The origin of cancer stem cells
Authors: Hien T. Dang, Anuradha Budhu, Xin W. Wang
Journal: Journal of Hepatology (2014)

COMMENTARY ON: Identification of Liver Cancer Progenitors Whose Malignant Progression Depends on Autocrine IL-6 Signaling. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE, Jepsen K, Frazer KA, Harismendy O, Hatziapostolou M, Iliopoulos D, Suetsugu A, Hoffman RM, Tateishi R, Koike K, Karin M. Cell. 2013 Oct 10, 155(2):384–96. doi: 10.1016/j.cell.2013.09.031. Copyright © 2013. Abstract reprinted by permission from Elsevier Inc. http://www.ncbi.nlm.nih.gov/pubmed/24120137 Abstract: Hepatocellular carcinoma (HCC) is a slowly developing malignancy postulated to evolve from premalignant lesions in chronically damaged livers. However, it was never established that premalignant lesions actually contain tumor progenitors that give rise to cancer. Here, we describe the isolation and characterization of HCC progenitor cells (HcPCs) from different mouse HCC models. Unlike fully malignant HCC, HcPCs give rise to cancer only when introduced into a liver undergoing chronic damage and compensatory proliferation. Although HcPCs exhibit a similar transcriptomic profile to bipotential hepatobiliary progenitors, the latter do not give rise to tumors. Cells resembling HcPCs reside within dysplastic lesions that appear several months before HCC nodules. Unlike early hepatocarcinogenesis, which depends on paracrine IL-6 production by inflammatory cells, due to upregulation of LIN28 expression, HcPCs had acquired autocrine IL-6 signaling that stimulates their in vivo growth and malignant progression. This may be a general mechanism that drives other IL-6-producing malignancies. Hepatocellular carcinoma (HCC) is the fifth and seventh most common cancer in men and women in the world, respectively [[1]El-Serag H.B. Hepatocellular carcinoma.N Engl J Med. 2011; 365: 1118-1127Crossref PubMed Scopus (3152) Google Scholar]. The diverse etiology of HCC includes hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcoholic disease, and obesity. These diverse factors often lead to cirrhosis, which is present in more than 80 to 90% of HCC patients [[1]El-Serag H.B. Hepatocellular carcinoma.N Engl J Med. 2011; 365: 1118-1127Crossref PubMed Scopus (3152) Google Scholar]. Moreover, these factors contribute to tumor heterogeneity and play a significant role in the development of HCC, making current systemic therapies unsatisfactory. Current studies suggest that HCC can be derived from cancer stem cells (CSCs), which can contribute to tumor heterogeneity and chemoresistance. However, the origins of CSCs are still debatable. In a study by He and colleagues, the authors provide evidence for the existence of hepatic cancer progenitor cells (HcPCs) in preneoplastic regions of foci altered hepatocytes (FAH), which have cancer stem cell-like characteristics. Interestingly, the authors demonstrate that there are multiple cell types that reside within the FAH, including CD44+ CSCs, suggesting that the FAH may serve as a niche for CSC proliferation. In liver cancer, early observations of highly proliferative preneoplastic nodules or FAH in chemical hepatocarcinogenesis rodent models suggested that HCC arose from mature hepatocytes [[2]Sell S. Cellular origin of hepatocellular carcinomas.Semin Cell Dev Biol. 2002; 13: 419-424Crossref PubMed Scopus (79) Google Scholar]. Moreover, similar lesions are frequently observed in human HCC samples [[3]Su Q. Benner A. Hofmann W.J. Otto G. Pichlmayr R. Bannasch P. Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia.Virchows Arch. 1997; 431: 391-406Crossref PubMed Scopus (81) Google Scholar]. However, current studies indicate that HCC can also arise from adult liver progenitor cells or liver CSCs [[2]Sell S. Cellular origin of hepatocellular carcinomas.Semin Cell Dev Biol. 2002; 13: 419-424Crossref PubMed Scopus (79) Google Scholar]. CSCs are neoplastic cells that possess distinct survival mechanisms and stem cell properties that are crucial for the maintenance and propagation of the tumor. Although the origins of CSCs are not well established, CSCs are hypothesized to originate from tumor progenitor cells, stem cells, or dedifferentiated cells that have acquired CSC characteristics. Notably, recent studies in mice revealed that any cell type in the hepatic lineage can undergo oncogenic reprogramming into a CSC [[4]Holczbauer A. Factor V.M. Andersen J.B. Marquardt J.U. Kleiner D.E. Raggi C. et al.Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types.Gastroenterology. 