肝细胞癌源自肝细胞而不是从祖/胆道隔室

StephenW

    The Journal of Clinical Investigation
   

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment
Xueru Mu1,2, Regina Español-Suñer3, Ingmar Mederacke1, Silvia Affò1, Rita Manco3, Christine Sempoux4, Frédéric P. Lemaigre5, Arlind Adili6, Detian Yuan6, Achim Weber7, Kristian Unger8, Mathias Heikenwälder6, Isabelle A. Leclercq3, and Robert F. Schwabe1

1Department of Medicine, Columbia University, New York, New York, USA.

2Institute of Oncology, Provincial Hospital Affiliated with Shandong University, Shandong University, Jinan, China.

3Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.

4Department of Pathology, St. Luc University Hospital and Université catholique de Louvain, Brussels, Belgium.

5Liver and Pancreas Development Unit, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.

6Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.

7Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.

8Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Address correspondence to: Robert F. Schwabe, 1150 St. Nicholas Ave., Russ Berrie Pavilion, Room 412C, New York, New York 10032, USA. Phone: 212.851.5462; E-mail: [email protected]. Or to: Isabelle Leclercq, Avenue Mounier 53, B1.52.01, tour Vesale +2, 1200 Brussels, Belgium. Phone: 32.2764.5273; E-mail: [email protected].

Authorship note: Xueru Mu and Regina Español-Suñer contributed equally to this work.



    Abstract

    In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19–, A6- and α-fetoprotein–positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.

StephenW

临床研究杂志
   

肝细胞癌源自肝细胞而不是从祖/胆道隔室
Xueru Mu1,2，里贾纳西班牙语-Suñer3，英格玛Mederacke1，西尔维娅Affò1，丽塔Manco3，恭Sempoux4，弗雷德里克体育Lemaigre5，Arlind Adili6，德天Yuan6阿齐姆·Weber7，克里斯蒂安Unger8，马蒂亚斯Heikenwälder6，伊莎贝尔A. Leclercq3，和罗伯特˚F 。Schwabe1

医学教研室，哥伦比亚大学，纽约州，纽约州，美国。

2中国科学院肿瘤，附属省立与山东大学，山东大学，济南，中国医院。

3Laboratory肝，胃肠科，研究所德RECHERCHEExpérimentale等倩碧，鲁汶天主教大学，布鲁塞尔，比利时。

4Department病理学，圣吕克大学附属医院和鲁汶天主教大学，布鲁塞尔，比利时。

5Liver和胰腺发展股，德迪夫学院，鲁汶天主教大学，布鲁塞尔，比利时。

6Institute病毒学，慕尼黑工业大学/亥姆霍兹慕尼黑中心，德国慕尼黑。

7Institute外科病理学，苏黎世大学医院，瑞士苏黎世。

8Research单位辐射细胞遗传学的，亥姆霍兹慕尼黑中心，德国研究环境健康中心，德国Neuherberg。

通讯地址：罗伯特·施瓦布1150圣尼古拉斯大道，拉斯BERRIE馆，室412C，纽约州，纽约州10032，USA。电话：212.851.5462;电子邮箱：[email protected]。或邮寄至：伊莎贝尔·勒克莱尔，大道穆尼耶53，B1.52.01，旅游Vesale +2，1200布鲁塞尔，比利时。电话：32.2764.5273;电子邮箱：[email protected]。

作者注：Xueru亩，里贾纳西班牙语 - 苏涅尔同等贡献这项工作。



    抽象的

    在许多器官，包括肠和皮肤，癌症从干细胞或祖隔室的细胞起源。尽管它的命名，肝细胞癌（HCC）的细胞来源仍然遥遥无期。在对比大多数器官，肝脏缺乏定义的干细胞群的器官维护。以往的研究表明，胆道隔间内肝细胞和兼性祖细胞能够产生肝癌。作为肝癌与祖签名进行预后更差，了解肝癌的起源的临床意义。在这里，我们用互补的命运追踪的方法来标记祖/胆汁舱和肝细胞在小鼠肝癌。在遗传毒性和遗传模型，肝癌出现完全由肝细胞，但从来没有从祖/胆汁舱。细胞角蛋白19-，在肿瘤内A6-，α胎蛋白阳性细胞的肝细胞衍生的。总之，肝细胞代表起源于小鼠细胞为肝癌，和祖签名不反映祖起源，但是肝细胞衍生的肿瘤细胞的去分

