丹参、红花对黑色素瘤转移的干预及其作用环节探讨
摘要
肿瘤转移是肿瘤患者死亡的主要原因，活血化瘀是中医临床用于肿瘤的治则之一。目前对活血化瘀药临床用于治疗肿瘤存在着较大的争论，一种观点认为活血化瘀药可以抑制肿瘤转移，改善肿瘤患者血液高凝状态，防止肿瘤栓子形成，对脱离原发瘤并移行进入血液循环的肿瘤细胞有直接或间接抑杀作用；另一种观点则认为活血化瘀药可以促进肿瘤转移，认为该类药物使肿瘤细胞更易于运行至转移位。因此，研究活血化瘀药物对肿瘤转移的影响及作用机理，对临床运用活血化瘀类中药防治肿瘤及肿瘤转移有现实的意义。本研究主要选取丹参、红花等活血化瘀代表药物，以尿激酶、肝素等抗凝药物作为对照，分析它们对肿瘤转移的影响及作用机理。
研究主要由以下几部分组成：
第一部分观察活血化瘀药丹参、红花对小鼠黑色素瘤细胞肺转移的影响。选用C57小鼠，于后肢足垫皮下注射黑色素瘤细胞，造成自发性转移模型；于尾静脉注射黑色素瘤细胞，造成实验性转移模型，观测小鼠肺结节数及肺重量。研究结果显示：对自发性肿瘤转移模型，丹参(指所研究的剂量下，以下同)促进肿瘤的肺转移；对实验性肿瘤转移模型，未观察到结节数的变化，但肺重量增加；对实验性及自发性的转移模型，不论是结节数还是肺重量，红花均无明显的影响，尿激酶对自发性及实验性的肿瘤转移都有促进的转移作用，对实验性肺转移的肺重量没有影响。对自发性及实验性的肿瘤转移模型，肝素钠抑制结节数，对转移模型肺的重量也有减轻作用。发现活血化瘀药对两种转移模型的影响有所不同，提示活血化瘀药丹参、红花影响肿瘤转移的步骤不同。
第二部分观察活血化瘀药丹参、红花对黑色素瘤细胞增殖的影响，为下步的研究提供研究剂量依据。采用MTT法研究活血化瘀药对肿瘤细胞增殖能力，肿瘤增殖是肿瘤转移的必要条件，当肿瘤细胞生长到一定的大小时，肿瘤细胞会因缺血缺氧等因素的刺激而形成血管，同时也会改变肿瘤细胞表面的分子特点，从而促进肿瘤细胞的转移。研究结果提示：尿激酶、肝素钠对黑色素瘤细胞的增殖影响较小，而丹参、红花则对肿瘤细胞增殖有一定的抑制作用。
第三部分：观察活血化瘀药丹参、红花对肿瘤细胞间及肿瘤细胞与基质间粘附能力的影响。同质型粘附主要由肿瘤细胞表面的粘附分子E-cadherin参与，而异质型粘附则主要由integrin和免疫球蛋白参与。采用琼脂糖阻断细胞与培养板间的粘附，研究肿瘤细胞间的粘附；采用Matrigel作为肿瘤基质的配体，研究肿瘤细胞与基质间的粘附，同时用RT-PCR法研究药物对肿瘤细胞E-cadherin表达的影响。研究结果提示：红花对肿瘤细胞间的粘附有抑制作用，并且可以抑制E-cadherin的表达。肝素钠及尿激酶对同质型粘附及E-cadherin的表达均无影响。丹参对肿瘤细胞间的粘附无影响，但对E-cadherin的表达却有增强作用。肿瘤细胞与基质间的粘附和药物的加入时间有一定的关系，当药物与细胞同时加入时抑制作用较强，而当肿瘤细胞和基质已经粘附时，加入药物则影响较小，红花及丹参对肿瘤细胞与基质间的粘附有较强的抑制作用。
第四部分：观察活血化瘀药丹参、红花对肿瘤细胞运动能力的影响。肿瘤细胞的运动能力是影响肿瘤转移的又一个重要因素。利用胶体金可以形成小颗粒，铺于载玻片上，观察肿瘤细胞的运动轨迹；划痕实验是将细胞以较高密度的种植于载玻片上，在细胞间造成等宽的划痕，观察肿瘤细胞整体的运动形式；胶原原位运动侵袭实验是将肿瘤细胞种植于胶原上，在一定时间内观察肿瘤细胞侵袭初期伸出伪足的能力。胶体金吞噬实验表明尿激酶、丹参可以增加肿瘤细胞运动能力，使其运动的面积增加，红花和肝素钠没有影响。划痕实验表明尿激酶、丹参有促进其向中间运动的能力，肝素钠有抑制作用，红花没有影响。对胶原原位运动侵袭的实验表明丹参、尿激酶促进肿瘤细胞在Ⅰ型胶原上伸出伪足，使肿瘤细胞的运动能力增加，促进其向胶原下侵袭，肝素对肿瘤细胞的抑制其伸伪足的作用，红花对肿瘤细胞的伪足没影响。
第五部分：体外方法观察活血化瘀药丹参、红花对肿瘤细胞侵袭基质能力的影响。肿瘤细胞侵袭基质的能力是考察肿瘤转移的一个重要的方面，本实验是将基质胶(Matrigel)涂于膜性支持物上，肿瘤细胞种置于上室，观察肿瘤细胞穿过基质膜的作用。研究结果表明：尿激酶、丹参可以促进黑色瘤细胞对Matrigel的侵袭能力，而肝素对黑色素瘤细胞的侵袭能力有抑制作用，红花没有影响。
第六部分：观察活血化瘀药丹参、红花对肿瘤细胞分泌金属蛋白酶活性的影响。采用电泳技术及金属蛋白酶可以酶解明胶的特点，对分泌性的MMP-2／MMP-9活性进行考察。研究结果表明：尿激酶对肿瘤细胞分泌的MMP-2有增强作用，对MMP-9的活性没有影响。肝素对MMP-2、MMP-9均有抑制作用，而红花及丹参则对MMP-2和MMP-9的活性都无影响。
第七部分：观察活血化瘀药丹参、红花对金属蛋白酶及其抑制剂表达的影响。运用RT-PCR的技术研究活血化瘀药物对它们表达的影响，反映药物对肿瘤转移的影响。研究结果表明：尿激酶能增加MMP-2的表达，对MMP-9的表达没有影响，抑制TIMP-1的表达，对TIMP-2的表达没有影响；丹参则对MMP-9、TIMP-1、TIMP-2的表达有增强作用，对MMP-9的表达没有影响；红花对MMP-9、TIMP-2的表达有抑制作用，对MMP-2、TIMP-1的表达没有影响；肝素能抑制MMP-2的表达，对TIMP-1、TIMP-2的表达也有增强作用，但对MMP-9的表达没有影响。将MMP-2及MMP-9的表达相加，与TIMP-1与TIMP-2之和相比，则可以得到尿激酶、丹参表达的MMP较TIMP多，而肝素则减少MMP与TIMP表达的比值，红花对比值没有影响。
