**9. Liver cancer stem cell**

48 Hepatocellular Carcinoma – Basic Research

On the other hand, various microRNAs with tumor suppressing capacity are lost or underexpressed in HCC. Restoration of their expression in HCC is another effective approach against HCC. Previous studies suggested a strong association between low miR-26 expression and both prognosis and response to interferon therapy in patients with HCC (Ji et al., 2009). Low miR-26 expression is highly associated with tumor formation in vivo, and replenishing miR-26 in liver tumors with the use of gene therapy could generate potent antitumor effects. miR-26a in particular is substantially reduced in MYC-induced HCC (Ji et al., 2009). The replacement therapy of miR-26 is considered safe, because miR-26 is expressed by most normal cells and is unlikely to be toxic. Other than miR-26, miR-122 is significantly downregulated in liver cancer with intrahepatic metastasis. Restoration of miR-122 reduced cell migration, invasion and colony formation ability in vitro, and tumorigenesis, angiogenesis and metastasis in vivo (Coulouarn et al., 2009). Currently, more microRNAs with antitumor effect including miR-199a/b-3p were identified and potentially

To note, increased activity of RNA-induced silencing complex (RISC) was observed in HCC (Yoo et al., 2011). The role of RISC is critical in facilitating activity of RNAi including microRNA-mediated target silencing. The components of RISC including AEG-1 and SND1 were both overexpressed in HCC, which leads to the hyperactivity of RISC. Increased RISC activity resulted in an accelerated degradation of numerous tumor suppressor genes that are the target of various oncomiRs. Report showed that inhibition of RISC activity by knocking down SND1 abrogated cell growth in HCC cells in vitro and in vivo (Yoo et al., 2011). It not only unveils a new microRNA associated pro-tumorigenic mechanism, but also provides an additional approach to disrupt microRNA-mediated

In eukaryotes, there are abundant amount of transcripts which are long in length and lack any substantial open reading frame as well as protein coding capacity. Increasing evidences suggested that these long non-coding RNAs (lncRNA) play critical role in cellular processes such as development, via the modulation of chromatin structure. Some of them possess the ability to modulate cancer epigenome and contribute to different pathological conditions such as tumor invasion and metastasis. A better understanding in the oncogenic

Highly upregulated in liver cancer (HULC) is an lncRNA that is frequently overexpressed in HCC. siRNA knockdown of HULC in HCC cell lines was able to alter the expression of genes described in the context of HCC (Panzitt et al., 2007). Reduction of cellular HULC upregulated genes participates in diverse biological processes including cell differentiation, cell adhesion, protein phosphorylation and tumor suppression. Another study reported that HULC was also expressed in metastasized tumor nodules in liver originated from colorectal cancer, but not in primary colorectal cancer (Matouk et al., 2009). It suggested that expression of HULC might be a pre-requisite for any tumor formed in liver. The importance of HULC in HCC is further supported by the observation that HULC expression is strongly linked to HBV infection (Matouk et al., 2009). Due to the high specificity of HULC for cancer

play a pivotal role in the combat against HCC (Hou et al., 2011).

mechanisms of lncRNA will unveil a new direction in cancer therapy.

located in liver, it is worthy of studying its potential role in managing HCC.

tumorigenic effect during HCC remedy.

**8.2 Long non-coding RNA** 

Accumulating evidences support that the development of HCC is based on the cancer stem cell (CSC) model. In this hypothesis, there is only a subset of cells within a tumor or in the cell pool that sustains malignant growth. Such cellular subset is referred to as the cancerinitiating cells or cancer-propagating cells (Visvader, 2011). It provides the explanations for cancer initiation, local recurrence, metastasis and therapy resistance which raised enormous controversies in the past. CSCs have been identified in many cancer types including HCC (Mishra et al., 2009). In this regard, CSC should be the principal target of HCC therapy. However, conventional methods such as chemotherapy and radiotherapy are ineffective because of the CSC resistant properties, as well as their pro-angiogenic effect. Studies are vigorously conducted to develop effective methods to extinguish CSC in HCC.

