“了解肿瘤，关注肿瘤干细胞”-No. 2010-6-（5）之肿瘤微环境
[i=s] 本帖最后由 饶冠华 于 2010-6-14 11:05 编辑 [/i]“了解肿瘤，关注肿瘤干细胞”-No. 2010-6-（5）之肿瘤微环境
讨论话题：“[color=Red]肿瘤微环境对肿瘤的作用到底有多大呢？肿瘤微环境、肿瘤基质、肿瘤基质细胞又分别包括什么成分？”[/color]
活动规则：希望大家踊跃发言，另外回答问题如果附上相关的[color=Magenta]参考文献信息[/color]将给予更多的[color=Magenta]包包奖励[/color]。
活动时间：2010/06/14~2010/06/30
[color=Blue]另外一个小通知：由于最近较忙，因此本活动改成每月一次。谢谢大家的关注。[/color]
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引言：再谈肿瘤干细胞与肿瘤微环境之间的关系之前，我们先来看二则小故事吧。
[color=SeaGreen]记得以前读过一个狼孩的故事。一九二零年，在印度加尔各答西面的丛林中，人们发现两个狼哺育的女孩，大的年约七、八岁，小的约两岁。两人回到人类世界后，都在孤儿院里养育，分别取名为卡玛拉与阿玛拉。她们的言语、动作姿势、情绪反应等方面都能看出很明显的狼的生活痕迹。她们不会说话，发音独特，不是人的声音。不会用手，也不会直立行走，只能依靠两手、两脚或两手、两膝爬行。她们惧怕人，白天一动也不动，一到夜间，到处乱窜，象狼那样嚎叫，人的行为和习惯几乎没有，而具有不完全的狼的习性。
阿玛拉在回到人间的第十一个月就死去了。卡玛拉在两年后才会发两个单词的音，四年后掌握了六个单词，直到十六、七岁死时才学会四十多个单词、而且没有真正学会说话，智力只相当于三四岁的孩子。而且她的动作姿势的变化也很缓慢。
在荆州市蓝星城有一个浙江老板，他一个人在荆州打拼了十几年，随着事业的不断扩展，三年前举家迁到荆州，他有一个6岁的儿子和一个8岁的女儿，一对儿女来荆州不到三年时间，现在说得一口流利的沙市话了，而他们的老爸至今还是说着一口夹带一点沙市口音的浙江普通话。[/color]
想必狼孩的故事大家小时候就听过吧，那么从这两个故事中，我们能得到什么样的启发呢？卡玛拉和蓝星城浙江老板的故事告诉我们，语言关键期对于儿童掌握语言是多么重要。
再转回到我们要谈的话题，看看肿瘤发生发展与肿瘤微环境的关系，是不是也有相类似的地方？
记得有文献报道过如果把肿瘤细胞放在胚胎干细胞的微环境中，会发现这些原本具有肿瘤转移能力的细胞开始丧失或者降低肿瘤形成和转移的能力，并伴随着肿瘤细胞凋亡【1】，也还有文章报道说将肿瘤细胞转到胚胎微环境下之后，可以将肿瘤细胞逆转为正常形态的细胞【2】。也还有文献报道用斑马鱼胚胎提取的蛋白可以诱导结肠癌细胞发生凋亡【3】。
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[color=Red]因此从上面的信息我可以推测一下以下几个关于肿瘤发生的观点：
1. 肿瘤起始细胞的来源绝大部分都是起源于正常组织中那些具有可塑性的细胞，包括：干细胞以及祖细胞。而来源于高端分化的细胞的可能性极其低下。
2. 在肿瘤发生的初始阶段，外界环境的恶化或者改变是具有不可替代的作用。
3. 关于囊胚微环境逆转肿瘤表型的问题，如果是低分化的肿瘤细胞（也就是具有可塑性的肿瘤细胞），则有可能逆转为正常表型，并且可导致成瘤能力的降低。而对于高度分化的肿瘤细胞，则通向的是消亡之路，也就是说更多的会发生凋亡。
4. 对肿瘤微环境的研究要远比一头扎在基因组堆里以及信号通路中要来的重要，而且对于临床治疗会更加实用。
5. 针对当前肿瘤治疗手段的一点看法：目前肿瘤一般采取的治疗手段都是手术切除，然后进行放疗和化疗。个人认为这种方法完全是拆东墙补西墙，并且由此得益的患者并不是很多（指放疗和化疗）。放疗和化疗不应该以损害患者免疫抵抗力作为代价，因为这样使体内微环境变得更加恶劣，看上去是消灭了肿瘤细胞，但事实上反而帮助了肿瘤细胞存活和转移。因此，个人认为以后的肿瘤治疗之路应该是：手术之后，然后大力提高患者机体免疫能力与健康程度，用少许药物进行辅助治疗。[/color]
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欢迎对以上信息发表自己的观点和看法，也欢迎大家拍砖讨论。
参考文献：
【1】 Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4329-34. Epub 2008 Mar 11.
