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肿瘤微环境（tumor microenvironment ）

热度 3已有 7412 次阅读 2011-5-10 16:37

Nature杂志：肿瘤的第七种特征

发表时间：2009-07-24 发表者：江涛 (访问人次：2483)

      以往认为肿瘤有六个特征：不死性，迁移性，失去接触抑制，生长信号的自给自足，对程序性细胞死亡的逃逸，增长血管的能力。最新研究表明，肿瘤还具备第七种特征：肿瘤相关性炎症。北京天坛医院神经外科江涛
    恶性肿瘤以其转移能力为特征，那就是侵犯解剖意义上的远处正常组织，于该处接种并且生长。在这个复杂并且高度选择性的过程中，肿瘤细胞离开他们原始的生长部位，通过如血型途径和淋巴管途径等不同的途径进行播散。不是所有的肿瘤细胞都可以转移，因为成功的转移依靠肿瘤细胞内在的特征及源自肿瘤微环境的一些因素。例如，微环境提供肿瘤内部或周围血管与淋巴管，包括免疫细胞和它们分泌产物的炎性环境，以及以细胞外基质形式存在的可提供进一步生长的支架。关于这方面，Kim等学者意外发现了联系肿瘤微环境的验证与转移的分子通路。
    炎症与肿瘤的关联在得到了很好的阐述。包括炎性肠病等数种炎性疾病会增加肿瘤的风险。相反的，在流行病学意义上与明显的炎症无关的肿瘤（如乳腺癌），肿瘤基因的活化会导致炎症分子的产生及炎症细胞的聚集。在肿瘤微环境中，炎症细胞和分子几乎影响到肿瘤进展的每一方面，包括肿瘤细胞的转移能力。
    2000年，Hanahan和 Weinberg5提出了肿瘤具备的六个特征的模型。他们是不受限制的复制能力，增长血管的能力（血管发生），对程序性细胞死亡的逃逸，生长信号的自给自足，对生长抑制剂的不敏感，组织侵犯和转移。Kim与其同事的发现2，加上3，4的研究，表明这个模型应该进行修订，加上肿瘤相关性炎症作为其另一个特征。
    一组细胞因子蛋白，包括IL-1, IL-6, TNF 和RANKL，激活炎症并且被认为能够通过作用于细胞播散与在继发部位种植相关的几个步骤从而增加肿瘤细胞转移能力。炎症因子下游的关键转录因子NF-kappaB被这些因子活化并且促进炎症3。在肿瘤微环境中的主要的炎症因子的来源是被成为巨噬细胞的专化的白细胞。肿瘤相关的巨噬细胞不仅通过产生细胞因子，而且通过分泌生长因子和基质讲解酶来辅助肿瘤细胞的恶性行为。
    Kim等探索联系肿瘤分子，巨噬细胞和转移关系的分子通路。通过净化肿瘤细胞（路易士肺癌细胞株）生长的基质成分，他们分离出诱使巨噬细胞产生细胞因子的一个因素。他们鉴定了这个肿瘤衍生的巨噬细胞活化因子为多功能蛋白聚糖，一种人类肿瘤中经常上调表达的细胞外基质的组成蛋白。作者们发现多功能蛋白聚糖能够被TLR2 和 TLR6识别，属于微生物衍生的分子和组织破坏的细胞感受器家族的两种受体蛋白。他们继续用RNA干扰技术使多功能糖蛋白沉默，而且用TNF和TLR缺失的小鼠。在所获证据的基础上，作者提出，路易士肺癌的模型，肿瘤衍生的多功能蛋白聚糖通过TLR2/TLR6作用于巨噬细胞，从而产生加强转移的炎症因子。
    Kim及其同事的观察情调了细胞外基质在肿瘤相关性炎症中的重要性。基质像一个细胞因子和生长因子的贮存场所，特别是血管内皮生长因子，它由炎症性白细胞产生的酶动员并且促进肿瘤进展过程中的血管形成。另外，由人乳头状病毒病毒导致的肿瘤的进展过程中，被称为B细胞的免疫细胞通过产生聚集于细胞外基质的抗体悄悄地汇集炎症。甚者，称为SPARC的巨噬细胞衍生的细胞外基质蛋白易化肿瘤的运动和转移。因此看来，细胞外基质成分不仅起到支架的作用，或是在肿瘤侵袭过程中的酶解底物，而是一种肿瘤相关性炎症的核心成分。
    目前的研究提供了联系炎症和肿瘤进展过程中获得转移能力的分子通路的出乎意料的前景。在模型中评价多功能蛋白聚糖和其它细胞外基质蛋白的重要性来反应人类肿瘤的多样性是必须的，通过这个工作可能会翻开肿瘤治疗策略的新的一页。