#### **9.1 Cancer stem cell markers**

Numerous surface markers for HCC stem cells were identified, and they include CD133, CD90, CD44, CD13 and EpCAM. Although their roles in liver CSC are unclear, studies showed that targeting these markers can specifically harm CSC with high efficacy. It is reported that tumorigenicity and invasive capacity of liver CSC were impaired by targeting CSC surface marker EpCAM, leading to reduction of CSC pool (Yamashita et al., 2009). Besides, inhibition of CD44 in HCC cells could enhance apoptosis, reduce tumorigenicity and invasion. Interestingly, isoforms of CD44 are differentially expressed between HCC and normal hepatocytes. Targeting of the CD44 isoforms prevalent in HCC was able to selectively deplete HCC cells without harming normal cells (Miletti-González et al., 2005). Therefore, direct targeting of CSC-specific markers may also be a promising therapeutic strategy to eradicate liver CSC.

#### **9.2 Stemness signaling**

Cancer stem cells share various common characters with somatic and embryonic stem cells. Many signaling pathways observed exclusively in stem cells can also be detected in cancer stem cells. These signalings include Wnt/β-catenin, Hedgehog and Notch signaling (Mishra et al., 2009). Disturbing the signalings involved in normal stem cell fate reportedly decreased the self-renewal and proliferating capabilities of CSCs. For example, small molecule inhibitor of hedgehog pathway could reduce the likely CSC with progenitor

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment 51

fibroblast-like cells provide a supportive environment for stem cells through insulin-like growth factor 2 (Martínez-Iglesias et al., 2008). Targeting insulin like growth factor 2 therefore can manipulate the stem cell microenvironment. Apart from the molecular content surrounding liver CSC, there is accumulating evidence that the physical environment is a critical mediator of HCC tumor behaviour. The stiffness of matrix is a strong predictor of HCC development. Increasing stiffness was found to promote HCC cell proliferation. On the other hand, a soft environment induces reversible stem cell characteristics in HCC (Schrader et al., 2011). With understanding of critical factors influencing liver CSC, comprehensive approach will be developed to eradicate these primary targets in HCC.

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**10. References** 

marker aldehyde dehydrogenase in pancreatic cancer (Feldmann et al., 2007); Targeting Notch pathway was able to inhibit cancer stem cell self-renewal and decreases tumor growth (Cheng et al., 2004); The Wnt pathway can be inhibited by blocking the β-catenin interaction with TCF gene, and as such there was a reduction of CSC cells and spheroid formation (Lepourcelet et al., 2004). Apart from tumor promoting effects, stem cell signalings could induce resistances and recurrences to different cancer therapies in HCC. HCC cells survived through radiation, and acquired radioresistance was found to have Wnt/β-catenin signaling activated (Woodward et al., 2007). Relapse of HCC after radiation was also associated with the induction of Notch and Hedgehog signaling pathways which sustained HCC cell self-renewal and tumorigenicity (Clement et al., 2007).

Recently, the STAT3/IL-6 signaling is revealed as another pathway activated in liver CSC and plays an important role in maintaining the liver CSC. Activation of IL-6 pathway is suggested to be a consequence of TGF-β signaling defects (Tang et al., 2008). Impaired TGFβ signaling is a piece of useful information to distinguish liver CSC from normal stem cells. Hence, targeting IL-6 pathway might be a specific way to target liver CSC without affecting somatic stem cells. STAT3/IL-6 pathway inhibition by small inhibitor is also effective in HCC with lesion of TGF-β signaling, attenuating tumorigensis of HCC (He et al., 2004).