Human embryonic stem cell microenvironment suppresses the tumorigenic phenotype of aggressive cancer cells.
Postovit LM, Margaryan NV, Seftor EA, Kirschmann DA, Lipavsky A, Wheaton WW, Abbott DE, Seftor RE, Hendrix MJ.
Program in Cancer Biology and Epigenomics, Children's Memorial Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614, USA.
Abstract
Embryonic stem cells sustain a microenvironment that facilitates a balance of self-renewal and differentiation. Aggressive cancer cells, expressing a multipotent, embryonic cell-like phenotype, engage in a dynamic reciprocity with a microenvironment that promotes plasticity and tumorigenicity. However, the cancer-associated milieu lacks the appropriate regulatory mechanisms to maintain a normal cellular phenotype. Previous work from our laboratory reported that aggressive melanoma and breast carcinoma express the embryonic morphogen Nodal, which is essential for human embryonic stem cell (hESC) pluripotency. Based on the aberrant expression of this embryonic plasticity gene by tumor cells, this current study tested whether these cells could respond to regulatory cues controlling the Nodal signaling pathway, which might be sequestered within the microenvironment of hESCs, resulting in the suppression of the tumorigenic phenotype. Specifically, we discovered that metastatic tumor cells do not express the inhibitor to Nodal, Lefty, allowing them to overexpress this embryonic morphogen in an unregulated manner. However, exposure of the tumor cells to a hESC microenvironment (containing Lefty) leads to a dramatic down-regulation in their Nodal expression concomitant with a reduction in clonogenicity and tumorigenesis accompanied by an increase in apoptosis. Furthermore, this ability to suppress the tumorigenic phenotype is directly associated with the secretion of Lefty, exclusive to hESCs, because it is not detected in other stem cell types, normal cell types, or trophoblasts. The tumor-suppressive effects of the hESC microenvironment, by neutralizing the expression of Nodal in aggressive tumor cells, provide previously unexplored therapeutic modalities for cancer treatment.
【2】。Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3752-7. Epub 2006 Feb 27.
Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment.
Kulesa PM, Kasemeier-Kulesa JC, Teddy JM, Margaryan NV, Seftor EA, Seftor RE, Hendrix MJ.
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. [email]pmk@stowers-institute.org[/email]
Abstract
Human metastatic melanoma cells express a dedifferentiated, plastic phenotype, which may serve as a selective advantage, because melanoma cells invade various microenvironments. Over the last three decades, there has been an increased focus on the role of the tumor microenvironment in cancer progression, with the goal of reversing the metastatic phenotype. Here, using an embryonic chick model, we explore the possibility of reverting the metastatic melanoma phenotype to its cell type of origin, the neural-crest-derived melanocyte. GFP-labeled adult human metastatic melanoma cells were transplanted in ovo adjacent to host chick premigratory neural crest cells and analyzed 48 and 96 h after egg reincubation. Interestingly, the transplanted melanoma cells do not form tumors. Instead, we find that transplanted melanoma cells invade surrounding chick tissues in a programmed manner, distributing along host neural-crest-cell migratory pathways. The invading melanoma cells display neural-crest-cell-like morphologies and populate host peripheral structures, including the branchial arches, dorsal root and sympathetic ganglia. Analysis of a melanocyte-specific phenotype marker (MART-1) and a neuronal marker (Tuj1) revealed a subpopulation of melanoma cells that invade the chick periphery and express MART-1 and Tuj1. Our results demonstrate the ability of adult human metastatic melanoma cells to respond to chick embryonic environmental cues, a subset of which may undergo a reprogramming of their metastatic phenotype. This model has the potential to provide insights into the regulation of tumor cell plasticity by an embryonic milieu, which may hold significant therapeutic promise.