2013; 145: 221-231Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar]. The study by He and colleagues in Cell demonstrates that IL-6 signaling is required for promoting HcPCs tumorigenicity (Fig. 1). The role of preneoplastic lesions in HCC is debatable. FAH consists of highly proliferative cells compared to the parenchyma. Although these preneoplastic regions are predictive of HCC and are frequently found in cirrhotic livers, the overall histology does not indicate HCC, but rather, compensatory proliferation induced by cirrhosis [3Su Q. Benner A. Hofmann W.J. Otto G. Pichlmayr R. Bannasch P. Human hepatic preneoplasia: phenotypes and proliferation kinetics of foci and nodules of altered hepatocytes and their relationship to liver cell dysplasia.Virchows Arch. 1997; 431: 391-406Crossref PubMed Scopus (81) Google Scholar, 7Sell S. Leffert H.L. Liver cancer stem cells.J Clin Oncol. 2008; 26: 2800-2805Crossref PubMed Scopus (190) Google Scholar]. According to He and colleagues, FAH consists of aggregates of diverse HcPCs with elevated expression of various markers including CD44, EpCAM, and alpha-feto protein (AFP). Interestingly, the authors demonstrate that diethyl nitrosamine (DEN)-induced HcPCs have a similar transcriptome as HCC cells and bipotential progenitor cells. While there are similarities between progenitor cells and HcPCs, the authors further elegantly show that only HcPCs are tumorigenic in damaged livers (i.e., chronic injury and compensatory proliferation) through IL-6 autocrine signaling. Finally, He and colleagues show that IL-6 is required for the progression of HcPCs to HCC, however, the ablation of IL-6 does not completely inhibit tumor progression, suggesting that other factors such as CSF1 or TGFβ may be at play [8Budhu A. Wang X.W. Transforming the microenvironment: a trick of the metastatic cancer cell.Cancer Cell. 2012; 22: 279-280Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 9Budhu A. Forgues M. Ye Q.H. Jia H.L. He P. Zanetti K.A. et al.Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment.Cancer Cell. 2006; 10: 99-111Abstract Full Text Full Text PDF PubMed Scopus (685) Google Scholar]. This study, as with others, is pivotal in providing evidence of how the microenvironment, such as cirrhosis of the liver, affects tumorigenesis by providing a perfect niche for cellular proliferation. Currently, there is little evidence that CSCs are found within the FAH in humans, however, He’s study supports the novel model that HcPCs may be precursors of CSCs and that FAH can shelter CSCs. As discussed by He and colleagues, the heterogeneous expression of stem cell markers within the HcPC aggregates suggest that they are composed of more than one cell type including oval cells, normal hepatocytes, and differentiated progenitors cells. A subgroup of these cells may be different from CSCs in that they require the right milieu to become malignant; whereas CSCs are tumorigenic and can maintain and propagate tumors. Furthermore, FAH is also composed of multiple cell types, such as stromal and immune cells; all of which can provide a distinct microenvironment that is conducive to the regulation of stemness and proliferation of CSCs. Interestingly, only 5–7% of cirrhotic patients will develop HCC and most cirrhotic tissues contain FAHs [[1]El-Serag H.B. Hepatocellular carcinoma.N Engl J Med. 2011; 365: 1118-1127Crossref PubMed Scopus (3152) Google Scholar]. This leads to the question as to whether FAHs of cirrhotic tissues from non-HCC patients also contain HcPCs. If so, why are they not tumorigenic? Is this tumorigenicity strictly due to the elevated levels of IL-6 or other cytokines necessary to induce the stemness properties necessary for tumor growth? The answer to these questions would enhance the understanding of how the microenvironment plays a role in tumor development. Furthermore, the observation that autocrine IL-6 signaling is important for the transformation of HcPCs suggests that IL-6 can be a candidate biomarker for early HCC detection. Moreover, elevated serum IL-6 levels are found in HCC and have been associated with metastatic HCC [[5]Budhu A. Wang X.W. The role of cytokines in hepatocellular carcinoma.J Leukoc Biol. 2006; 80: 1197-1213Crossref PubMed Scopus (228) Google Scholar]. In fact, studies have suggested that IL-6 may be more sensitive in identifying HCC than AFP, the most commonly used biomarker for HCC detection [[6]Porta C. De A.M. Quaglini S. Paglino C. Tagliani F. Boncimino A. et al.Circulating interleukin-6 as a tumor marker for hepatocellular carcinoma.Ann Oncol. 2008; 19: 353-358Crossref PubMed Scopus (126) Google Scholar]. However, IL-6 plays two significant roles in the liver, (A) as a pro-inflammatory cytokine produced by Kupffer cells during acute phase response and (B) as a tumor promoter in damaged liver. Because of IL-6’s dual role, at what point does IL-6 become a tumor promoter? Understanding the underlying role of IL-6 during the progression of HCC may shed light on the appropriate stage of hepatocarcinogenesis at which IL-6 may be a prognostic HCC marker. While many questions remain, this study provides insight into the origin of HCCs and enhances our understanding of the microenvironment’s role in tumor development. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.