第24届亚太地区肝脏研究协会年会（APASL 2014）于2014年3月12～15日在澳大利亚布里斯班召开。会上来自香港大学病理系的Irene O.L.Ng博士介绍了肝癌干细胞的研究现状。
Irene O.L.Ng博士
原发性肝细胞癌（HCC）是世界五大常见癌症之一。HCC的根治性治疗方法包括手术及肝移植。然而，80%以上的HCC患者病情已到晚期，无法应用上述治疗方法。即使能够实施手术切除，术后的复发率也比较高，而且HCC术后的长期预后不能令人满意。经肝动脉栓塞化疗或全身化疗是HCC患者的二线治疗手段。但由于化疗药物的毒性及肿瘤抗化疗药性强，所以整体治疗效果并不理想。
癌干细胞（CSCs）或肿瘤启动细胞（T-ICs）是肿瘤中具有类似正常干细胞特征的亚群细胞，具有自我更新和分化潜能，这些癌干细胞比肿瘤内其他较成熟的癌细胞对传统化疗更具抗药性。研究证实，T-ICs是肿瘤化疗后复发的主要原因之一。因此认识T-ICs及其相关致病通道，对于研究肝癌新型治疗模式具有重要意义。针对特异性CSCs的靶向治疗将来可能会成为根治癌症的手段之一。
研究者在免疫功能缺失的小鼠体内成功建立了异种移植的HCC小鼠模型，使T-IC具有自我更新、分化及促进肿瘤生长的能力。研究人员首先在小鼠体内植入人HCC细胞，然后使用顺铂（HCC常用化疗药物之一）进行化疗，再将对化疗呈抗药性的肿瘤细胞接种在另一只小鼠身上，小鼠出现了肿瘤复发。研究者进一步发现是CD24+细胞促进了残余肿瘤的增长。CD24+细胞对于肿瘤的自我维持、复制、分化及转移具有重要意义，并直接影响患者的临床预后。利用慢病毒敲除方法，研究者发现CD24是肝T-IC的细胞表面标志物，并通过激活STAT3信号维持肝癌干细胞自我更新和促使肿瘤形成的功能。此研究结果为研发治疗肝癌的标靶药物提供了一个重要的靶点，即CD24+肝T-IC。
而且，研究者在另一研究中发现CD47也具有促进肿瘤复制、自我更新的能力。CD47表达于肝T-IC，可导致肿瘤复发、自我更新和转移，明显影响患者的临床预后。敲除CD47基因后，干细胞的能力就被减弱。CD47+肝癌细胞分泌组织蛋白酶S（CTSS），通过CTSS / PAR2循环调控肝T-IC。体内试验证实抑制CD47表达，就能抑制肝癌生长，通过阻断CTSS / PAR2信号转导，可提高肿瘤对化疗的敏感性。这些研究结果表明，CD47及其信号通路可能成为肝癌治疗的一个重要靶点。
原文阅读》》》Liver Cancer Stem Cells
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. The curative treatment for HCC is liver transplantation or surgical resect ion. However , 80% of HCC c a s e s a r e presented at advanced stages, and are no longer operable. Even after surgical resection, the long-term prognosis of HCC remains unsatisfactory due to high recurrence rates. For HCC patients in advanced stages, chemotherapy by way of either trans-arterial or systemic chemo-embolisation is the second-line treatment. Unfortunately, the overall response rate is unsatisfactory due to the highly chemo-resistant nature of the tumour and the toxicity of chemotherapeutic agents.
Cancer stem cells (CSCs) or tumor-initiating cells (T-ICs) are a subpopulation capable of self-renewal and tumour initiation, and are more resistant to chemo-therapeutic drugs. They have be en shown to cause tumour recurrence upon chemotherapy. Identification of T-ICs and their related pathways are therefore priorities for the development of new therapeutic paradigms. In particular, therapies that specifically target CSCs are believed to be strategic in cancer treatment.
We established chemo-resistant HCC xenograft tumours in immune-compromised mice , in which an enriched T-IC population was capable of tumour initiation and self-renewal. With this model, we found CD24 to be up-regulated in residual chemo-resistant tumours, when compared with bulk tumour upon treatment with cisplatin, a chemotherapeutic drug frequently used in HCC patients. CD24+ HCC cells were found to be critical for the maintenance, self - renewal , differentiation, and metastasis of tumours, and to significantly impact patients’ clinicaloutcome . With a lentiviral -based knockdown approach, CD24 was found to be a functional liver T-IC marker that drives T-IC genesis through STAT3 -mediated NANOG regulation. Our findings point to a CD24 cascade in liver T-ICs that may provide an attractive therapeut ic target for HCC patients.
In addition, in another study, we enriched a T-IC population capable of tumour initiation and self - renewal via serial passages of hepatospheres with chemotherapeutic agents. In the chemo-resistant hepatospheres, CD47 was found to be up-regulated when compared with differentiated progenies. CD47 is preferentially expressed in liver T-ICs, which contributed to tumour initiation, self-renewal and metastasis, and significantly affected patients’ clinical outcome. Knockdown of CD47 suppressed the stem/progenitor cell characteristics. CD47+ HCC cells preferentially secreted cathepsin S (CTSS), which regulates liver T-ICs through the CTSS/PAR2 loop. Suppression of CD47 suppressed the growth of HCC in vivo and exerted a chemo-sensitisation effect through blockade of CTSS/PAR2 signaling. These data suggest that CD47 and its signaling pathway may also be an attractive therapeutic target for HCC therapy.