第八部分：讨论与结论
The high mortality rates associated with cancer are caused by the metastatic spread of tumor cells from the site of their origin. The studies often focus on metastasis of tumor cells. Metastasis is a sequential process, contingent on tumour cells breaking off from the primary tumour, travelling through the bloodstream, and stopping at a distant site. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. At the core of the metastatic process lie the changing adhesive preferences of the cancer cells that dictate their reciprocal interactions with the ECM and neighboring stromal cells. At the molecular level, adhesion and deadhesion as well as cytoskeletal remodeling are not only a prerequisite for cellular motility, but are also linked to proliferation and survival (antiapoptotic) pathways through integrins. Integrin engagement activates a battery of downstream molecules crucial for motile function and survival.
One of the therapeutic principles is to promote blood circulation to remove blood stasis (PCRS). At present, conflicting ideas are held in the application of this therapy in clinical use for treating tumor. One idea goes that the drugs for invigorating blood circulation and eliminating stasis (DIBCES) can restrain metastasis, improving the hypercoagulabale state (HCS) and preventing the formation of tumor embolus. Also, it can directly or indirectly restrain or kill the tumor cells deviating from the primary tumor and enter blood circulation; while there is another idea that this drug can promote metastasis and make tumor cells more liable to transmit to the loci. Therefore, conducting research on the effects and mechanism of action of DIBCES on metastasis is of practical significance to use this kind of PCRS to prevent and treat tumor and its metastasis. This study focuses on the typical drugs such as Danshen (DS), Honghua (HH) and takes the anticoagulants like urokinase and heparin as the control drugs in order to analyze their effects and mechanism of action on tumor metastasis.
