炎症：癌症的第七特征

(2009-01-03 19:51:41)

*（硕士生复试的一篇文章转到这里）

标签：杂谈

分类：医学前沿

ancer: Inflaming metancer: Inflaming metMantovani A. 2009. Cancer: Inflaming metastasis. Nature. 457(7225): 36-37. astasis. Nature. 457

Cancer: Inflaming metastasis

Alberto Mantovani1

Cancer can be defined by six hallmarks, including uncontrollable growth, immortality and the ability to invade other tissues. Increasing evidence suggests that a seventh feature should make this list — inflammation.(7225): 36-37. Canc

Malignant tumours are characterized by their ability to metastasize, that is, to invade anatomically distant normal tissues and to seed and grow there. During this complex and highly selective process, tumour cells leave their primary site and disseminate by various routes, such as the blood and lymph vessels. Not all cancer cells can metastasize1, because successful metastasis depends both on intrinsic properties of the tumour cells and on factors derived from the tumour microenvironment. For example, the microenvironment provides blood and lymphatic vessels in and around the tumour, an inflammatory milieu consisting of immune cells and their secretory products, and a scaffold in the form of the extracellular matrix for further growth. Writing in this issue, Kim et al.2 shed light on the unexpected molecular pathways that link inflammation in the tumour microenvironment to metastasis (page 102).

Mantovani A. 2009. C

The link between inflammation and cancer is well documented3, 4. Several inflammatory diseases, including inflammatory bowel disease, increase the risk of cancer. Conversely, in tumours that are epidemiologically unrelated to overt inflammatory conditions (such as breast cancer), the activation of oncogenes can orchestrate the production of inflammatory molecules and the recruitment of inflammatory cells. In the tumour microenvironment, inflammatory cells and molecules influence almost every aspect of cancer progress, including the tumour cells' ability to metastasize3. Thus, whereas there were previously six recognized hallmarks of cancer — unlimited replicative potential, self-sufficiency in growth signals, insensitivity to growth inhibitors, evasion of programmed cell death, ability to develop blood vessels, and tissue invasion and metastasis5 — cancer-related inflammation now emerges as number seven (Fig. 1).

Figure 1: The hallmarks of cancer.

Figure 1 : The hallmarks of cancer. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comancer: Inflaming met

In 2000, Hanahan and Weinberg5 proposed a model to define the six properties that a tumour acquires. These are unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, and tissue invasion and metastasis. Kim and colleagues' findings2, together with those of other studies3, 4, indicate that this model should be revised to include cancer-related inflammation as an additional hallmark. (Adapted from ref. 5.)

High resolution image and legend (54K)(7225): 36-37. Canc

A group of cytokine proteins, including IL-1, IL-6, TNF and RANKL, activate inflammation and are known to augment tumour cells' ability to metastasize by affecting several steps in the cells' dissemination and implantation at secondary sites3, 6, 7. Inflammatory cytokines lie downstream of the 'master' gene transcription factor for promoting inflammation — NF-kappaB — which is itself activated by them3. A major source of inflammatory cytokines in the tumour microenvironment are specialized white blood cells called macrophages. Tumour-associated macrophages assist the malignant behaviour of tumour cells, not just by producing cytokines, but also by secreting growth factors and matrix-degrading enzymes8, 9, 10.

astasis. Nature. 457

Kim et al.2 explored the molecular pathways linking tumour cells, macrophages and metastasis. By purifying the components of the medium in which the tumour cells (the Lewis lung carcinoma cell line) were grown, they isolated a factor that induced cytokine production by macrophages. They identified this tumour-derived macrophage activator as versican, a protein of the extracellular matrix that is frequently upregulated in human tumours. The authors found that versican is recognized by TLR2 and TLR6, two receptor proteins that belong to a family of cellular sensors of microbially derived molecules and tissue damage. They then went on to silence versican in tumour cells by an RNA interference technique, and to use mice in which TNF and TLR were absent. On the basis of the evidence obtained, the authors propose that, in the Lewis lung carcinoma model, tumour-derived versican acts on macrophages through TLR2/TLR6, leading to the production of inflammatory cytokines, which enhance metastasis.

Kim and colleagues' observations highlight the importance of the extracellular matrix in cancer-related inflammation. The matrix acts as a depot of cytokines and growth factors, in particular vascular endothelial growth factor, which is mobilized by enzymes originating from inflammatory white blood cells and which promotes blood-vessel formation during tumour progression4, 5. Moreover, during the development of cancers caused by human papillomavirus, immune cells called B cells orchestrate inflammation remotely by producing antibodies that become localized in the extracellular matrix11. What's more, a macrophage-derived extracellular-matrix protein called SPARC facilitates tumour-cell motility and metastasis12. So it seems that extracellular-matrix components are much more than a scaffold, or a substrate to be consumed during tumour-cell invasion, but instead represent a central component of cancer-related inflammation.(7225): 36-37. Canc

The present study2 offers unexpected vistas on the molecular pathways that link inflammation to acquisition of the capacity to metastasize during tumour progression. It will be essential to assess the significance of versican and other extracellular-matrix proteins in models that reflect the diversity of human cancer, for from such work innovative therapeutic strategies may follow.

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References

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1. Fidler, I. J. Nature Rev. Cancer 3, 453–458 (2003). | Article |

2. Kim, S. et al. Nature 457, 102–106 (2009). | Article |

3. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Nature 454, 436–444 (2008). | Article | PubMed | ChemPort |Mantovani A. 2009. C

4. Coussens, L. M. & Werb, Z. Nature 420, 860–867 (2002). | Article | PubMed | ISI | ChemPort |

5. Hanahan, D. & Weinberg, R. A. Cell 100, 57–70 (2000). | Article | PubMed | ISI | ChemPort |

6. Giavazzi, R. et al. Cancer Res. 50, 4771–4775 (1990). | PubMed | ISI | ChemPort |ancer: Inflaming met

7. Luo, J. L. et al. Nature 446, 690–694 (2007). | Article | PubMed | ISI | ChemPort |

8. Wyckoff, J. B. et al. Cancer Res. 67, 2649–2656 (2007). | Article | PubMed | ISI | ChemPort |

9. Mantovani, A., Schioppa, T., Porta, C., Allavena, P. & Sica, A. Cancer Metastasis Rev. 25, 315–322 (2006). | Article | PubMed | ISI |(7225): 36-37. Canc

10. Yang, L. et al. Cancer Cell 13, 23–35 (2008). | Article | PubMed | ChemPort |

11. de Visser, K. E., Korets, L. V. & Coussens, L. M. Cancer Cell 7, 411–423 (2005). | Article | PubMed | ISI | ChemPort |

12. Sangaletti, S. et al. Cancer Res. 68, 9050–9059 (2008). | Article | PubMed | ChemPort |ancer: Inflaming met

专题：Nature报道

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。

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。

肿瘤特征图

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。（生物谷Bioon.com）

生物谷推荐原始出处：

Nature 457, 36-37 (1 January 2009) | doi:10.1038/457036b

Cancer: Inflaming metastasis

Alberto Mantovani1

Cancer can be defined by six hallmarks, including uncontrollable growth, immortality and the ability to invade other tissues. Increasing evidence suggests that a seventh feature should make this list — inflammation.

1 Alberto Mantovani is at the Istituto Clinico Humanitas IRCCS, and the University of Milan, Rozzano, Milan 20089, Italy.

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