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骨骼肌转移瘤罕见性及其机理的实验研究

Experimental study on mechanism and rarity of metastases in skeletal muscle

摘要:

目的探讨骨骼肌转移瘤罕见性的机理.方法经Wistar大鼠髂动脉、尾静脉注入Walker256癌肉瘤细胞,建立恶性肿瘤经血循环向骨骼肌及肺转移的动物模型,并进行了大体及组织学观察.用免疫组化方法观察了血管内皮细胞粘附分子(VCAM-1)在这些器官中的表达.原代培养的新生Wistar大鼠骨骼肌细胞,用MTT法分析骨骼肌细胞条件培养液(skeletal muscle conditioned medium, MCM)对不同肿瘤细胞系的体外抑瘤作用,并观察了骨骼肌源性抑瘤物的生物化学特性,及其对肿瘤细胞凋亡及形态学方面的影响.结果实验组经髂动脉注入瘤细胞后,肌纤维间无实验性转移灶形成;对照组经尾静脉注入瘤细胞后,14天处死及自然死亡鼠全部形成多发的实验性肺转移灶(共17只).实验组大腿骨骼肌微血管内皮VCAM-1的表达在注瘤第7天以后显著上升(P<0.001),对照组肺微血管内皮VCAM-1在注瘤第7天以后亦显著上升(P=0.018),且实验组大腿骨骼肌与对照组肺微血管内皮细胞VCAM-1阳性率无显著差异(P>0.05).体外研究表明,MCM与哺乳动物源性肿瘤细胞(小鼠骨髓瘤SP2/0, Wistar大鼠癌肉瘤Walker256),人源性白血病细胞(人慢性粒细胞白血病K562,人急性淋巴细胞白血病HL60)、实体瘤细胞(人结肠腺癌细胞LS-174-T,人前列腺癌细胞PC3-M),以及不同转移潜能肺巨细胞癌细胞(人肺巨细胞癌低转移株PLA801-C,人肺巨细胞癌高转移株PLA801-D)共同培养后,肿瘤细胞的增殖显著下降(P<0.01~0.05), 瘤细胞增殖呈不同程度MCM浓度依赖性.MCM与正常细胞(兔关节骺板细胞RGP-2)共同培养后,正常细胞增殖无下降.同一来源肺巨细胞癌细胞,高转移株的增殖在MCM稀释至原液的6.25%时仍见显著受抑,而低转移株的增殖在MCM稀释至原液的25%时即无显著受抑.MCM经截留分子量10.0 KDa的超滤膜进行超滤、热灭活及胰蛋白酶处理后,MTT分析显示,骨骼肌源性抑瘤物分子量≤10.0 KDa,不耐热而耐胰蛋白酶.骨骼肌源性抑瘤物可直接破坏肿瘤细胞膜,而不导致肿瘤细胞凋亡.结论临床上广泛存在的骨骼肌转移瘤罕见性,可在动物模型中观察到.骨骼肌微血管内皮细胞VCAM-1表达的变化,不能解释骨骼肌转移瘤罕见性.新生抑鼠骨骼肌细胞可产生某种抑瘤物,可能是骨骼肌转移瘤罕见性现象的关键因素.

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abstracts:

Objective To investigate the reasons for the rarity of metastases in skeletal muscle.Methods By injecting tumor cells (Walker256 rat carcinosarcoma) through the iliac artery (experimental group) and the tail vein (control group), animal models of blood-borne metastases were established. The quadriceps femoris muscle and lungs were observed grossly and microscopically. Immunohistochemistry was applied to investigate the expression of vascular cell adhesion molecule-1 (VCAM-1) in the microvascular endothelium of these organs. Primary culture of rat skeletal muscle cells was established and conditioned medium (MCM) was collected. Effects of MCM on several tumor cell lines and the biochemical characteristics of skeletal muscle delivered tumor factor(s) were tested by MTT assay. Apoptosis and morphological examination were carried out to investigate the antitumor mechanisms of MCM.Results In the experimental group, there were no definite metastases observed in muscle cells. In the control group, lung metastases were present in the lungs of all rats that were sacrificed at the 14th day or died spontaneously (17 rats in all). There was no significant difference between the increase in VCAM-1 in quadriceps femoris muscle 7 days after iliac artery injection and that in lungs 7 days after tail vein injection (P>0.05). In vitro studies showed that the proliferation of tumor cell lines of mouse SP2/0 myeloma, rat Walker256 carcinosarcoma or human chronic granulocytic leukemia K562, human acute lymphatic leukemia HL-60, LS-174-T colon adenocarcinoma, PC3-M prostatic carcinoma and lung giant cell carcinoma with different metastatic potency (PLA801-C with low metastatic potency, PLA801-D with high metastatic potency) was significantly inhibited when cultured with MCM (P<0.01-0.05). Proliferation of malignant cells showed a dose-dependent decrease, to a certain degree. Proliferation of normal rabbit joint epiphysial disk cells (RGP-2) were not affected by MCM. Proliferation of lung giant cell carcinoma cells with high metastatic potency showed a significant decrease even when cultured in highly diluted MCM (6.25% of primary MCM), when compared with the strain of low metastatic potency. Following ultrafiltration, boiling at 100℃, and treatment with trypsin, skeletal muscle delivered tumor factor(s) were found to be a low molecular weight (MW≤10.0 KDa) component which was trypsin resistant but not heat resistant. The factor(s) did not induce apoptosis in K562 cells but caused direct destruction of the cytoplasmic membrane.Conclusions The rarity of metastases in skeletal muscles, generally accepted in the clinical setting, can be reproduced in an animal model. It does not seem to be related to VCAM-1 expression in the microvessels of these organs. Skeletal muscle delivered factor(s) play a key role in the mechanism of the rarity of metastases in skeletal muscle.

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