StephenW

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, with approximately 700,000 new cases diagnosed every year (1, 2). HCC typically develops in patients with chronic liver disease. Among these, viral hepatitis, nonalcoholic fatty liver disease, and alcoholic liver disease are the leading causes of HCC (2). Chronic liver injury, triggering permanent hepatocellular damage, hepatocyte regeneration, and inflammation, is thought to be the unifying principle that promotes carcinogenesis in these pathophysiologically distinct diseases. In the developing liver, bipotent hepatoblasts differentiate into hepatocytes and cholangiocytes and function as a main cellular source for both lineages (3). However, in the adult liver, cell turnover is minimal, and bipotent progenitors are typically absent (3). In contrast to many organs that have a hierarchical organization depending on well-defined stem cell populations, such as intestine and skin (4–6), the fully differentiated hepatocyte is endowed with an almost infinite capacity to regenerate (7). Accordingly, regeneration following most types of injury or after partial hepatectomy is achieved from the hepatocyte pool without major contribution of progenitor cells (3, 8). However, when liver injury is chronic and when the ability of mature hepatocytes to proliferate is blocked, a reserve cell compartment located within the biliary compartment — often termed oval cells or liver progenitor cells (LPCs) — expands in patients and in experimental injury models and may contribute to the formation of hepatocytes (3, 7, 9–13). However, several recent fate-tracing studies have challenged a major role for the LPC/biliary compartment in the formation of hepatocytes, showing either no or only very little contribution to the hepatocyte pool (8, 14–18). On the other hand, the LPC/biliary compartment is capable of generating functional hepatocytes in zebrafish (19), indicating that its contribution may be model-, disease-, or species-specific. Moreover, recent studies have suggested that hepatic stellate cells (HSCs) may function as multipotent progenitor cells that generate functional hepatocytes and cholangiocytes (20). Thus, 3 potential cellular sources — hepatocytes, the LPC/biliary compartment and HSCs — may, in theory, function as progenitor cells and the cellular source for newly generated hepatocytes.

In view of the key roles of stem and progenitor cells in the maintenance of many tissues, it is not surprising that these are also the cells of origin in cancer of the intestine (21, 22), skin (23, 24), and hematopoietic system (25). In contrast, the cellular origin of HCC remains elusive, with the above-discussed contributors to homeostasis and regeneration of the adult liver, namely hepatocytes, the LPC/biliary compartment, and HSCs, representing potential sources. Of note, the expansion of LPCs has consistently been noted after treatment with hepatic carcinogens (26, 27), which has led to the suggestion that HCC may be derived from the LPC/biliary compartment (26, 28, 29). Moreover, the expression of progenitor markers and accumulation of LPCs are commonly observed in rodent models as well as in human HCC (30, 31). Therefore, the reemergence of LPCs in the chronically injured liver may link regeneration to hepatocarcinogenesis. As HCC with a progenitor signature is clinically more aggressive, it has been suggested that the progenitor origin of HCC determines tumor biology and negatively affects outcome (31). Importantly, both LPCs and hepatocytes have the capacity to generate tumors in vivo when transduced with H-RAS and SV40LT (32). However, the relative contribution of these 2 cell types to cancer formation in the context of chronic hepatocellular injury in vivo remains unknown. The high degree of plasticity in the liver is further highlighted by recent studies showing that cholangiocarcinoma can be derived not only from cholangiocytes (33) but also from hepatocytes (34, 35). Given these findings in cholangiocarcinoma, it is conceivable that there are also multiple cellular sources for HCC. Using complementary strategies to label the LPC/biliary compartment, hepatocytes, and HSCs, we demonstrate that hepatocytes, but neither the LPC/biliary compartment nor HSCs, function as a cellular source for HCC. Moreover, LPCs found in HCC were derived from hepatocytes, suggesting that hepatocyte-derived HCC may dedifferentiate into an LPC-like immature phenotype.