【3】Zebrafish embryo proteins induce apoptosis in human colon cancer cells (Caco2)
Alessandra Cucina1, Pier-Mario Biava2, Fabrizio D’Anselmi1, Pierpaolo Coluccia1, Filippo Conti3, Roberta di Clemente3, Alfredo Miccheli3, Luigi Frati4, Alberto Gulino4 and Mariano Bizzarri4
(1) Department of Surgery “Pietro Valdoni”, Università La Sapienza, Roma
(2) Foundation for Research into the Biological Therapy of Cancer, Milano
(3) Department of Chemistry, Università La Sapienza, Roma
(4) Department of Experimental Medicine and Pathology, Università La Sapienza, via Scarpa 14-16, 00161 Roma
Published online: 27 June 2006
Abstract Previous studies have shown that proteins extracted from Zebrafish embryo share some cytostatic characteristics in cancer cells. Our study was conducted to ascertain the biological properties of this protein network. Cancer cell growth and apoptosis were studied in Caco2 cells treated with embryonic extracts. Cell proliferation was significantly inhibited in a dose-dependent manner. Cell-cycle analysis in treated cells revealed a marked accumulation in the G2/M phase preceding induction of apoptosis. Embryo proteins induced a significant reduction in FLIP levels, and increased caspase-3 and caspase-8 activity as well as the apoptotic rate. Increased phosphorylated pRb values were obtained in treated Caco2 cells: the modified balance in pRb phosphorylation was associated with an increase in E2F1 values and c-Myc over-expression. Our data support previous reports of an apoptotic enhancing effect displayed by embryo extracts, mainly through the pRb/E2F1 apoptotic pathway, which thus suggests that Zebrafish embryo proteins have complex anti-cancer properties.
Keywords Apoptosis - Zebrafish embryo proteins - Caco2 - E2F1 - c-FLIPS 好想法~赞！ excellence.
要治实体瘤，如果肿瘤微环境这一关过不了，其它的都是空谈。
只要恶性质的肿瘤微环境没有排除，那个肿瘤启始细胞就可事实上产生，临床表象就是复发，性质基本一样的恶性肿瘤。 Good Seeds in Bad Soil. 肿瘤研究要从多方面着手，对于分子通路，也有很大的临床价值，如分子标记提早发现病症，用于诊断，及预防 [i=s] 本帖最后由 wangxie 于 2010-6-22 17:22 编辑 [/i]
很好的角度 [i=s] 本帖最后由 wangxie 于 2010-6-22 17:21 编辑 [/i]
“微环境与肿瘤细胞”似乎也是一个“先有鸡还是先有蛋”的问题。但无论孰先孰后，都可以成为对肿瘤进行研究的切入点。总之，基因不会代表一切，更不能决定一切。 个人觉得环境的影响因素还是蛮大的，现在相比过去我们接触到了更多的物质，而其中有些就是致癌物，当人体接触这些物质的时候会引发相应的反应从而改变体内的微环境，这就有可能导致肿瘤的发生，这也可能是现在肿瘤的发病率比以前高的原因，不过也不排除由于以前检测技术落后及平均寿命较短造成的统计上的差别 最近看了点表观遗传学的，觉得环境因素影响还是大一点吧，大家都知道很多癌症跟基因的低甲基化和抑癌基因的高甲基化有关，还有基因组印迹、组蛋白的修饰，而母本在怀孕期间如果过多服用甲基化物会导致子代甲基化提高，而他的基因序列是没有改变的 种子与土壤的关系由来已久，贫瘠的土壤与富饶的土壤生长出来的庄家就是不一样。在肿瘤的研究中，微环境确实起到不可估量的作用，细胞周围的基质，产生的物质，细胞的类型，他们之间的关系确实非同寻常，可是，从怎样的一个角度研究更容易着手，需要思考。
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