃粘膜作为标本,通过免疫组化检测CCR4在各标本中的表达；单变量分析CCR4表达与临床各病理参数的关系。
细胞培养人胃癌细胞株MGC-803、AGS、BGC-823、MKN-45、SGC-7901,和小鼠胃癌细胞MFC,运用RT-PCR、Western-blot方法检测CCR4在各胃癌细胞系中的mRNA水平和蛋白水平的表达。
用MDC对CCR4表达阳性的细胞株进行体外实验,通过四甲基偶氮唑蓝(MTT)法和Transwell小室迁移实验检测不同浓度CCL22对胃癌细胞株的增殖和趋化的影响。
向615小鼠腹腔内注射0.2ml Dil荧光颗粒标记的CCR4阳性表达的MFC悬液(含癌细胞4×105)制备腹膜乳斑转移模型,12小时后通过免疫荧光观察大网膜。免疫组化检测大网膜乳斑区MDC/CCL22表达。
小鼠腹腔注入0.2ml MFC细胞悬液(含癌细胞5×106个),制备MFC腹膜转移模型。5天后抽取腹腔腹水,在有血性腹水的小鼠中随机抽取10只,并取数量相等的腹腔内注射生理盐水的615小鼠作为对照组。在腹腔注射后第6、8、10天,抽取小鼠的腹水,运用酶连免疫吸附法(Elisa)分别检测MFC组和对照组腹水中CCL22的浓度。
结果：
1.56例胃癌原发灶中,有41例CCR4表达阳性,阳性率为73.21%；56例转移淋巴结中36例呈阳性表达,表达率64.29%12例大网膜转移灶中10例表达CCR4,阳性率为83.33%;12例癌旁正常胃粘膜均未发现CCR4的表达。单变量分析56例胃癌原发灶中的CCR4表达水平与临床各病理参数的关系发现：CCR4在原发灶中的表达与胃癌分化程度相关(P<0.05),而与病人年龄、肿瘤大小、位置、分期、淋巴结转移等无关(P>0.05)。
2. RT-PCR结果显示CCR4的mRNA在5种人胃癌细胞株MGC-803、AGS、BGC-823、MKN-45、SGC-7901和小鼠胃癌MFC中均有表达。Western-blot检测CCR4蛋白在各细胞系的表达水平结果与RT-PCR相符。体外实验显示MDC可以促进BGC-823细胞的增殖和趋化,在一定的浓度范围内呈剂量依赖性。
3.腹腔注射的MFC初期转移在大网膜乳斑区；免疫组化显示在胃癌腹膜转移的过程中,乳斑区有CCR4.CCL22表达。CC122在MFC组腹水中的浓度显著高于对照组,有统计学意义(P<0.05)。
结论：
CCR4在部分胃癌中有表达,MDC/CCL22可以促进BGC-823细胞的增殖和增加它的迁移能力。胃癌腹膜转移早期特异选择的部位是乳斑区,趋化因子MDC／CCL22-CCR4轴在胃癌腹膜乳斑转移中起作用,CCR4可能成为未来腹膜转移防治的潜在的靶点。
Peritoneal metastasis occurred in 40%-50% out of whole cases of advanced gastric carcinoma, which is a frequent cause of death in these patients. The formation of peritoneal metastasis of gastric cancer is a complex pathophysiological process, which is hypothesized to be related to cancer cell activity, peritoneal characteristics and other factors such as multiple adhesion molecules, proteolytic enzyme, cytokine, angiogenesis factor and so on.
