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In response to this stimulus, the normally quiescent hepatocytes leave G0 to enter the cell cycle under the influence of many growth factors. Hepatocyte proliferation begins in the periportal region of the liver and spreads to the centrilobular region. This regenerative response requires each hepatocyte to undergo only 2 rounds of replication to restore normal liver size. Hepatocytes are capable of large-scale clonal expansion within a diseased liver. Following very extensive liver damage or in situations in which hepatocyte regeneration after damage is compromised, a potential stem cell component located within the smallest branches of the intrahepatic biliary tree is activated.

Hepatic progenitor cells HPCs amplify a biliary population of transit amplifying cells that are bipotential, capable of differentiating into either hepatocytes or cholangiocytes. These cells have been observed after severe hepatocellular necrosis, chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease. It is thought that the activation of a potential stem cell compartment leads to the formation of reactive ductules, anastomosing cords of immature biliary cells with an oval nucleus and small rim of cytoplasm.

Differentiation toward the hepatocyte lineage occurs via intermediate hepatocytes, polygonal cells with a size and phenotype intermediate between progenitor cells and hepatocytes. Intermediate hepatocytes become more numerous with time and extend further into the liver lobules.

This sequence of changes suggests gradual differentiation of human progenitor cells into intermediate hepatocytes. The Hepatocyte proliferation rate increases in chronic hepatitis with increased histological appearance of cellular damages until cirrhosis is reached, at which point the proliferation rate falls [ 14 ]. This fall probably reflects replicative senescence, although the diversion of blood flow through the liver probably plays a part [ 15 ].

The reduction in hepatocyte proliferation indices in chronic hepatitis occurs concurrently with the activation of HPCs [ 16 , 17 ]. The development of an oval cell reaction in response to hepatocyte replicative senescence has been demonstrated in a transgenic mouse model of fatty liver and DNA damage [ 18 ]. In this model, mice developed fatty livers and large number of senescent hepatocytes.

A striking oval cell response related to the number of senescent mature hepatocytes. The hepatocytes generated from oval cells in severely-damaged cirrhotic livers may have a high risk for neoplastic transformation. Stem cells in the liver are proposed to be from two origins: endogenous or intrahepatic and exogenous or extrahepatic. Included in the intrahepatic stem cell compartment are the HPCs which are greater in number but with short-term proliferative capacity. HPCs are thought to be localized within the canals of Hering, interlobular bile ducts [ 19 , 20 ]. Included in the extrahepatic stem cell compartment are cells derived from bone marrow and peripheral blood cells; these cells are usually few but with long-term proliferation capacity [ 21 - 23 ].

These tumors also consist of cells that have an intermediate phenotype between progenitors and mature hepatocytes. In fact, patients who have HCCs that express hepatocyte and biliary cell markers such as albumin, CK7 and CK10 carry a significantly poorer prognosis and have a higher recurrence rate after surgical resection and liver transplantation [ 28 ]. Cells resembling HPCs have also been noted in hepatoblastoma; the most common liver tumors in children which are widely believed to be stem cell derived given there can be both epithelial and mesenchymal tissue components.

These tumors can even have structures mimicking intrahepatic bile ducts and form ductal plate-like structures [ 29 ] Fig. Normal hepatic stem cells are characterized by their ability to self-renew and differentiate, which leads to formation of a normal liver tissues. Consequently, these cells function as cancer stem cells and contribute to the formation of bulk tumors. The CSC hypothesis is based on the idea that stem cells are present also in cancer tissue and a hierarchy of cells is formed, as is the case with normal tissue.

Tumor formation, growth, and propagation are maintained by a minute proportion of cells with stem cell-like properties. SP cells in HCC cells possess high proliferation potential, tumorigenicity, and anti-apoptotic properties compared with those of non-SP cells [ 30 , 31 ]. Additionally, this surface molecule is also highly expressed in premalignant hepatic tissues, HPCs and bile duct epithelium, but not in most adult hepatocytes [ 35 - 37 ].

However, since that incidence and mortality of ICCs clarifying the origin of these tumors is important. Recent studies suggest that some ICCs could arise from liver stem cells rather than from mature cholangiocytes [ 38 ]. This concept is supported by the identification of a combined hepatocellular cholangiocarcinoma CHC , which have morphological and phenotypical intermediate features between HCC and ICC [ 39 ]. The ability of HPCs to differentiate towards the biliary and the hepatocytic lineages gave rise to the hypothesis that transformed HPCs are the source of origin of intermediate primary liver carcinomas.

