Moving Targets in Hepatocellular Carcinoma : Hepatic Progenitor Cells as Novel Targets for Tyrosine Kinase Inhibitors

lactoferrin as a marker of fecal leukocytes. J Clin Microbiol 1992; 30:1238 – 42. 15. Quiroga T, Garcia P, Goycoolea M, et al. Fecal lactoferrin as a marker of fecal leukocytes. J Clin Microbiol 1994;32:2629 –30. 16. Fine KD, Ogunji F, George J, et al. Utility of a rapid fecal latex agglutination test detecting the neutrophil protein, lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J Gastroenterol 1998;93:1300 –5. 17. Evans LT, Kim WR, Poterucha JJ, Kamath PS. Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites. Hepatology 2003;37:897–901. 18. Jeffries MA, Stern MA, Gunaratnam NT, Fontana RJ. Unsuspected infection is infrequent in asymptomatic outpatients with refractory ascites undergoing therapeutic paracentesis. Am J Gastroenterol 1999;94:2972– 6.


Moving Targets in Hepatocellular Carcinoma: Hepatic Progenitor Cells as Novel Targets for Tyrosine Kinase Inhibitors
See "c-kit Inhibition by Imatinib Mesylate Attenuates Progenitor Cell Expansion and Inhibits Liver Tumor Formation in Mice" by Knight B, Tirnitz-Parker J, and Olynyk J, on page 969.
H epatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, primarily because of endemic hepatitis B in Africa and Asia.It is also the most rapidly increasing cause of cancer death in the United States owing to increased numbers of patients with chronic hepatitis C, and migration from endemic areas. 1 Because the majority of HCC patients present at an advanced stage, only about 20%-30% receive potentially curative therapy such as resection or transplantation. 2,3ystemic treatments for advanced HCC have been disappointing historically.Underlying cirrhosis, found in about 80% of Western HCC patients, limits patient tolerance to many traditional anticancer agents.Furthermore, expression of P-glycoprotein pumps in HCC tumors leads to drug resistance.Most important, until recently, there has been a limited understanding of the pathogenesis underlying this disease.
Mechanisms of HCC pathogenesis are now beginning to be clarified. 4It is now known that several tumor suppressors or protooncogenes are mutated in HCC, including p53, Rb, and IGF. 4 In addition, many intracellular signaling pathways have now been shown to contribute to HCC growth.Clinically, among the most important are those related to vascular endothelial growth factor (VEGF), epidermal growth factor, and their downstream signaling cascades. 5t the 2007 American Society of Clinical Oncology meeting, sorafenib, an oral multikinase inhibitor of raf kinase, VEGFR2, VEGFR3, and platelet-derived growth factor receptor (PDGFR)-␤ kinases, was reported to lead to an improvement in overall survival by about 3 months when compared with placebo in a large, randomized trial of advanced HCC patients.These data were recently published in the New England Journal of Medicine. 6Other drugs targeting molecular pathways in HCC also show promise, including other tyrosine kinase inhibitors, such as erlotinib (a tyrosine kinase inhibitor against EGFR), 7 and more "promiscuous" kinase inhibitors such as sunitinib (which targets VEGFR, c-kit, and PDGFR). 8In addition to tyrosine kinase inhibitors, drugs targeting the ligands for some of these receptors also show activity against HCC, particularly bevacizumab, a monoclonal antibody against VEGF. 9matinib mesylate is also an inhibitor of several tyrosine kinases, including PDGFR, c-kit, and the bcr-abl fusion product.This drug has proven efficacy against diseases that involve each of these molecular targets, most notably chronic myelogenous leukemia, which involves a constitutively active tyrosine kinase caused by the bcr-abl translocation. 10Up to 25% of HCCs are reported to express c-kit, 11,12 suggesting the possible utility of studying imatinib in HCC.