#### **9.3 Differentiation pathway**

Like other cancer types, HCC cells are highly heterogenous. It is believed that liver cancer stem cells are the initiator in establishing the heterogenous background of the tumor, whilst liver CSC themselves remains undifferentiated (Visvader, 2011). Forced differentiation of the CSC in HCC is a relevant approach to deplete the CSC in the cancer cell pool. Differentiation of cancer cells into less aggressive forms has been a successful strategy as demonstrated in the treatment of acute promyelocytic leukemia. The application of all-trans retinoic acid after normal chemotherapy resulted in a 90% remission and 70% cure rate in acute promyelocytic leukemia. Differentiation therapy can be an appealing and effective treatment against HCC (Massard et al., 2006).

It is reported that force expression of hepatocyte nuclear factor 4-α (HNF4-α) could promote the differentiation of hepatoma cells to normal hepatocytes. Most importantly, there is a reduction of stemness genes and a decrease of CD133+ /CD90+ subpopulation during the differentiation. HNF4-α is able to induce cell cycle arrest, cell senescense in HCC cells as well as the tumorigenic ability in mice (Yin et al., 2008). Systemic and intratumoral administration of HNF4-α carrying adenovirus could respectively prevent tumor metastasis and exhibit antitumor effect. Understanding the differentiation pathways in liver CSC allows identification of key differentiating factors (Yin et al., 2008). Identification of valid differentiation pathways in CSC enables scientists to explore a new avenue in countering liver CSC.

#### **9.4 Cancer stem cell niche**

Other novel ideas for stem cell targeting therapy include the disruption of the tumor niche essential for CSC homeostasis (Gokmen-Polar et al., 2008). The specified microenvironment where stem cells reside often dictates self-renewal and reproduction. Alteration of stem cell niche components can effectively change stem cell fate, as in the case of experimental parathyroid hormone induction. Furthermore, human embryonic stem cell–derived fibroblast-like cells provide a supportive environment for stem cells through insulin-like growth factor 2 (Martínez-Iglesias et al., 2008). Targeting insulin like growth factor 2 therefore can manipulate the stem cell microenvironment. Apart from the molecular content surrounding liver CSC, there is accumulating evidence that the physical environment is a critical mediator of HCC tumor behaviour. The stiffness of matrix is a strong predictor of HCC development. Increasing stiffness was found to promote HCC cell proliferation. On the other hand, a soft environment induces reversible stem cell characteristics in HCC (Schrader et al., 2011). With understanding of critical factors influencing liver CSC, comprehensive approach will be developed to eradicate these primary targets in HCC.

#### **10. References**

50 Hepatocellular Carcinoma – Basic Research

marker aldehyde dehydrogenase in pancreatic cancer (Feldmann et al., 2007); Targeting Notch pathway was able to inhibit cancer stem cell self-renewal and decreases tumor growth (Cheng et al., 2004); The Wnt pathway can be inhibited by blocking the β-catenin interaction with TCF gene, and as such there was a reduction of CSC cells and spheroid formation (Lepourcelet et al., 2004). Apart from tumor promoting effects, stem cell signalings could induce resistances and recurrences to different cancer therapies in HCC. HCC cells survived through radiation, and acquired radioresistance was found to have Wnt/β-catenin signaling activated (Woodward et al., 2007). Relapse of HCC after radiation was also associated with the induction of Notch and Hedgehog signaling pathways which

Recently, the STAT3/IL-6 signaling is revealed as another pathway activated in liver CSC and plays an important role in maintaining the liver CSC. Activation of IL-6 pathway is suggested to be a consequence of TGF-β signaling defects (Tang et al., 2008). Impaired TGFβ signaling is a piece of useful information to distinguish liver CSC from normal stem cells. Hence, targeting IL-6 pathway might be a specific way to target liver CSC without affecting somatic stem cells. STAT3/IL-6 pathway inhibition by small inhibitor is also effective in HCC with lesion of TGF-β signaling, attenuating tumorigensis of HCC (He et al., 2004).