肿瘤微环境

与癌变相关的一些列遗传事件及非遗传都需要通过微环境来实现：组织缺氧、酸中毒、间质高压形成，大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征，这种特性对于肿瘤的增殖、侵袭、迁移、黏附能力及新生血管的形成具有重要影响。包括生长因子，细胞因子，荷尔蒙和蛋白酶等可溶分子；像细胞外基质成分和指导细胞-细胞间相互作用等的不可溶因素。

微环境调节对肿瘤的抑制作用相关报道：

Science:癌细胞中的“来吃我”信号 http://www.stemcell8.cn/thread-32899-1-1.html

Genes & Dev. ：PML分子可限制癌细胞增殖的次数 http://www.stemcell8.cn/thread-33299-1-1.html

抑制癌变干细胞胞而保护造血干细胞的药物 http://www.stemcell8.cn/thread-1572-1-1.html

BJC：可诱导正常细胞抑制癌细胞生长 http://www.stemcell8.cn/thread-13688-1-1.html

治癌新思路——“以癌治癌” http://www.stemcell8.cn/thread-34147-1-1.html

【PubMed综述】抑制性肿瘤微环境：肿瘤免疫治疗的挑战 http://www.stemcell8.cn/thread-39556-1-1.html

干细胞、肿瘤干细胞与高压氧微环境 http://www.stemcell8.cn/thread-33899-1-1.html

微环境与肿瘤干细胞 http://www.stemcell8.cn/thread-27152-1-1.html

关于肿瘤微环境和迁移的一篇review http://www.stemcell8.cn/thread-18784-1-1.html

分析了基质金属蛋白酶对肿瘤微环境的调节作用 http://www.stemcell8.cn/thread-19828-1-1.html

“了解肿瘤，关注肿瘤干细胞”-No. 2010-6-（5）之肿瘤微环境 http://www.stemcell8.cn/thread-22698-1-1.html

结肠癌干细胞与微环境调控 http://www.stemcell8.cn/thread-23893-1-1.html

Nature：癌细胞的微环境 http://www.stemcell8.cn/thread-19588-1-1.html

低氧是干细胞微环境的关键组成部分 http://www.stemcell8.cn/thread-25341-1-1.html

高压氧微环境对干细胞增殖分化的影响 http://www.stemcell8.cn/thread-22897-1-1.html

肿瘤微环境（tumor microenvironment）：肿瘤局部浸润的免疫细胞、间质细胞及所分泌的活性介质等与肿瘤细胞共同构成的局部内环境。肿瘤的发生和转移与肿瘤细胞所处的内外环境有着密切关系。它不仅包括肿瘤所在组织的结构、功能和代谢，而且亦与肿瘤细胞自身的(核和胞质)内在环境有关。肿瘤细胞可以通过自分泌和旁分泌，改变和维持自身生存和发展的条件，促进肿瘤的生长和发展。全身和局部组织亦可通过代谢、分泌、免疫、结构和功能的改变，限制和影响肿瘤的发生和发展。肿瘤与环境，两者既是相互依存，相互促进，又是相互拮抗，相互斗争的。它是现代肿瘤生物学的一个关键和核心的问题。近年来由于肿瘤细胞学和分子生物学的进展，人们对于肿瘤和环境的相互关系有了更加深入的了解。这不仅对于认识肿瘤的发生、发展、转移等有着重要的意义，而且对于肿瘤的诊断、防治和预后亦有着重要的作用。

http://old.biovip.com/content/20060516/44875.htm

没有任何一种肿瘤是孤岛，在肿瘤周边细胞群体中存在的化学或者物理外力，即肿瘤微环境，对于肿瘤的生长与转移有非常大的影响。利用这种所谓的“生态学”因素作为癌症治疗的靶位点实际上已经比科学家们所意识到的应用得更广泛了。现在对肿瘤治疗的新观念就是通过瞄准肿瘤微环境来治疗肿瘤，该治疗方法的基础是肿瘤可能依赖肿瘤细胞本身外部的许多局部因素。这些细胞，与癌细胞不一样，总体来说遗传较稳定,因此具有很少的抵抗治疗可能。

传统观点认为，体细胞遭遇突变后会比邻近的细胞增殖更快，导致了癌症的发生。这使得癌细胞易受裂解细胞的靶标介质如：放射性疗法，细胞毒性化学疗法（cytotoxic chemotherapies）和最近的靶标治疗法攻击。不过这种关于癌症的观点总体上过度简单化了。肿瘤细胞与其余的身体部分紧密共生，并且能指导几种正常的生理过程为加速它们的生长与转移服务。因此应当认识到癌症扩散不仅仅是一种肿瘤细胞自我发生的结果，这种认识将暗示着肿瘤环境中的额外成分可能为肿瘤治疗提供有用的靶标。