Furthermore, in a few cases of human ICCs, it has been reported that some tumor cells express specific markers of liver stem cells, indicating a possible stem cell origin [ 42 , 43 ]. However, there is currently not enough data to make a statement regarding a stem cell origin of ICC and further immunohistochemical characteristics related to the expression of hepatic stem cell markers in ICCs should be elucidated.

The Wnt pathway diversifies into two main branches, i. Wnt ligands signal through binding to seven transmembrane Frizzled Fzd receptors and single transmembrane lipoprotein receptor-related protein LRP 5 or 6 co-receptors [ 50 ]. Non-canonical signaling, which is much less defined, is mediated by ligands such as Wnt11 that uses the same Fzd receptors [ 56 ].

The Wnt-Fzd complex interacts with heterotrimeric G and Dv1 proteins to activate phospholipase C, which then generates diacylglycerol and inositol-phosphatase from phosphatidyl inositol 4, 5-biphosphate and increase intracellular calcium concentration. The Wnt-Fzd-G protein complex can also stimulate p38 kinase and activate phosphodiesterase 6, which hydrolyzes cyclic GMP and results in the inactivation of protein kinase G and an increase in intracellular calcium.

Both pathways interact with each other, and in some cases, non-canonical signaling antagonizes the canonical pathway [ 57 ]. While most of the proceeding mutations have not been detected in allelotype analysis, it is salient to note that deletions in the AXIN1 locus 16p have been described in HCC. Hepatoblastoma is a malignant embryonal tumor of the liver, which differs from HCC by distinct morphological patterns reminiscent of hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes, and of their arrangement in the developing liver. Integrated molecular and genetic studies of hepatoblastoma disclosed two major molecular subclasses of tumors that relate early and late phases of prenatal liver development.

Correlation between stage of hepatic differentiation and clinical manifestation, notably vascular invasion, metastatic spread, and patient survival, was also established [ 66 ]. In addition, expression of EpCAM was observed during fetal liver development, liver regeneration, and liver repair associated with cirrhosis. A number of EpCAM-regulated target genes have been identified including c-myc and cyclins, and additional genes involved in cell growth and proliferation, cell cycle, and cell death. These findings indicated that expression of EpCAM strongly linked with proliferation of stem cells and cancer development by cancer initiating cells after aberrant EpCAM re-expression.

Smad signaling has been shown to be pivotal for embryogenic hepatocyte proliferation, as well as in the formation of gastrointestinal cancers [ 71 , 72 ]. However, Smad proteins shown to be impaired in other cancers appear to play a minor role in HCC [ 76 , 77 ]. EMT leads to enhanced migration and invasiveness [ 84 ].

The Notch signaling pathway plays an important role in stem cell self-renewal and differentiation [ 87 - 90 ]. However, other signaling pathways influence whether Notch functions as a tumor suppressor or oncogene in a particular tissue [ 91 ].

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Notch signaling plays a well-defined role in liver embryogenesis and bile duct formation. In addition, Notch family members are involved in angiogenesis and endothelial sprouting [ 95 - 97 ]. The activated intracellular form of Notch3, as well as the notch ligand Jagged, is highly expressed in HCC [ 98 - ]. Notch-dependent transformation is associated with extracellular signal-regulated kinase activation downstream of the Ras pathway, which increases Notch mRNA stability and is required for transcription of the Notch target gene, Hes-1 [ , ]. Recent evidence indicates that activation of Notch1 signaling increases the expression level of death receptor 5 DR5 with enhancement of TRAIL-induced apoptosis in vitro and in vivo [ , ].

Inhibitors of the NOTCH pathway are currently under investigation in clinical trials for treating solid tumors although the effectiveness of NOTCH pathway inhibitors in treating liver cancer remains unclear. Conserved from Drosophilia to humans, the Hedgehog HH pathway has a central role in embryonic development and adult tissue homeostasis by controlling cell fate specification and pattern formation [ 49 , ].

In the absence of ligand, Ptc antagonizes the pathway by preventing the activity of another transmembrane protein Smoothened Smo [ , ]. Binding of HH ligands to Ptc relieves this inhibition and activates target gene transcription factors Gli-1, Gli-2, Gli-3 [ , ]. The different Gli proteins exhibit activating or repressing transcriptional activators depending on proteolytic processing of the full-length proteins.