This study falls into the following parts:
PartⅠAn observation on the effects of PCRS like DS and HH on the cell lung metastasis of mouse melanoma. C57 mice were selected and hypodermically injected melanoma cells into the foot pad of the posterior limb, which led to spontaneous metastasis model; while injected in vena caudalis can lead to experimental metastasis model. The observation was made on the Pulmonary nodus and the lung weight, and the findings show that as to the spontaneous metastasis model, the use of DS (the dosage used in research, the same can be said of the following) can promote the lung metastasis of tumor; While as to the experimental metastasis model, no changes happened in number of the nodus but the increased weight were detected; As to the both metastasis models, HH exerts no apparent effects on the number of nodus or the lung weight. Urokinase can enhance the metastasis in either model, while has no effect on the lung weight in the experimental model. The use of heparin sodium is able to restrain the number of nodus and lead to the lung weight loss in either model. The discovery of the varied effects of DIBCES on the two metastasis models indicates the difference in the procedure of this kind of drugs on tumor metastasis.
PartⅡAn observation was made on the effect of Chinese DIBCES on the cell multiplication of melanoma to provide the evidence of the dosage for further research. The research was made by means of MTT on the activity of DIBCES in tumor cell multiplication. Tumor proliferation is the prerequisite of metastasis. Growing to a certain size, the tumor cells may form blood vessels for lack of blood or oxygen and alter the molecule feature of the tumor cells surface simultaneously to promote the metastasis of tumor cells accordingly. The findings suggest that urokinase and heparin sodium have slight effect on the proliferation of melanoma cells, while DS and HH have certain depressant effect on tumor cells.
PartⅢThe extracellular domain of E-cadherin interacts in a homophilic manner with E-cadherin molecules on the surface of neighboring cells. Loss or reduction of E-cadherin expression correlates with enhanced aggressiveness and dedifferentiation in most carcinomas. Recent studies highlight the role of other members of the cadherin family in tumor cell invasion and metastasis. An observation was made on the effect of Chinese DIBCES on the adherence ability between tumor cells and matrix. Tumor metastasis begins with adherence, which includes homogenous adherence (the adherence between tumor cells) and heterogonous adherence (the adherence between tumor cells and matrix. The decrease of homogenous adherence will promote metastasis, while the decline of heterogonous adherence will restrain metastasis. The homogenous adherence mainly involves the E-cadherin on the surface of tumor cells, while the heterogonous adherence mainly involves integrin and immunoglobulin. The adherence between Sepharose blocking cells and culture board was adopted to study the adherence between the tumor cells, and Matrigel was taken as the ligand of tumor matrix to study the adherence between tumor cells and matrix. Meanwhile, the RT-PCR approach was employed to study the impact of drugs on the E-cadherin expression of tumor cells The findings suggest that HH can restrain the adherence between tumor cells and heparin sodium and urokinase exerts no effect on the humongous adherence and E-cadherin expression. DS poses no impact on the adherence between tumor cells while has enhancement property on E-cadherin expression. There is a certain connection between the adherence between tumor cells and matrix and the time when the drugs are added. The imultaneous addition of drugs and cells will exert a stronger depressant effect, while the drugs will pose a minor effect when the tumor cells and matrix have adhered. DS and HH have strong depressant effect on the adherence between tumor cells and matrix, that is, they have the power to restrain tumor metastasis.