发育生物学家长期以来认识到器官形成是通过指引器官的不同组织之间精致，动态的相互作用而成，如上皮组织与基质的相互作用。这些复杂的“对话”由以下成分进行：包括生长因子，细胞因子，荷尔蒙和蛋白酶等可溶分子；像细胞外基质成分和指导细胞-细胞间相互作用等的不可溶因素。正常细胞与癌细胞，尤其是后者，都存在于一个复杂的细胞生态系统中，如存在于基质细胞、内皮细胞、淋巴细胞、巨噬细胞、肥大细胞，和其它一些细胞类型中。所有这些可以通过并列分泌（juxtacrine）和邻分泌（paracrine）机制相互作用。目前，肿瘤的发生学说认为肿瘤是由肿瘤上皮细胞与其它类型细胞相互作用而来，这种说法变得更为普遍。

和所有的固体组织一样，肿瘤细胞需要血液脉管系统提供养其，营养和处理代谢废物的手段，以便使其生长超过1-2 mm3。因此肿瘤细胞指引血管新生（angiogenesis）的正常生理过程达到聚集内皮细胞和血液提供的目的。它们甚至伪装成内皮细胞进行该过程。

自从病理学者在对肿瘤进行最早期的检查时，在大部分的固体肿瘤的微环境中，他们观察到了像巨噬细胞等的免疫系统细胞。这些长期以来一直被认为是人体对肿瘤进行免疫反应的正宗据。最近，科学家认识到这些免疫细胞的渗透经常是一种不良预后（poor prognosis）的指示，尤其是在乳癌、前列腺癌、卵巢癌和宫颈癌中。这些表面上看起来是“好心的”免疫细胞实际上是通过趋药性信号分子（chemotactic signaling molecules）召集到肿瘤灶的。巨噬细胞富含生长因子，细胞因子和蛋白酶，而这些因素被认为具有促进肿瘤转移的作用。

肿瘤细胞中的结缔组织基质的性质与正常的宿主组织具有根本性的的不同，宿主器官相对来说更柔软和柔韧，而肿瘤更纤维化。这种硬度则经常是个体开始注意到肿瘤的原因。最近的研究表明这些组织机械性能的改变即是恶性肿瘤发生的原因。由肿瘤微环境内的纤维原细胞导致的结缔组织生成性反应基质（desmoplastic reactive stroma）的产物是对肿瘤进行反应的一种信号。

The Tumor Microenvironment

Contents

Definition of the Tumor Microenvironment

http://www.stemcell8.cn/home-spacecp-ac-blog.html

The tumor microenvironment is a complex system of many cells, which all participate in tumor progression, "including endothelial cells and their precursors, pericytes, smooth-muscle cells, fibroblasts of various phenotypes, myofibroblasts, neutrophils and other granulocytes (eosinophils and basophils), mast cells, T, B and natural killer lymphocytes, and antigen-presenting cells such as macrophages and dendritic cells." [1] The cells, vessels, and molecules that surround a tumor influence the tumor cells, and the microenvironment can be changed by the tumor. [2]

Carcinoma in situ (CIS)

High grade dysplasia (carcinoma in situ)
in the uterine cervix [3]

During the early growth of tumors, cancer cells form a lesion in a microenvironment of a particular tissue, often the epithelium. The lesion is separated from the surrounding tissue and within the basement membrane. This is the carinoma in situ, and the stroma of the CIS, called 'reactive stroma', is similar to stroma seen during wound healing. [4]

Significance of the Tumor Microenvironment

Carcinogenesis and tumour angiogenesis result not only from the interaction of cancer cells with endothelial cells. The microenvironment may be a primary factor determining whether epithelial cells grow continuously and invade or, at the opposite extreme, are eliminated. [1] Tumors can circumvent inhibitory signals during their progression and even exploit the surrounding cells to grow, invade, and metastasize. [5]

The order of events during inflammation and repair become disorganized during carcinogenesis. Tumors can be viewed as 'wounds that do not heal', and granulocytes, macrophages, endothelial cells, and fibroblasts - cells involved with acute inflammation - react in a way to promote the survival and replication of cancer cells. [1] Recent data indicates that stromal and inflammatory cells are involved in directing formation of blood vessels to a tumor. [1]

Components of the Microenvironment

The components of the microenvironment can be grouped into four categories [6]:

Cancer cells
Non-cancer cells
Secreted soluble factors
Non-cellular solid material, including the extra-cellular matrix

The Role of Surrounding Cells in Cancer Development Fibroblasts Definition

NIH/3T3 Fibroblasts in cell culture [7]

Fibroblasts are the principal cellular component of connective tissue. They are non-vascular, non-epithelial, and non-inflammatory cells embedded in the fibrillar matrix of connective tissue, which fibroblasts produce.