Gli-1 and Gli-2 mainly act as transcriptional activators, while Gli-3 generates a repressor form Gli3R in the absence or inhibition of HH signaling [ , , ]. Although functional significance of Gli-3 has been demonstrated by genetic inactivation [ ] , the molecular mechanisms that control Gli-3 interactions and targets are largely undefined, whereas the dynamic interplay between Gli-1 and Gli-2 signaling is well documented. Sonic is the predominant isoform in the liver. Furthermore, tumorigenic activation of Smo can mediate overexpression of c-myc, a gene known to play an important pathogenic role in liver carcinogenesis [ ].

Moreover, recent studies also showed that activation of Hedgehog signaling is critically related to CSCs and EMT features in many types of cancers including colon, gastric, esophagus, hepatic, and other cancers. BMI1 is a part of the polycomb group genes PcG that are highly conserved throughout evolution.

BMI acts as an epigenetic chromatin modifier and is known for its contribution to embryonic and stem cell self-renewal programs [ ]. It is frequently overexpressed in different cancer types and disruption of BMI1 signaling has been linked to the activation of the hedgehog pathway in some cancers, such as medulloblastoma [ , ].

Furthermore, BMI1 upregulation is associated with malignant transformation and acquisition of the malignant phenotype in HCC [ ]. Aberrant BMI1 expression is reported in many CSC populations and it has been shown to have a critical role in maintaining and propagating the SP population in liver cancer. In addition to these signaling pathways, signal transducer and activator of transcription 3 STAT3 , mainly activated by IL-6 and its related cytokine, and IL has been shown to play key roles in acute phase response, a protection against liver injury, the promotion of liver regeneration [ ].

Furthermore, hyperactive STAT3 signaling results in expansion of oval cell numbers and trigger wound healing, cell migration, and proliferation [ , ]. This signaling pathway may take part an important role of maintenance of CSCs. Breakage of the signaling network for normal stem cells leads to the transformation to CSC. Alternatively, acquisition of self-renewal potential in progenitor cells due to epigenetic change or genetic alteration of stem cell signaling related genes gives rise to CSC.

MiRNAs play critical roles in many biological processes including cancer by directly interacting with specific messenger RNAs mRNAs through base pairing and then inhibiting expression of the target genes through a variety of molecular mechanisms. MiRNAs can undergo aberrant regulation during carcinogenesis, and they can act as oncogenes or tumor suppressor genes. Disruption of miRNA expression levels in tumor cells may result from distorted epigenetic regulation of miRNA expression, abnormalities in miRNA processing genes and proteins, and the location of miRNAs at cancer-associated genomic regions.

In liver carcinogenesis, miRs have been found to have both tumor suppressive miR, miR, miR and oncogenic miRb, miR, miR activity [ - ]. Clearly, miRNAs play a critical role in carcinogenesis and oncogenesis. Emerging evidence suggests that certain abnormal miRNA expression induces CSC dysregulation, resulting in unlimited self-renewal and cancer progression. Lin28 was first characterized in the nematode Caenorhabditis elegans as an important regulator of developmental timing [ , ].

Overexpression of these stem cell factors has been reported to promote oncogenesis by driving self-renewal and proliferation [ ]. Moreover, poorly differentiated, aggressive human tumors have recently been shown to have an embryonic stem cell-like gene expression signature; these stem cell factors have also been reported to have roles in tumor progression. The mammalian homologs of lin, Lin28 and Lin28b, bind to the terminal loop of the precursors of let-7 family miRNAs and block their processing into mature miRNAs [ , ].

Moreover, LIN28B-expression was associated with a significantly increased incidence of early recurrence. The initiation of hepatocarcinogenesis is linked to chronic inflammation clinically and epidemiologically.

Cancer stem cells, the ultimate targets in cancer therapy | OTT

Mir was first characterized in the patients with acute myeloid leukemia as a predictor of prognosis. Moreover, miR family members were highly expressed in embryogenic livers and isolated hepatic stem cells. Forced expression of miR induces stemness of HCC cells while inhibiting miR results in cell differentiation and inhibition of tumorigenicity. The successful eradication of cancer requires anticancer therapy that affects the differentiated cancer cells and the potential CSC population [ , ].

At present, conventional anticancer therapies include chemotherapy, radiation and immunotherapy kill rapidly growing differentiated tumor cells, thus reducing tumor mass but potentially leave behind cancer-initiating cells. Therapies that exclusively address the pool of differentiated cancer cells but fail to eradicate the CSC compartment might ultimately result in relapse and the proliferation of therapy-resistant and more aggressive tumor cells.