Chemokines belongs to one type of cytokines which have chemotactic effect. According to the relative position of cysteine, chemokines can be divided into four categories:C, CC, CXC, and CX3C. Chemokines and their receptors get involved in many physiological and pathological processes (inflammatory responses, lymphocyte homing, immune response, infections, autoimmune diseases, graft rejection and angiogenesis and so on) and play important roles in them. In recent years, more and more evidence emerged to demonstrate that chemokines are closely related to the tumor growth, invasion and metastasis. The role that chemokines play in the formation of the peritoneal milky spots metastasis of gastric cancer is still unclear. There were studies which had shown that Stromal cell-derived factor-1(SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) might participate in peritoneal metastasis of gastric cancer on the basis that AMD3100, the blocking agent of CXCR4, can inhibit peritoneal metastasis of gastric cancer. Omental milky spots is the lymphoid tissue in peritoneum and composed of macrophages and lymphocytes. Macrophages secrete macrophage-derived factors (MDC/CCL22, the CC chemokines subfamily members) when they are stimulated by external factors. The receptor of CCL22 is CC-type chemokine receptor 4 (CCR4). The purpose of this study is to assay the expression of chemokine receptor 4 (CCR4) in the primary gastric cancer and analyze the relationship between the expression of chemokine receptor 4 and the clinic pathologic parameters; investigate the relationship between chemokines and the formation of metastasis of gastric carcinoma; construct the mold of the mouse milky spot metastasis of gastric cancer and observe the structure of these metastasis; verify the hypothesis that the preference of metastasis of gastric carcinoma is the milky spot of peritoneal; inspect the expressions of MDC/CCL22 and their recptor CCR4 in the milky spot of peritoneal; explore the relationship between the MDC/CCL22-CCR4 axis and the milky spot metastasis of gastric carcinoma and provide new strategy to treat peritoneal metastasis of gastric carcinoma.
Methods:
Pathological specimens of 56 cases of gastric cancer,56 cases of lymph node metastasis,12 specimens of omental metastasis of gastric carcinoma,10 specimens of normal gastric mucosa were included. The expression of CCR4 in the all specimens were detected by immunohistochemistry. The relationship between the expression of CCR4 and clinic pathological parameter were analyzed by the single-variable analysis.
The human gastric cancer cell lines MGC-803, AGS, BGC-823, MKN-45 and SGC-7901 and the mouse gastric cancer cell lines MFC were cultivated in RPMI 1640 or DMEM supplemented with 10% fetal bovine serum. The expressions of CCR4 at the level of mRNA and protein in cell line MGC-803, AGS, BGC-823, MKN-45, SGC-7901,MFC,were detected by RT-PCR and Western-blot respectively.
CCL22 with different concentrations was supplemented to the culture medium of BGC-823 in which CCR4 was highly expressed. Subsequently, the effects of CCL22 on the proliferation and chemotaxis of CCR4 were assayed by MTT and Transwell plates.
The expression of CCR4 at mRNA level were detected by RT-PCR in the MFC. The suspension of fluorescence labeling (Dil) MFC in which CCR4 was highly expressed were injected into the abdominal cavity. The omental were observed by confocal fluorescence microscope 12h later. The expression of MDC in milky spot were detected by immuno histochemistry.
In addition,615 mice peritoneal cavity was injected 0.2ml MFC cell suspension (containing 5×106 cells in number) in order to product the peritoneal metastasis model of MFC. Include 10 mice which have bloody ascites 5 days later as the experimental group. Meanwhile, take the 10 mice which were injected normal saline in their abdominal cavity as the control group.Ascites were collected in two groups at 6th day,8th day,10th day and The concentration of CCL22 were detected by Enzyme linked immunosorbent assay.
Results:
1. CCR4 was expressed in 41 cases of primary gastric carcinoma and the positive rate is 73.21%. CCR4 was expressed in 36 cases of lymph node metastasis and the positive rate is 64.29%. CCR4 was expressed in 10 cases of omental metastasis and the positive rate is 83.33%. CCR4 was not detected in the normal gastric mucosa. The expression of CCR4 in the primary gastric carcinoma is highly related to the tumor differentiation (P< 0.05), however it is not related to the other pathological parameter such as age, tumor size, location, phage, stage and lymph node metastasis and so on.
2. CCR4 was detected to be highly expressed in the 5 human gastric cell lines:MGC-803, AGS, BGC-823, MKN-45 and SGC-7901 by RT-PCR and Western-blot. MDC could promote the proliferation and chemotaxis of BGC-823 dose-dependently in a certain range of concentration.
3. CCR4 was detected to be expressed in the cell line MFC. In the specimens of milky spot metastasis, CCR4 and CCL22 were detected by immunohistochemistry to be positive. The concentrations of CCL22 in the abdominal fluid in the group of MFC were higher than the control group, there are statistical significant difference between them (P<0.05).
Conclusions:
CCR4 was expressed in parts of gastric carcinoma. MDC/CCL22 could promote the proliferation and chemotaxis of BGC-823. The early omental metastasis of gastric carcinoma is prone to the milky spot. The axis of MDC/CCL22-CCR4 play a important role in the milky spot metastasis of gastric carcinoma and CCR4 maybe the new target for the treatment of milky spot metastasis of gastric carcinoma.
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