StephenW

肝细胞癌（HCC）是癌症死亡率的全球第三大原因，大约有70万确诊，每年新发病例（1,2）。肝癌通常发展慢性肝病。在这些中，病毒性肝炎，非酒精性脂肪肝疾病，酒精性肝病是HCC的主导原因（2）。慢性肝损伤，引发永久肝细胞损伤，肝细胞的再生，和发炎，被认为是统一原则促进致癌在这些病理生理学不同的疾病。在发育肝，肝细胞双潜能分化成肝细胞和胆管和功能作为两个谱系（3）的主细胞来源。然而，在成人肝脏，细胞更新是最小的，并且双潜能祖细胞通常不存在（3）。在对比的是具有分级组织根据明确定义的干细胞群，例如肠和皮肤（4-6），完全分化的肝细胞被赋予了几乎无限再生能力（7）许多器官。因此，再生以下大多数类型的损伤或肝部分切除后从肝细胞池来实现而不祖细胞的主要贡献（3,8）。然而，当肝损伤是慢性和当成熟肝细胞的增殖的能力被阻止，位于所述胆室中的储备细胞室 - 通常被称为卵圆细胞或肝祖细胞（LPCS） - 扩展的患者和在实验性损伤模型和可能有助于肝细胞（3，7，9-13）的形成。然而，最近的几个命运追踪研究已经质疑用于LPC /胆道隔室中的肝细胞的形成了主要作用，示出或者没有或只对肝细胞池（8，14-18）非常少的贡献。另一方面中，LPC /胆道隔室是能够产生在斑马鱼（19）功能性肝细胞，这表明它的贡献可能是建模，无病，或种类特异性的。此外，最近的研究表明，肝星状细胞（HSC）可以用作产生功能肝细胞和胆管（20）多潜能祖细胞。因此，3潜在的蜂窝源 - 肝细胞中，LPC /胆道隔室和造血干细胞 - 可在理论上，功能作为祖细胞和为新生成的肝细胞的细胞来源。

鉴于干细胞和祖细胞中的许多组织的维持的关键角色，这并不奇怪，这些也都是起源的细胞在肠（21，22），皮肤（23，24），和造血癌症系统（25）。与此相反，肝癌的细胞来源仍然难以捉摸，与以上讨论的贡献者稳态和成人肝脏，即肝细胞中，LPC /胆道隔室的再生，以及造血干细胞，代表的潜在来源。值得注意的是，LPCS的扩张一直被指出肝致癌物（26，27），这导致了建议，HCC可以从LPC /胆室（26，28，29）衍生处理后。此外，祖标记和LPCS的积累表达的啮齿类动物模型，以及在人HCC（30，31）通常观察到。因此，LPCS在慢性损伤肝脏的再度出现可能链接再生肝癌。作为肝癌与祖签名是临床上更积极，已经提出，HCC的祖起源确定肿瘤生物学和负面影响预后（31）。重要的是，既LPCS和肝细胞具有当用H-RAS和SV40LT（32）转导产生的肿瘤在体内的能力。然而，这些2细胞类型的癌症的形成在慢性肝细胞损伤的体内的上下文相对贡献仍然不明。在肝脏中高程度的塑性是由最近的研究显示，胆管癌进一步强调可从胆管（33），但也从肝细胞（34，35）不仅而得。在胆管癌根据这些发现，可以想到，也有多个蜂窝来源的肝癌。使用互补战略，以标记LPC /胆汁舱，肝细胞和造血干细胞，我们表明，肝细胞，但无论是LPC /胆汁舱，也没有造血干细胞，功能为肝癌细胞的来源。此外，在HCC发现LPCS来源于肝细胞，这表明肝细胞衍生的肝癌可脱分化成的LPC状未成熟表型。