PartⅣCollective cell movement represents an effcient dissemination strategy in epithelial and mesenchymal cancers. Single cell motility suggests an effcient cellular and molecular plasticity in tumor cell migration strategies. The transition from proteolytic mesenchymal toward nonproteolytic 'amoeboid' movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis. An observation was made on the effect of DIBCES on the locomotory capacity of tumor cells, which is another important factor affecting tumor metastasis. Extracorporeal kinesis experiment demonstrates that the movement of tumor cells has direct correlation with the capacity of metastasis. There are two kinds of movement patterns for tumor cells: stationary motility and translocative motility. Gold colloid, which can form microaggregate, can be spread on glass slide to observe the movement track of tumor cells. Scratch test, a test in which cells are implanted on glass slide in high density, aequilatus scratches are made between the cells to observe the overall movement pattern of tumor cells. In collogen static exercise invasion experiment, tumor cells are implanted on collogen to observe the capacity of extruding spurious at the initial stage of tumor cells invasion within a certain period of time. The above mentioned experiments are conducted to study the movement capacity of tumor cells from different perspectives. The gold colloid phagocytosis test shows that urokinase, DS can promote the movement capacity of tumor cells and enlarge the motion area, while HH and proved with no effect. The scratch test reveals that urokinase, and DS have the power to enhance its movement towards the center, heparin sodium has depressant effect while HH with no effect. The collogen static exercise invasion experiment demonstrates that DS and urokinase enhance tumor cells protrude spurious on Collagen typeⅠ, strengthening the movement capacity of tumor cells and promoting its invasion downwards the collagen; heparin sodium can restrain the tumor cells from protruding spurious, while HH shows no effect on the spurious of tumor cells.
PartⅤAn extracorporeal approach was adopted to observe the effect of on the invasion capacity of tumor cells into matrix, which plays an important part in evaluation of tumor metastasis. In this experiment, Matrigel was applied on Membranate plank and the tumor cells were implanted in the upper chamber to observe the tumor cells permeating the matrix membrane. The findings show that urokinase and DS can promote the invasive ability of melanoma cells into the Matrigel, while heparin sodium restrains this ability and HH shows no effects.
PallⅥThe principal classes of enzymes that degrade the ECM and cell associated proteins are the matrix metalloproteinases (MMPs), a family of membrane-anchored and-secreted proteinases and tissue serine proteinases, including urokinase plasminogen activator, thrombin, and plasmin. Degradation and remodeling of the ECM, including the basement membrane, by proteolytic enzymes are essential steps in the process of cancer invasion, intra- and extravasation, and colonization at distant sites. Metalloproteases are thus important in many aspects of invasion and metastasis, ranging from cell proliferation and remodeling of the ECM to angiogenesis and cell migration. An observation was made on the effect of DIBCES on the activity of metalloprotease excreted by tumor cells. The metalloprotease excreted by tumor cells (MMP-2/MMP-9) and the activity of Membranate metalloprotease on its surface is vital for tumor cells to breakthrough the barrier of matrix. To investigate the activity of secretory MMP-2/MMP-9 with electrophoretic technique and the characteristics of the enzymolysis effect of metalloprotease on gelatinum. The findings indicates that urokinase can enhance the MMP-2 excreted by tumor cells and has no effect on the activity of MMP-9; Heparin sodium can restrain MMP-2 and MMP-9, while DS and HH pose no effect on the activity of MMP-2 and MMP-9.
PartⅦMost of these processes require a delicate balance between the functions of MMPs and tissue inhibitors of metalloproteases (TIMPs). TIMPs are a family of secreted proteins that selectively, but reversibly. During the invasive events, TIMPs are expressed primarily by the cancer cells and are thought to serve as a regulatory mechanism for fine tuning the activity of stromal MMPs, so that the cancer cells can have an active role in determining where and when they invade. An observation was made on the effect of DIBCES on metalloprotease and its suppressor expression. Metalloprotease expression has direct correlation with tumor metastasis while has inverse correlation with its suppressor (TIMP-1, TIMP-2) expression. The activity of metalloprotease can be restrained by suppressor. The technique of RT-PCR was employed to study the effect of DIBCES on their expressions and reveal the impact of drugs on tumor metastasis. The findings show that urokinase can promote the expression of MMP-2 and has no effect on the expression of MMP-9. It can also restrain the expression of TIMP-1, while has no effect on the expression ofTIMP-2; DS can enhance the expressions of MMP-9、TIMP-1、TIMP-2, while has no effect on TIMP-2. HH can restrain the expressions of MMP-9、TIMP-2 and has no effect on MMP-2、TIMP-1; Heparin can restrain the expression of MMP-2 and enhance the expressions of TIMP-1、TIMP-2, while has no effect on MMP-9. The comparison between the total expressions of MMP-2 and MMP-9 and that of TIMP-1 and TIMP-2 shows that urokinase, DS express more MMP than TIMP, while heparin decreases the expression ratio of MMP and TIMP, and HH poses no effect on the ratio.