In addition to direct targeting of tumor-related growth pathways, other paradigms for treating cancer have emerged using tyrosine kinase inhibitors.One of these includes targeting the tumor "stroma," including endothelial cells and fibroblasts which support cancer cell growth.For instance, Bergers et al 13 showed that, by targeting PDGFR, they could dysregulate periendothelial cells in a mouse model of islet cell cancer.This mechanism complemented direct targeting of VEGF receptors on endothelial cells by a different tyrosine kinase inhibitor. 13Similarly, in the liver, hepatic fibroblasts and endothelial cells may contribute to carcinogenesis.Animal models of HCC have revealed that targeting endothelial cell proliferation can lead to a reduction in activated cancer growth pathways. 14Thus, targeting the "soil" as well as the tumorigenic "seeds" may provide additional treatment benefits against HCC and other cancers.Now, Knight et al 15 in this issue of GASTROENTEROLOGY suggest another possible mechanism of antitumor activity using imatinib for HCC by targeting presumptive hepatic progenitor cells.Hepatic regeneration from chronic liver injury involves recruitment of progenitor cells from the adult liver's stem cell compartment.These progenitor cells, some of which are c-kit positive, may also be associated with carcinogenesis. 16This has led to the theory that HCC may arise in part from maturation arrest of these progenitor cells. 17Thus, targeting this population of cells using imatinib or other drugs may inhibit tumorigenesis.
The authors evaluated different types of liver inflammation by studying mice receiving a choline-deficient diet, and human liver tissue from subjects with chronic hepatitis B. They found up-regulation of PDGF-C and c-kit expression in the choline-deficient animal model, and c-kit-positive progenitor cells were observed adjacent to hepatocytes in all the human sections.The number of c-kit-positive cells in the human specimens also correlated with disease severity.Use of imatinib led to decreased proliferation of liver progenitor cells in culture, and reduced numbers of liver progenitor cells and liver tumors in the choline-deficient mice.
In an earlier publication, the same authors noted similar antiproliferative effects of ␣-interferon on hepatic progeni-tor cells in pretreatment and posttreatment liver biopsies in patients with hepatitis C.They found a 50% decrease in the numbers of c-kit-positive hepatic progenitor cells in humans treated with interferon.In choline-deficient mice, they found a 4-fold reduction in the number of oval progenitor cells. 16In clinical support of these data, interferon has been demonstrated to decrease the subsequent risk of HCC in cirrhotics with hepatitis C virus, and numbers of hepatic progenitor cells may be lower in those who have responded to interferon therapy. 18nfortunately, 2 phase II human trials using imatinib in advanced HCC have been disappointing, with no objective responses observed in those with established HCC. 19,20It is possible that imatinib or similar drugs may play a more active role in HCC chemoprevention by targeting liver progenitor cells that are up-regulated in the context of inflammation.Imatinib may be more effective when also used in combination with anti-VEGF treatment or other therapies.
Many other questions remain.The authors show that some liver progenitor cells are c-kit positive, and that these cells have some carcinogenic properties.However, there is no consensus about which specific markers best define hepatic progenitor cells or HCC stem cells or whether c-kit is the most promising target for therapy.The phenotype of HCC cancer stem cells is currently under active investigation.Initial studies suggested that CD133 ϩ cells might define tumorigenic progenitors in HCC, 21 but Yang et al 22,23 subsequently showed that Editorials continued CD90 ϩ and CD45 Ϫ cells may be more sensitive markers of hepatic cancer stem cells.
It is also unknown whether one cell target will ultimately be adequate to destroy the reservoir of progenitor cells, or whether complete eradication of these cells is necessary for effective prevention and/or treatment of HCC in humans.Furthermore, as Knight et al 15 point out, the adverse effects of targeted therapies in these settings is unclear.In particular, imatinib can cause fluid retention and hepatic toxicity, both of which may make it difficult to use in patients with established cirrhosis, especially in the context of chemoprevention.
Liver tumors with progenitor cell characteristics may be particularly aggressive clinically.Lee et al 24 have shown that patients with HCCs with a gene expression profile similar to hepatic progenitor cells had a worse prognosis than those without this pattern.Similar to the situation in HER-2-positive breast cancer, markers for tumor aggressiveness may ultimately yield novel prevention and/or treatment opportunities. 25Although much remains to be learned, targeting hepatic progenitor cells in HCC is a novel treatment paradigm as presented in this issue that will complement the development of therapeutics directed against tumor and stromal cells (Fig- ure).Hopefully, this will lead to improved outcomes for our patients in the future.