文章：

在癌症中靶向LOX家族的基本原理

The rationale for targeting the LOX family in cancer

原文发布日期：2012-07-19

DOI: 10.1038/nrc3319

类型: Review Article

开放获取: 否

要点：

1. The lysyl oxidase (LOX) family of proteins are secreted amine oxidases, the primary function of which is the covalent crosslinking of collagens and elastin in the extracellular matrix. The function of these enzymes is required for the structural integrity of many tissues.
2. Inappropriate expression of these enzymes has been observed in a number of human diseases (many involving a fibrotic response), in particular cancer. Increased fibrotic foci have been associated with the progression of several cancers. Increased expression of LOX and LOX-like 2 (LOXL2) has been linked to regions of desmoplasia observed in aggressive cancers. Most importantly, increased expression of LOX and LOXL2 significantly correlates with decreased survival in a number of clinical cancer studies.
3. Conflicting results have been reported for the LOX family functioning as both tumour suppressors and metastasis promoters, possibly as a result of their multiple temporal and spatial expression patterns, which may confer differential functions. However, strong evidence suggests that the extracellular activity of these proteins in remodelling the extracellular matrix facilitates tumour cell invasion and metastasis.
4. Preclinical studies involving the targeting of LOX or LOXL2 by small irreversible competitive inhibitors, as well as specific function-blocking antibodies to prevent metastasis, have been efficacious. So far, no detrimental side effects or tumour progression (owing to the proposed tumour suppressive roles of these proteins) have been noted with the use of specific antibody inhibitors.
5. Targeting the LOX family is an exciting prospect in the development of new drugs to prevent the progression and metastasis of cancer.

要点翻译：

1. 赖氨酰氧化酶（LOX）蛋白家族是一类分泌型胺氧化酶，其主要功能是在细胞外基质中实现胶原蛋白和弹性蛋白的共价交联。这些酶对维持多种组织的结构完整性至关重要。
2. 研究发现，这些酶的表达异常与多种人类疾病（尤其涉及纤维化反应的疾病）相关，特别是在癌症中。纤维化灶的增加与多种癌症的进展密切相关。LOX及LOXL2表达上调与侵袭性癌症中观察到的促结缔组织增生区域存在关联。最重要的是，多项临床癌症研究表明，LOX和LOXL2表达升高与患者生存率显著降低相关。
3. 现有研究对LOX家族的作用存在争议：既有报道称其具有肿瘤抑制功能，也有证据表明其促进肿瘤转移。这种矛盾可能源于该家族蛋白在时空表达上的多样性，从而导致功能差异。但强有力证据表明，这些蛋白通过重塑细胞外基质的胞外活性，促进肿瘤细胞侵袭和转移。
4. 临床前研究通过小分子不可逆竞争性抑制剂靶向LOX/LOXL2，或使用特异性功能阻断抗体来预防转移，均已取得显著成效。目前使用特异性抗体抑制剂尚未发现因该蛋白家族潜在抑癌作用导致的毒副作用或肿瘤进展。
5. 靶向LOX家族为开发新型抗癌药物、阻止癌症进展和转移提供了令人期待的研究方向。

英文摘要：

The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.

摘要翻译： 

针对胞外蛋白的治疗性靶向正变得极具吸引力，证据表明肿瘤微环境在肿瘤启动和进展的各个方面均起关键作用。赖氨酰氧化酶（LOX）蛋白家族由肿瘤分泌，目前大量研究致力于阐明其在癌症中的作用。在本综述中，我们讨论该家族成员在肿瘤微环境重塑中的作用，以及其在肿瘤发生和转移中的矛盾角色。我们还探讨靶向该蛋白家族如何可能为癌症治疗开辟新途径。

原文链接：

The rationale for targeting the LOX family in cancer