PartⅧDiscussion and conclusion
研究主要由以下几部分组成：
第一部分观察活血化瘀药丹参、红花对小鼠黑色素瘤细胞肺转移的影响。选用C57小鼠，于后肢足垫皮下注射黑色素瘤细胞，造成自发性转移模型；于尾静脉注射黑色素瘤细胞，造成实验性转移模型，观测小鼠肺结节数及肺重量。研究结果显示：对自发性肿瘤转移模型，丹参(指所研究的剂量下，以下同)促进肿瘤的肺转移；对实验性肿瘤转移模型，未观察到结节数的变化，但肺重量增加；对实验性及自发性的转移模型，不论是结节数还是肺重量，红花均无明显的影响，尿激酶对自发性及实验性的肿瘤转移都有促进的转移作用，对实验性肺转移的肺重量没有影响。对自发性及实验性的肿瘤转移模型，肝素钠抑制结节数，对转移模型肺的重量也有减轻作用。发现活血化瘀药对两种转移模型的影响有所不同，提示活血化瘀药丹参、红花影响肿瘤转移的步骤不同。
第二部分观察活血化瘀药丹参、红花对黑色素瘤细胞增殖的影响，为下步的研究提供研究剂量依据。采用MTT法研究活血化瘀药对肿瘤细胞增殖能力，肿瘤增殖是肿瘤转移的必要条件，当肿瘤细胞生长到一定的大小时，肿瘤细胞会因缺血缺氧等因素的刺激而形成血管，同时也会改变肿瘤细胞表面的分子特点，从而促进肿瘤细胞的转移。研究结果提示：尿激酶、肝素钠对黑色素瘤细胞的增殖影响较小，而丹参、红花则对肿瘤细胞增殖有一定的抑制作用。
第三部分：观察活血化瘀药丹参、红花对肿瘤细胞间及肿瘤细胞与基质间粘附能力的影响。同质型粘附主要由肿瘤细胞表面的粘附分子E-cadherin参与，而异质型粘附则主要由integrin和免疫球蛋白参与。采用琼脂糖阻断细胞与培养板间的粘附，研究肿瘤细胞间的粘附；采用Matrigel作为肿瘤基质的配体，研究肿瘤细胞与基质间的粘附，同时用RT-PCR法研究药物对肿瘤细胞E-cadherin表达的影响。研究结果提示：红花对肿瘤细胞间的粘附有抑制作用，并且可以抑制E-cadherin的表达。肝素钠及尿激酶对同质型粘附及E-cadherin的表达均无影响。丹参对肿瘤细胞间的粘附无影响，但对E-cadherin的表达却有增强作用。肿瘤细胞与基质间的粘附和药物的加入时间有一定的关系，当药物与细胞同时加入时抑制作用较强，而当肿瘤细胞和基质已经粘附时，加入药物则影响较小，红花及丹参对肿瘤细胞与基质间的粘附有较强的抑制作用。
第四部分：观察活血化瘀药丹参、红花对肿瘤细胞运动能力的影响。肿瘤细胞的运动能力是影响肿瘤转移的又一个重要因素。利用胶体金可以形成小颗粒，铺于载玻片上，观察肿瘤细胞的运动轨迹；划痕实验是将细胞以较高密度的种植于载玻片上，在细胞间造成等宽的划痕，观察肿瘤细胞整体的运动形式；胶原原位运动侵袭实验是将肿瘤细胞种植于胶原上，在一定时间内观察肿瘤细胞侵袭初期伸出伪足的能力。胶体金吞噬实验表明尿激酶、丹参可以增加肿瘤细胞运动能力，使其运动的面积增加，红花和肝素钠没有影响。划痕实验表明尿激酶、丹参有促进其向中间运动的能力，肝素钠有抑制作用，红花没有影响。对胶原原位运动侵袭的实验表明丹参、尿激酶促进肿瘤细胞在Ⅰ型胶原上伸出伪足，使肿瘤细胞的运动能力增加，促进其向胶原下侵袭，肝素对肿瘤细胞的抑制其伸伪足的作用，红花对肿瘤细胞的伪足没影响。
第五部分：体外方法观察活血化瘀药丹参、红花对肿瘤细胞侵袭基质能力的影响。肿瘤细胞侵袭基质的能力是考察肿瘤转移的一个重要的方面，本实验是将基质胶(Matrigel)涂于膜性支持物上，肿瘤细胞种置于上室，观察肿瘤细胞穿过基质膜的作用。研究结果表明：尿激酶、丹参可以促进黑色瘤细胞对Matrigel的侵袭能力，而肝素对黑色素瘤细胞的侵袭能力有抑制作用，红花没有影响。
第六部分：观察活血化瘀药丹参、红花对肿瘤细胞分泌金属蛋白酶活性的影响。采用电泳技术及金属蛋白酶可以酶解明胶的特点，对分泌性的MMP-2／MMP-9活性进行考察。研究结果表明：尿激酶对肿瘤细胞分泌的MMP-2有增强作用，对MMP-9的活性没有影响。肝素对MMP-2、MMP-9均有抑制作用，而红花及丹参则对MMP-2和MMP-9的活性都无影响。
第七部分：观察活血化瘀药丹参、红花对金属蛋白酶及其抑制剂表达的影响。运用RT-PCR的技术研究活血化瘀药物对它们表达的影响，反映药物对肿瘤转移的影响。研究结果表明：尿激酶能增加MMP-2的表达，对MMP-9的表达没有影响，抑制TIMP-1的表达，对TIMP-2的表达没有影响；丹参则对MMP-9、TIMP-1、TIMP-2的表达有增强作用，对MMP-9的表达没有影响；红花对MMP-9、TIMP-2的表达有抑制作用，对MMP-2、TIMP-1的表达没有影响；肝素能抑制MMP-2的表达，对TIMP-1、TIMP-2的表达也有增强作用，但对MMP-9的表达没有影响。将MMP-2及MMP-9的表达相加，与TIMP-1与TIMP-2之和相比，则可以得到尿激酶、丹参表达的MMP较TIMP多，而肝素则减少MMP与TIMP表达的比值，红花对比值没有影响。
第八部分：讨论与结论