Typical Role of CellsFibroblasts help in the healing of wounds by invading lesions, generating extra cellular matrix and facilitating contractions of healing wounds. [4]

Role in Cancer DevelopmentData indicates that fibroblasts are involved in defining the rate and extent of cancer progression. [4] Reactive stroma provides oncogenic signals facilitating tumorigenesis, and there are increased numbers of fibroblasts in reactive stroma. The overall effect, though, of altered ECM secreted and organized by fibroblasts is not understood well.

Tumor Angiogenesis

Vascular endothelial growth factor helps through the extravasation of fibrin to attract fibroblasts to the site of tumors, and the attracted cells, including fibroblasts, inflammatory cells, and endothelial cells, produce ECM rich in fibronectin and type I collagen, which is conducive to initiating tumor angiogenesis. [4]

Metastasis

Fibroblasts are a source of ECM-degrading proteases, including MMPs, which may allow cancer cells to cross boundaries of tissue and escape, MMPs also affect the motility and invasiveness of cancer cells.

Studies also indicate that activated fibroblasts at the site of metastases promote the proliferation of cancer cells. [4]

A blood smear showing a neutrophil
granulocyte; the three-lobulated nucleus
can be seen. [8]

Neutrophils DefinitionNeutrophils are a type of white blood cells - the most abundant type - forming a part of the immune system

Neutrophils are able to both promote tumor elimination or increase the growth of tumor cells.

Cascade of FactorsThe neutrophil-dependent release of vascular endothelial growth factor A is associated with an angiogenic factor made in tumors. Endothelial cell invasion and vessel formation ultimately result from a cascade of events. Chemokines that act on the CXCR2 receptor recruit neutrophils and then vascular endothelial growth factor and matrix metalloproteinase 9. [1]

A macrophage of a mouse stretching its "arms"
(Pseudopodia) to engulf two particles,
possibly pathogens [9]

Macrophages DefinitionMacrophages are white blood cells that phagocytose (engulf and digest) debris of cells and pathogens. They stimulate lymphocytes and immune cells to act against the pathogen. [9]

Change of PhenotypeThe phenotype of tumor-associated macrophages (M2) may be very different from normal macrophages (M1). There may be additional types of macrophages based on the microenvironment. [1]

Influence on Tumor CellsM2 macrophages may influence tumor cells directly and promote aggressiveness. They may help to free prostrate cancer cells from androgen dependence, which is a step in the progression of malignancy.

Histological section through testicular parenchyma
of a boar. 1 Lumen of Tubulus seminiferus contortus,
2 spermatids, 3 spermatocytes, 4 spermatogonia,
5 Sertoli cell, 6 Myofibroblasts, 7 Leydig cells, 8 capillaries [10]

Myofibroblast DefinitionA myofibroblast is a type of cell that is between a fibroblast and a smooth muscle cell in differentiation. These cells serve different roles in various organs, produce several growth factors, cytokines, chemokines, and ECM components, and express many receptors. They are a source and target of soluble mediators. [1]

Role in Tumor DevelopmentMyofibroblasts may increase tumour growth and expansion once invasion of tissue is initiated, and they are activated when tissue integrity is compromised.

Adipocytes
DefinitionAdipocytes are the type of cells that primarily constitute adipose tissue, which secretes several specific cytokines (the adipokines leptin, adiponectin, resistin and visfatin), and a specialty of adipocytes is storing energy as fat.

Role in Cancer DevelopmentAdipose tissue secretes metalloproteinases, which influence inflammation and angiogenesis.

Communication between a Tumor and its SurroundingsHomeostasis in healthy tissue is achieved by a balance of cell proliferation and death maintained by intercellular communication. [5] Communication between a tumor and the surroundings includes pro- and anti-tumor interactions.