An ideal drug regime would kill differentiated cancer cells and, at the same time, specifically, selectively and quickly target and kill CSCs to avoid toxic side effects for other cell types and to disrupt the self-protection potential of CSCs. Moreover, CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit in treatment. The use of combinations of therapies may be needed to overcome the complex network of signaling pathways, and ultimately inhibit the signaling that controls tumor growth and survival.

In addition to the factors in which CSCs possess by themselves, microenvironment surrounding them is important for maintenance, such as angiogenesis, vasculogenesis, and hypoxia. Many new therapeutic strategies targeting CSCs at various stages of differentiation and microenvironment of CSCs have been tried. We will be discussed below Fig. Let-7 and Lin28 in Development and Tumorigenesis. Top During normal development, the RNA-binding protein Lin28 is highly expressed in stem and progenitor cells. Lin28 blocks processing of let-7 miRNA precursor molecules into mature miRNAs, thereby maintains expression of genes that drive self-renewal and proliferation.

As progenitor cells differentiate, Lin28 expression decreases, which allows let-7 processing and increased production of mature let-7 miRNAs. Let-7 miRNAs repress the expression of genes involved in self-renewal resulting in lineage commitment and terminal differentiation. An imbalance between Lin28 and let-7 induced by these molecules can result in cellular transformation. CSCs are protected from conventional therapies by changing their microenvironment and self-protection. Specifically targeting any of these areas may lead to the eradication of the CSCs.

Targeting key signaling pathways for CSC self-renewal is one approach to therapy [ , , ]. Furthermore, antibody-based therapeutic approaches targeting EpCAM are currently being developed [ , ]. The Hedgehog pathway is another potentially druggable target for CSC eradication.

Several small-molecule modulators of Sonic hedgehog signaling have been used to regulate the activity of this pathway in medulloblastoma, basal cell carcinoma, pancreatic cancer, prostate cancer and developmental disorders [ ]. In liver cells, suppression of the Sonic Hedgehog pathway by siRNA not only decreased HCC cell proliferation but also chemosensitized the cells to 5-fluorouracil 5-FU and to the induction of cell apoptosis [ ].

Furthermore, in hepatoblastoma, blocking Hh signaling with the antagonist cyclopamine had a strong inhibitory effect on cell proliferation of hepatoblastoma cell lines [ ].

Understanding and targeting cancer stem cells: therapeutic implications and challenges

Thus, targeting intracellular pathways associated with self-renewal of CSCs remains a viable approach to be extended in the near future. Therefore, inhibition of IL-6 signaling may be a potential therapeutic strategy in liver cancer treatment [ , ]. CSC cells, which only make up a small proportion in cancer, have the capability to sustain tumor growth and are more resistant to conventional chemotherapy than other differentiated cancer cells. One approach to treat malignancies is to induce differentiation of the CSC cells. Differentiation therapy could force hepatoma cells to differentiate and lose their self-renewal property.

Interferon therapy is effective for eradicating hepatitis viruses and also preventing the development of HCC. Interferon alpha treatment accelerated hepatocytic and biliary differentiation in oval cell lines [ ]. These findings indicate that combination of differentiation therapy and conventional chemotherapy may be an effective treatment of HCC. The identification of CSC markers and their exploitation in targeted chemotherapy is an important research goal.

Given the phenotypic similarities between CSCs and normal stem cells, it is reasonable to infer that the surface phenotype of CSCs resembles that of normal hepatic stem cells. In addition, suppression of CD by a murine antibody to human CD conjugated to a potent cytotoxic drug reduced the proliferation rate of Hep3B cells in vitro and delayed tumor growth in a SCID mouse model [ ]. These findings suggest that targeting of CD might be a novel therapeutic strategy for liver tumors. A recent study suggested that CSC phenotype could be precisely defined by co-expression of CD and CD44 cell surface markers [ ].

In addition, recent studies also revealed that blocking CD44 signaling using an anti-CD44 antibody might be a potential strategy to eradicate liver CSCs and consequently cure those patients [ ]. Clinical trials have been conducted in various cancers, including breast, prostate and colon cancers [ , ].


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In mouse xenograft models, combination of a CD13 inhibitor and 5-FU dramatically reduced tumor volume compared with either agent alone. Induction of tumor hypoxia combined with chemotherapy by transcatheter transarterial chemoembolization has been widely used in treating unresectable HCC, but tumor response rate is unsatisfactory and only a subgroup of patients benefit from this treatment [ , ].