The high mortality rates associated with cancer are caused by the metastatic spread of tumor cells from the site of their origin. The studies often focus on metastasis of tumor cells. Metastasis is a sequential process, contingent on tumour cells breaking off from the primary tumour, travelling through the bloodstream, and stopping at a distant site. In carcinomas, the influences of the microenvironment are mediated, in large part, by bidirectional interactions (adhesion, survival, proteolysis, migration, immune escape mechanisms lymph-/angiogenesis, and homing on target organs) between epithelial tumor cells and neighboring stromal cells, such as fibroblasts as well as endothelial and immune cells. At the core of the metastatic process lie the changing adhesive preferences of the cancer cells that dictate their reciprocal interactions with the ECM and neighboring stromal cells. At the molecular level, adhesion and deadhesion as well as cytoskeletal remodeling are not only a prerequisite for cellular motility, but are also linked to proliferation and survival (antiapoptotic) pathways through integrins. Integrin engagement activates a battery of downstream molecules crucial for motile function and survival.
One of the therapeutic principles is to promote blood circulation to remove blood stasis (PCRS). At present, conflicting ideas are held in the application of this therapy in clinical use for treating tumor. One idea goes that the drugs for invigorating blood circulation and eliminating stasis (DIBCES) can restrain metastasis, improving the hypercoagulabale state (HCS) and preventing the formation of tumor embolus. Also, it can directly or indirectly restrain or kill the tumor cells deviating from the primary tumor and enter blood circulation; while there is another idea that this drug can promote metastasis and make tumor cells more liable to transmit to the loci. Therefore, conducting research on the effects and mechanism of action of DIBCES on metastasis is of practical significance to use this kind of PCRS to prevent and treat tumor and its metastasis. This study focuses on the typical drugs such as Danshen (DS), Honghua (HH) and takes the anticoagulants like urokinase and heparin as the control drugs in order to analyze their effects and mechanism of action on tumor metastasis.
