文章：

模拟人类皮肤组织中的癌症

Modelling cancer in human skin tissue

原文发布日期：2006-03-01

DOI: 10.1038/nrc1838

类型: Review Article

开放获取: 否

要点：

1. Malignant conversion of human tissue can be achieved rapidly in a three-dimensionally faithful human tissue context that contains primary human cells, epithelial basement-membrane zone and extracellular matrix by using high-efficiency gene transfer and regeneration of human skin on immune-deficient mice.
2. Human skin tissue can be converted directly into the three most common human skin cancers by introducing as few as one, two or three specific, defined genetic elements that are implicated in the development of these tumours.
3. Malignant conversion to basal cell carcinoma can be achieved with only one genetic alteration in human skin — overexpression of active sonic hedgehog (SHH).
4. Lethal squamous-cell carcinoma can be induced in regenerated human skin through the expression of oncogenic HRAS and only one other genetic element that facilitates escape from G1 cell-cycle arrest, including cyclin-dependent kinase 4 (CDK4) or the nuclear factor-κB inhibitor, IκBα.
5. Induction of human melanocytic neoplasia that is indistinguishable from locally invasive malignant melanoma results from expression of oncogenic NRAS and the catalytic subunit of human telomerase reverse transcriptase (TERT) in combination with either CDK4 or dominant-negative p53.
6. Human-tissue cancer models indicate that genomic catastrophe and memory-based inflammatory immune responses are not required for epithelial carcinogenesis. These models also indicate that traditional in vitro measures of neoplastic transformation, such as immortalization and anchorage-independent growth on soft agar, might not be reliable surrogate measures of human tissue tumorigenicity in vivo.
7. The oncogenic potency of specific cancer-associated mutants such as BRAF^V600E, the mutant that is most commonly found in malignant melanoma, can be directly tested in human tissue.
8. Human-tissue cancer models might facilitate the validation of therapeutic interventions against human protein targets in a native human tissue environment. An example of this is the identification of type VII collagen blockade as a strategy to inhibit neoplastic invasion across the cutaneous basement-membrane zone.

要点翻译：

1. 在包含原代人类细胞、上皮基底膜区和细胞外基质的立体逼真的人类组织环境中，通过高效基因转移和在免疫缺陷小鼠上再生人类皮肤，可快速实现人类组织的恶性转化。
2. 通过引入少至一、二或三种与这些肿瘤发展相关的特定遗传元件，人类皮肤组织可直接转化为三种最常见的人类皮肤癌。
3. 仅需对人类皮肤进行一种遗传改变——过度表达活性音猬因子（SHH），即可实现向基底细胞癌的恶性转化。
4. 通过表达致癌HRAS及仅另一种促进G1期细胞周期阻滞逃逸的遗传元件（包括细胞周期蛋白依赖性激酶4（CDK4）或核因子κB抑制剂IκBα），可在再生人类皮肤中诱导致死性鳞状细胞癌。
5. 通过联合表达致癌NRAS、人端粒酶逆转录酶催化亚基（TERT）以及CDK4或显性失活p53，可诱导产生与局部浸润性恶性黑色素瘤无法区分的人类黑色素细胞肿瘤。
6. 人类组织癌症模型表明：上皮致癌作用不需要基因组 catastrophe 和基于记忆的炎症免疫反应。这些模型还提示，传统的体外肿瘤转化检测指标（如永生化能力和软琼脂锚定非依赖性生长）可能无法可靠替代人类组织体内致瘤性评估。
7. 可直接在人类组织中测试特定癌症相关突变体（如恶性黑色素瘤中最常见的BRAFV600E突变）的致癌效力。
8. 人类组织癌症模型或有助于在天然人类组织环境中验证针对人类蛋白靶点的治疗干预措施。例如已发现阻断VII型胶原是抑制肿瘤侵袭穿越皮肤基底膜区的有效策略。

英文摘要：

The capacity to induce neoplasia in human tissue in the laboratory has recently provided a new platform for cancer research. Malignant conversion can be achieved in vivo by expressing genes of interest in human tissue that has been regenerated on immune-deficient mice. Induction of cancer in regenerated human skin recapitulates the three-dimensional architecture, tissue polarity, basement membrane structure, extracellular matrix, oncogene signalling and therapeutic target proteins found in intact human skin in vivo. Human-tissue cancer models therefore provide an opportunity to elucidate fundamental cancer mechanisms, to assess the oncogenic potency of mutations associated with specific human cancers and to develop new cancer therapies.

摘要翻译： 

在实验室中诱导人体组织发生肿瘤的能力，近期为癌症研究提供了新的平台。通过将目标基因表达于免疫缺陷小鼠体内再生的人体组织中，可在体内实现恶性转化。在再生的人体皮肤中诱导癌症，能够重现完整人体皮肤在体内的三维结构、组织极性、基底膜结构、细胞外基质、癌基因信号传导及治疗靶点蛋白。因此，人体组织癌症模型为阐明癌症基本机制、评估与特定人类癌症相关突变的致癌潜力以及开发新型癌症疗法提供了契机。

原文链接：

Modelling cancer in human skin tissue