文章：

整合素在癌症中的生物学意义和治疗机会

Integrins in cancer: biological implications and therapeutic opportunities

原文发布日期：2010-01-01

DOI: 10.1038/nrc2748

类型: Review Article

开放获取: 否

要点：

1. Integrin signalling regulates diverse functions in tumour cells, including migration, invasion, proliferation and survival. In several tumour types, the expression of particular integrins correlates with increased disease progression and decreased patient survival.
2. In addition to tumour cells, integrins are also found on tumour-associated host cells, such as the vascular endothelium, perivascular cells, fibroblasts, bone marrow-derived cells and platelets. Integrin signalling crucially regulates the contribution of these cell types to cancer progression. Therefore, integrin antagonists may inhibit tumour progression by blocking crucial signalling events in both the tumour microenvironment and the tumour cells themselves.
3. Integrins have a profound influence on tumour cells, both in the ligated and unligated states, in which they regulate tumour cell survival and malignancy.
4. Although integrins alone are not oncogenic, recent data have found that some oncogenes may require integrin signalling for their ability to initiate tumour growth and invasion. These effects may be due to the important contribution of integrin signalling in maintaining the cancer stem cell population in a given tumour.
5. Crosstalk between integrins and growth factor or cytokine receptors on both tumour and host cell types is vital for many aspects of tumour progression. Mechanisms of crosstalk include both direct and indirect association of integrins with growth factor or cytokine receptors, which affects the expression, ligand affinity and signalling of the receptors.
6. The important contribution of integrins to the biology of both tumour cells and tumour-associated cell types has made them appealing targets for the design of specific therapeutics. Of particular interest, the integrin αv inhibitor cilengitide is now in a Phase III clinical trial in glioblastoma, and because this is the first integrin antagonist to achieve this milestone it places anti-integrin therapy on the doorstep of clinical availability.
7. In addition to their use as therapeutic targets, integrins can be imaging biomarkers for assessing the efficacy of anti-angiogenic and anti-tumour agents. Integrin-targeted nanoparticles with a diverse array of anti-tumour payloads also represent a particularly promising area of research that may decrease the toxicities associated with systemic delivery of radiation or chemotherapy.

要点翻译：

1. 整合素信号传导调控肿瘤细胞的多种功能，包括迁移、侵袭、增殖与存活。在多种肿瘤类型中，特定整合素的表达与疾病进展加速及患者生存率降低相关。
2. 除肿瘤细胞外，整合素还存在于肿瘤相关宿主细胞，如血管内皮细胞、血管周细胞、成纤维细胞、骨髓源性细胞及血小板。整合素信号传导对这些细胞类型促进癌症进展的过程起着关键调控作用。因此，整合素拮抗剂可通过同时阻断肿瘤微环境及肿瘤细胞内部的关键信号传导事件，从而抑制肿瘤进展。
3. 无论在配体结合或未结合状态下，整合素均能通过调控肿瘤细胞存活与恶性程度，对其产生深远影响。
4. 尽管整合素本身不具致癌性，但最新研究发现部分癌基因可能需要整合素信号传导才能启动肿瘤生长与侵袭。这些效应可能源于整合素信号传导对维持特定肿瘤中癌症干细胞群的重要贡献。
5. 整合素与生长因子或细胞因子受体在肿瘤细胞和宿主细胞中的交叉对话对肿瘤进展的诸多方面至关重要。这种交叉对话的机制包括整合素与生长因子或细胞因子受体的直接或间接结合，从而影响受体的表达、配体亲和力及信号传导。
6. 整合素对肿瘤细胞及肿瘤相关细胞生物学行为的重要贡献，使其成为特异性治疗药物设计的理想靶点。尤其引人关注的是，整合素αv抑制剂西仑吉肽目前已进入胶质母细胞瘤的III期临床试验。作为首个达到该里程碑的整合素拮抗剂，它标志着抗整合素疗法即将进入临床应用阶段。
7. 除作为治疗靶点外，整合素还可作为影像学生物标志物用于评估抗血管生成和抗肿瘤药物的疗效。同时，搭载多种抗肿瘤有效载荷的整合素靶向纳米颗粒也是一个极具前景的研究领域，有望降低全身性放疗或化疗相关的毒性反应。

英文摘要：

The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the αvβ3 and αvβ5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.

摘要翻译： 

整合素家族的细胞黏附受体调控着多种对实体瘤的发生、进展和转移至关重要的细胞功能。整合素在影响肿瘤进程的多种细胞类型中的重要作用，使其成为癌症治疗中一个具有吸引力的靶点。整合素拮抗剂，包括αvβ3和αvβ5抑制剂西仑吉肽，在II期临床试验中显示出了令人鼓舞的活性，目前西仑吉肽正在胶质母细胞瘤患者中进行III期试验。这些令人兴奋的临床进展强调了需要明确整合素拮抗剂如何影响肿瘤及其微环境。

原文链接：

Integrins in cancer: biological implications and therapeutic opportunities