This study falls into the following parts:
PartⅠAn observation on the effects of PCRS like DS and HH on the cell lung metastasis of mouse melanoma. C57 mice were selected and hypodermically injected melanoma cells into the foot pad of the posterior limb, which led to spontaneous metastasis model; while injected in vena caudalis can lead to experimental metastasis model. The observation was made on the Pulmonary nodus and the lung weight, and the findings show that as to the spontaneous metastasis model, the use of DS (the dosage used in research, the same can be said of the following) can promote the lung metastasis of tumor; While as to the experimental metastasis model, no changes happened in number of the nodus but the increased weight were detected; As to the both metastasis models, HH exerts no apparent effects on the number of nodus or the lung weight. Urokinase can enhance the metastasis in either model, while has no effect on the lung weight in the experimental model. The use of heparin sodium is able to restrain the number of nodus and lead to the lung weight loss in either model. The discovery of the varied effects of DIBCES on the two metastasis models indicates the difference in the procedure of this kind of drugs on tumor metastasis.
PartⅡAn observation was made on the effect of Chinese DIBCES on the cell multiplication of melanoma to provide the evidence of the dosage for further research. The research was made by means of MTT on the activity of DIBCES in tumor cell multiplication. Tumor proliferation is the prerequisite of metastasis. Growing to a certain size, the tumor cells may form blood vessels for lack of blood or oxygen and alter the molecule feature of the tumor cells surface simultaneously to promote the metastasis of tumor cells accordingly. The findings suggest that urokinase and heparin sodium have slight effect on the proliferation of melanoma cells, while DS and HH have certain depressant effect on tumor cells.
PartⅢThe extracellular domain of E-cadherin interacts in a homophilic manner with E-cadherin molecules on the surface of neighboring cells. Loss or reduction of E-cadherin expression correlates with enhanced aggressiveness and dedifferentiation in most carcinomas. Recent studies highlight the role of other members of the cadherin family in tumor cell invasion and metastasis. An observation was made on the effect of Chinese DIBCES on the adherence ability between tumor cells and matrix. Tumor metastasis begins with adherence, which includes homogenous adherence (the adherence between tumor cells) and heterogonous adherence (the adherence between tumor cells and matrix. The decrease of homogenous adherence will promote metastasis, while the decline of heterogonous adherence will restrain metastasis. The homogenous adherence mainly involves the E-cadherin on the surface of tumor cells, while the heterogonous adherence mainly involves integrin and immunoglobulin. The adherence between Sepharose blocking cells and culture board was adopted to study the adherence between the tumor cells, and Matrigel was taken as the ligand of tumor matrix to study the adherence between tumor cells and matrix. Meanwhile, the RT-PCR approach was employed to study the impact of drugs on the E-cadherin expression of tumor cells The findings suggest that HH can restrain the adherence between tumor cells and heparin sodium and urokinase exerts no effect on the humongous adherence and E-cadherin expression. DS poses no impact on the adherence between tumor cells while has enhancement property on E-cadherin expression. There is a certain connection between the adherence between tumor cells and matrix and the time when the drugs are added. The imultaneous addition of drugs and cells will exert a stronger depressant effect, while the drugs will pose a minor effect when the tumor cells and matrix have adhered. DS and HH have strong depressant effect on the adherence between tumor cells and matrix, that is, they have the power to restrain tumor metastasis.
PartⅣCollective cell movement represents an effcient dissemination strategy in epithelial and mesenchymal cancers. Single cell motility suggests an effcient cellular and molecular plasticity in tumor cell migration strategies. The transition from proteolytic mesenchymal toward nonproteolytic 'amoeboid' movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis. An observation was made on the effect of DIBCES on the locomotory capacity of tumor cells, which is another important factor affecting tumor metastasis. Extracorporeal kinesis experiment demonstrates that the movement of tumor cells has direct correlation with the capacity of metastasis. There are two kinds of movement patterns for tumor cells: stationary motility and translocative motility. Gold colloid, which can form microaggregate, can be spread on glass slide to observe the movement track of tumor cells. Scratch test, a test in which cells are implanted on glass slide in high density, aequilatus scratches are made between the cells to observe the overall movement pattern of tumor cells. In collogen static exercise invasion experiment, tumor cells are implanted on collogen to observe the capacity of extruding spurious at the initial stage of tumor cells invasion within a certain period of time. The above mentioned experiments are conducted to study the movement capacity of tumor cells from different perspectives. The gold colloid phagocytosis test shows that urokinase, DS can promote the movement capacity of tumor cells and enlarge the motion area, while HH and proved with no effect. The scratch test reveals that urokinase, and DS have the power to enhance its movement towards the center, heparin sodium has depressant effect while HH with no effect. The collogen static exercise invasion experiment demonstrates that DS and urokinase enhance tumor cells protrude spurious on Collagen typeⅠ, strengthening the movement capacity of tumor cells and promoting its invasion downwards the collagen; heparin sodium can restrain the tumor cells from protruding spurious, while HH shows no effect on the spurious of tumor cells.