Therefore, hypoxia-driven clonal selection of apoptosis-resistant tumor cells, together with hypoxia-induced MDR1 expression and angiogenesis, explain why hypoxic tumors are more resistance to conventional anticancer therapy. This justifies the current trials evaluating the use of anti-angiogenic therapy following HCC surgery. Several studies have established that tumor growth and invasion in HCC are dependent on dysregulated angiogenesis [ - ]. There is, therefore, a strong rationale for targeting growth factors that drive angiogenic process as a potential therapeutic strategy for the treatment of HCC.

The observation that tumors progress in patients with HCC despite the presence of tumor-specific immune responses suggests that development of HCC leads to a number of immunosuppressive mechanism, which are important to be considered when designing immunotherapy protocols. All these factors provide an environment that promotes angiogenesis, tumor survival and metastasis. Targeting regulatory T cells has been of great interest to potentially remove the suppression of effecter T cells and enhance tumor-specific immune response.

Depletion of regulatory T cells using anti-CD25 monoclonal antibodies or regulatory T cell-inhibiting agents, such as cyclophosphamide, has been shown to have anti-tumor effects in preclinical models [ - ]. In addition, MDSC suppress the cytokine production as well as the cytotoxic capacity of natural killer NK cells, playing a critical role in the host defense against cancer, in HCC patients [ ]. Impaired NK cells can affect anti-tumor immune responses, which contributes further to tumor escape from both innate and adaptive immune responses in patients with HCC.

It is believed that stem-like SP cells, which are known for their ability to efflux the DNA-binding dye Hoechst , confer resistance to chemotherapeutic drugs, including cisplatin and doxorubicin, through expression high levels of such ABC transporters [ , ]. These cells have been shown to harbor other CSC-like properties, and may be related to the metastatic potential and chemoresistance of HCC [ ].

Several experimental and clinical findings provide evidence that the number of CSCs in a cancer affects its radiocurability. Recurrent tumors after radiotherapy could originate from one surviving CSC, and a permanent local tumor control requires inactivation of all CSCs [ ]. Tumor cell hypoxia and tumor cell repopulation are the main factors causing radioresistance. Oxygen mediates the majority of the biological effects of sparsely ionizing radiation, and the response of cells to radiation depends strongly on the availability of oxygen. Various methods to deliver oxygen to cancer tissue have been studied.

Enhanced tumor oxygenation has previously been achieved in an animal model using the synthetic heme-based oxygen carrier, albumin-heme which is a recombinant human serum albumin-Fe cyclohexanoil heme rHSA-FeP. The rapid development of the CSC field, combined with genome-wide screening techniques, has allowed for the identification of important new CSC markers and pathways, and these discoveries have contributed to one of the most important developments in cancer treatment.

However, several important issues still remain to be resolved. For example, little is known about CSC directed therapies e. Initial results are promising, but its potential short- and long-term side effects of these therapies are unclear. Such treatment with off-target effects lead to acute and irreversible organ failure. Therefore, it is critical in delineating the molecular differences between CSCs and their tissue specific stem cell counterparts, to prevent damage to normal somatic stem cells and to ensure selectively targeting CSCs.

This growing knowledge base has the potential to identify candidate genes and pathways that are important for CSC survival and propagation but are not important for normal stem cell function. In addition, CSCs clearly have a complex pathogenesis, with the potential for considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit in treatment.

Use of combinations of therapies may be needed to overcome the complex network of signaling pathways, and ultimately inhibit the signaling that controls tumor growth and survival. However, use of a combination regimen can lead to tolerability and drug-drug interaction problems, and hence an alternative approach is to use molecularly targeted agents that have multiple modes of action.

It is useful to understand which combination regimen is the most effective for inhibiting CSC survival and propagation with the least impact on normal stem cell function. When a sufficient number of CSC markers become available and an ideal combination therapy identify, CSC-specific therapies might be developed that spare healthy stem cells and thus reduce side effects and retain regenerative tissue capacities.

Discoveries made in the CSC field will feed back into other areas of stem cell research because many marker gene products found in CSCs are shares with the normal stem cell population. It is also expected that a better understanding of the processes that control autonomous growth, differentiation and cell migration will contribute to novel regenerative-medicine-based treatments that will revolutionize therapeutic strategies and bring renewed hope to cancer patients.

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