Transforming Growth Factor β (TGF-β)
Influence of TGF-βTransforming growth factor β is a molecule that is a regulator of tumor progression. Secreted by cells within the tumor microenvironment, TGF-β powerfully inhibits cell growth, yet mutations in advanced carcinomas enable the cells to grow even in the presence of TGF-β. Rather than being inhibited by this molecule, tumors can utilize it to reduce the growth of neighboring normal cells. [6]

Conditions within the Tumor Microenvironment Massive Cell DeathCell death within the tumor microenvironment results in release of proteins and additional molecules.
HypoxiaHypoxia refers to low oxygen levels, and it results in generation of oxygen free radicals, leading to DNA damage, which is less efficient in a hypoxic environment. Damage of DNA increases the mutation rate, causing greater variation in the tumor population. Also, cells most fit to survive do in the harsh environment and continue to grow.

Low pHThere are acidic conditions within the tumor microenvironment.

Low Glucose Levels Abnormal Properties of Surrounding CellsThe normal cells that surround the tumor may develop mutations and is often disorganized. Two sources of the abnormalities could be (1) hypoxia and low pH of the tumor microenvironment that could induce mutations and (2) the soluble products, such as growth factors and cytokines, that are released from the tumor, which may affect gene expression of stromal cells. [6]

References

Nature Reviews Cancer 7, (February 2007)
"Dictionary of Cancer Terms" National Cancer Institute http://www.cancer.gov/templates/db_alpha.aspx?CdrID=561725 (Accessed March 17, 2009)
"Carcinoma in situ" Wikipedia http://en.wikipedia.org/wiki/Carcinoma_in_situ (Accessed March 16, 2009)
Nature Reviews Cancer 6, 392-401 (May 2006)
Nature Reviews Cancer, advance online publication, Published online 12 March 2008 | doi:10.1038/nrc2618
"Cancer Quest" Emory University http://www.cancerquest.org/index.cfm?page=4763 (Accessed March 17, 2009)
"Fibroblasts" Wikipedia http://en.wikipedia.org/wiki/Fibroblasts (Accessed March 16, 2009)
"Neutrophil Granulocyte" Wikipedia http://en.wikipedia.org/wiki/Neutrophil_granulocyte (Accessed March 17, 2009)
"Macrophage" Wikipedia http://en.wikipedia.org/wiki/Macrophage (Accessed March 17, 2009)
"Myofibroblast" WIkipedia http://en.wikipedia.org/wiki/Myofibroblast (Accessed March 17, 2009)

恶性肿瘤细胞质异型性表现

回目录

　　细胞质的多少，形态及特征性分化反映了肿瘤细胞的分化程度和恶性程度。

　　1.高分化恶性肿瘤：胞质丰富骨有特征性分化，例如鳞状细胞癌，癌细胞胞质丰富可出现圆形，梭形、纤维形和蝌蚪形癌细胞。其特征分化表现为鳞癌细胞胸质骨角化物，呈深红染色;腺癌细胞胞质内有分泌空泡，横纹肌肉瘤瘤细胞质内出现横纹等。

　　2.低分化恶性肿瘤：肿瘤细胞分化愈差，其胞质愈少，电镜下细胞器内质网。线粒体、高尔复合体、中心体愈少。

　　3.恶性肿瘤细胞胞质：呈嗜酸碱性染色即红中带蓝，全深染色这是由于癌细胞繁殖迅速，合成自身蛋白质较多，致甩质呈深红色;又由于合成蛋白质时核蛋白体增多，故胞质为嗜碱性略呈蓝色。

　　4.肿瘤细胞胞质内有时可见吞噬的异物，如红细胞、细胞碎片等。有时见癌细胞胞质内含有另一胩癌细胞，称封入细胞。
It's amazing. This guy is a brain surgeon. The complete misunderstanding of the implications of neoplastic transformation is pretty scary.

Just so people do understand what cancer says about evolution involves the tight regulation of selfishness of cells for the benefit of the organism as a whole. Cancer is the unfortunate result of transformation of a healthy cooperative cell into one that has lost the ability to cooperate with the host. Redundant mechanisms exist within a cell to prevent this behavior - apoptosis genes, DNA repair mechanisms, genes that force the cell to stop dividing in the presence of severe DNA damage etc. When these mechanisms are damaged, or overridden by the oncogenic transformation, the cell starts dividing and proliferating out of control, consuming energy, invading tissues, and trying to grow and survive all at the cost of the host. All of this makes sense from an evolutionary perspective. Multi-cellular organisms evolved so that cells within the organism would cooperate and work together for the common benefit of the organism as a whole. Cancer is almost like a cellular atavism - regression to the pre-multicellular state in which individual cells act selfishly for their own survival.

So, for Egnor's latest argument, I'd say this is a straw man. There is no reason that evolution that benefits a single cell over others would result in intelligence for the organism as a whole. It only ranks as a 2/5 on the denialism index (false expert, logical fallacy) it's a silly argument, and it doesn't deserve much attention. But damn if it ain't a funny one.