PartⅤAn extracorporeal approach was adopted to observe the effect of on the invasion capacity of tumor cells into matrix, which plays an important part in evaluation of tumor metastasis. In this experiment, Matrigel was applied on Membranate plank and the tumor cells were implanted in the upper chamber to observe the tumor cells permeating the matrix membrane. The findings show that urokinase and DS can promote the invasive ability of melanoma cells into the Matrigel, while heparin sodium restrains this ability and HH shows no effects.
PallⅥThe principal classes of enzymes that degrade the ECM and cell associated proteins are the matrix metalloproteinases (MMPs), a family of membrane-anchored and-secreted proteinases and tissue serine proteinases, including urokinase plasminogen activator, thrombin, and plasmin. Degradation and remodeling of the ECM, including the basement membrane, by proteolytic enzymes are essential steps in the process of cancer invasion, intra- and extravasation, and colonization at distant sites. Metalloproteases are thus important in many aspects of invasion and metastasis, ranging from cell proliferation and remodeling of the ECM to angiogenesis and cell migration. An observation was made on the effect of DIBCES on the activity of metalloprotease excreted by tumor cells. The metalloprotease excreted by tumor cells (MMP-2/MMP-9) and the activity of Membranate metalloprotease on its surface is vital for tumor cells to breakthrough the barrier of matrix. To investigate the activity of secretory MMP-2/MMP-9 with electrophoretic technique and the characteristics of the enzymolysis effect of metalloprotease on gelatinum. The findings indicates that urokinase can enhance the MMP-2 excreted by tumor cells and has no effect on the activity of MMP-9; Heparin sodium can restrain MMP-2 and MMP-9, while DS and HH pose no effect on the activity of MMP-2 and MMP-9.
PartⅦMost of these processes require a delicate balance between the functions of MMPs and tissue inhibitors of metalloproteases (TIMPs). TIMPs are a family of secreted proteins that selectively, but reversibly. During the invasive events, TIMPs are expressed primarily by the cancer cells and are thought to serve as a regulatory mechanism for fine tuning the activity of stromal MMPs, so that the cancer cells can have an active role in determining where and when they invade. An observation was made on the effect of DIBCES on metalloprotease and its suppressor expression. Metalloprotease expression has direct correlation with tumor metastasis while has inverse correlation with its suppressor (TIMP-1, TIMP-2) expression. The activity of metalloprotease can be restrained by suppressor. The technique of RT-PCR was employed to study the effect of DIBCES on their expressions and reveal the impact of drugs on tumor metastasis. The findings show that urokinase can promote the expression of MMP-2 and has no effect on the expression of MMP-9. It can also restrain the expression of TIMP-1, while has no effect on the expression ofTIMP-2; DS can enhance the expressions of MMP-9、TIMP-1、TIMP-2, while has no effect on TIMP-2. HH can restrain the expressions of MMP-9、TIMP-2 and has no effect on MMP-2、TIMP-1; Heparin can restrain the expression of MMP-2 and enhance the expressions of TIMP-1、TIMP-2, while has no effect on MMP-9. The comparison between the total expressions of MMP-2 and MMP-9 and that of TIMP-1 and TIMP-2 shows that urokinase, DS express more MMP than TIMP, while heparin decreases the expression ratio of MMP and TIMP, and HH poses no effect on the ratio.
PartⅧDiscussion and conclusion
引文
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