Like other cancer types, HCC cells are highly heterogenous. It is believed that liver cancer stem cells are the initiator in establishing the heterogenous background of the tumor, whilst liver CSC themselves remains undifferentiated (Visvader, 2011). Forced differentiation of the CSC in HCC is a relevant approach to deplete the CSC in the cancer cell pool. Differentiation of cancer cells into less aggressive forms has been a successful strategy as demonstrated in the treatment of acute promyelocytic leukemia. The application of all-trans retinoic acid after normal chemotherapy resulted in a 90% remission and 70% cure rate in acute promyelocytic leukemia. Differentiation therapy can be an appealing and effective

It is reported that force expression of hepatocyte nuclear factor 4-α (HNF4-α) could promote the differentiation of hepatoma cells to normal hepatocytes. Most importantly, there is a reduction of stemness genes and a decrease of CD133+ /CD90+ subpopulation during the differentiation. HNF4-α is able to induce cell cycle arrest, cell senescense in HCC cells as well as the tumorigenic ability in mice (Yin et al., 2008). Systemic and intratumoral administration of HNF4-α carrying adenovirus could respectively prevent tumor metastasis and exhibit antitumor effect. Understanding the differentiation pathways in liver CSC allows identification of key differentiating factors (Yin et al., 2008). Identification of valid differentiation pathways

Other novel ideas for stem cell targeting therapy include the disruption of the tumor niche essential for CSC homeostasis (Gokmen-Polar et al., 2008). The specified microenvironment where stem cells reside often dictates self-renewal and reproduction. Alteration of stem cell niche components can effectively change stem cell fate, as in the case of experimental parathyroid hormone induction. Furthermore, human embryonic stem cell–derived

in CSC enables scientists to explore a new avenue in countering liver CSC.

sustained HCC cell self-renewal and tumorigenicity (Clement et al., 2007).

**9.3 Differentiation pathway** 

**9.4 Cancer stem cell niche** 

treatment against HCC (Massard et al., 2006).


Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment 53

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**3** 

*Japan* 

**Clinical Significance of Serum Ornithine** 

**Carbamoyltransferase in Liver Diseases –** 

Katsutoshi Tokushige1, Etsuko Hashimoto1\*, Noriko Matsushita1,2,

*1Tokyo Women's Medical University, Department of* 

*2Tokyo Women's Medical University, Support Center for Women Health Care Professionals and Researchers Tokyo* 

*Medicine and Gastroenterology* 

*3YAMASA Corporation, Chiba* 

**Is the Ratio of OCT/ALT a New Tumor Marker?** 

Nobuyuki Torii1, Makiko Taniai1, Keiko Shiratori1 and Hiroshi Maruyama3

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer-related mortality (World Health Organization. Mortality database, 2010). According to the most recent nationwide Japanese registration data, primary liver cancer ranks fourth for men and sixth for women as cause of death from malignant neoplasm (Journal of Health and Welfare Statistics. Health and Welfare Statistics

The leading major causes of HCC in Japan are viruses, hepatitis C accounting for 70% and hepatitis B for 16% of all cases of HCC. Recently, the incidence of HCC in cases of non-viral liver disease has gradually increased (Ikai et al., 2010). According to our hospital database, increasing numbers of HCC cases arising from non-alcoholic steatohepatitis (NASH) have been seen, with such cases accounting for 4% of all cases of HCC each year since 2000. Together with the recent increase the metabolic syndrome population in Japan, cases of NASH have increased dramatically, and it is logical that the incidence of HCC in these

Since evaluation of viable HCC is important for monitoring and deciding therapeutic strategies, the serum tumor markers alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), the protein induced by vitamin K absence, as well as imaging provide useful information. However, a recent report demonstrated that AFP is not sensitive in NASH-related HCC (Hashimoto & Tokushige, 2011). Although DCP is highly specific for HCC, its sensitivity is reported to be no more than 50% in patients with HCC measuring 3cm or less in diameter (Okuda H et al., 2000). Moreover, DCP can be affected by some

patients can be expected to increase as well (Tokushige et al., 2010).

**1. Introduction** 

Association, 2009).

 \*

Corresponding Author

