Liver cancer stem cells: implications for a new therapeutic target (original) (raw)

Cancer stem cells in hepatocellular carcinoma: Recent progress and perspective

Cancer Letters, 2009

Although the "cancer stem cell (CSC)" hypothesis was first proposed roughly 50 years ago, recent progress in stem cell biology and technologies has successfully achieved the identification of CSCs in a variety of cancers. CSCs are defined as a minor population which possesses a prominent ability to generate new tumors that faithfully reproduce the phenotype of original tumors in xenotransplant assays. Additionally, CSCs are able to self-renew and generate differentiated progenies to organize a hierarchical cell system in a similar fashion to normal stem cells. Although not all types of cancer follow the CSC theory, it provides an attractive cellular mechanism to account for the therapeutic resistance and recurrence of the disease. A minor population with CSC properties has been detected in a number of established hepatocellular carcinoma (HCC) cell lines and extensive analyses characterizing the CSC system in primary HCC samples are now ongoing. Considering that HCC has high rates of recurrence and mortality, novel therapeutic approaches are urgently required. Although the clinical relevance of CSCs remains elusive, deep understanding of the cellular organization of HCC may allow us to develop therapies targeting specific cell types such as CSCs.

In Search of Liver Cancer Stem Cells

Stem Cell Reviews, 2008

Recent research efforts in stem cell and cancer biology have put forth a "stem cell model of carcinogenesis" which stipulates that the capability to maintain tumor formation and growth specifically resides in a small population of cells called cancer stem cells. The stem celllike characteristics of these cells, including their ability to self-renew and differentiate; and their limited number within the bulk of the tumor mass, are believed to account for their capability to escape conventional therapies. In the past few years, the hypothesis of stem cell-driven tumorigenesis in liver cancer has received substantial support from the recent ability to identify and isolate a subpopulation of liver cancer cells that is not only able to initiate tumor growth, but also serially establish themselves as tumor xenografts with high efficiency and consistency. In this review, stem cell biology that contributes to explain tumor development in the particular context of liver cancer will be discussed. We will begin by briefly considering the knowledge available on normal liver stem cells and their role in tissue renewal and regeneration. We will then summarize the current scientific knowledge of liver cancer stem cells, discuss their relevance to the diagnosis and treatment of the disease and consider the outstanding challenges and potential opportunities that lie ahead of us.

The Cancer Stem Cell in Hepatocellular Carcinoma

Cancers

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

Hepatic Cancer Stem Cells and Signaling Pathways

Loss of hepatocytes due to infection, inflammation or partial hepectomy simulates a response which helps in the liver restoration. This maintains homeostasis and keeps a check on the usual wear and tear in the liver. Cancer stem cells (CSCs) were demonstrated to be associated with myeloid leukemia. However, with recent advancements in the approaches and techniques, CSCs are also present within a wide variety of solid tumors and malignancies of epithelial origin. Identification of CSCs has been lately possible by characterization of specific surface markers and signaling events. Hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CC) constitute primary liver cancer. Deaths caused by HCC are much higher than the occurrence possibly due to its asymptomatic nature. The symptoms are manifested at a later stage by the time tumor has metastasized. CSC population, associated with HCC, is majorly responsible for chemo resistance and metastasis. Identifying CSC specific genes, cell surface markers and signaling pathways could help in the development of novel therapeutic approaches. Moreover, the role of micro RNAs (miRNAs) has been shown to be associated with the self-renewal of liver CSCs. This review deals with the understanding of liver CSCs, miRNAs and the signaling pathways involved.

Targeting cancer stem cells in hepatocellular carcinoma

Gastrointestinal Cancer: Targets and Therapy, 2014

The poor outcome of patients with hepatocellular carcinoma (HCC) is attributed to recurrence of the disease after curative treatment and the resistance of HCC cells to conventional chemotherapy, which may be explained partly by the function of liver cancer stem cells (CSCs). Liver CSCs have emerged as an important therapeutic target against HCC. Numerous surface markers for liver CSCs have been identified, and include CD133, CD90, CD44, CD13, and epithelial cell adhesion molecules. These surface markers serve not only as tools for identifying and isolating liver CSCs but also as therapeutic targets for eradicating these cells. In studies of animal models and large-scale genomic analyses of human HCC samples, many signaling pathways observed in normal stem cells have been found to be altered in liver CSCs, which accounts for the stemness and aggressive behavior of these cells. Antibodies and small molecule inhibitors targeting the signaling pathways have been evaluated at different levels of preclinical and clinical development. Another strategy is to promote the differentiation of liver CSCs to less aggressive HCC that is sensitive to conventional chemotherapy. Disruption of the tumor niche essential for liver CSC homeostasis has become a novel strategy in cancer treatment. To overcome the challenges in developing treatment for liver CSCs, more research into the genetic makeup of patient tumors that respond to treatment may lead to more effective therapy. Standardization of HCC CSC tumor markers would be helpful for measuring the CSC response to these agents. Herein, we review the current strategies for developing treatment to eradicate liver CSCs and to improve the outcome for patients with HCC.

Stem Cells in Hepatocarcinogenesis: Evidence from Genomic Data

Seminars in Liver Disease, 2010

Increasing evidence suggests that many, perhaps all solid tumors contain a subset of cells that possess functional properties similar to the normal tissue stem cells, including self-renewal, unlimited proliferative capacity, and pluripotency. The hierarchical cancer model that places a cancer stem cell (CSC) population at the apex of tumor formation is based on this notion. The cancer stem cell hypothesis posits that CSCs are responsible not only for tumor initiation, but also generation of metastasis and local recurrence after therapy. Current definitions of the CSC are based only on functional properties regardless of potential cellular origin. Histopathology investigations of chronic liver diseases and experimental studies support the existence of CSCs in liver cancer. In particular, recent advances in microarray technologies utilizing integrative comparative genomic analysis of human hepatocellular carcinoma specimens, cancer cell lines, and transgenic models establish the molecular similarities between CSC and normal tissue stem cells and highlight the importance of CSC for the prognosis of liver cancer patients. The results have also uncovered the key "stemness" and oncogenic pathways frequently disrupted during hepatocarcinogenesis providing the basis for identifying novel therapeutic targets against CSC.

Road to stemness in hepatocellular carcinoma

World journal of gastroenterology, 2017

Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma (HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin (CCO) and cancer-propagating cells, known as hepatic cancer stem cell (HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the ...

Clinical significance of hepatic cancer stem cells

Formosan Journal of Surgery, 2011

The human liver consists of three types of liver cells: mature hepatocytes, cholangiocytes, and bipolar adult hepatic stem/progenitor cells (HPC). These three types of cell are commonly regarded as the primary targets of malignant transformation in the liver, if exposed to carcinogens in vivo or in vitro. Activation and proliferation of hepatic progenitor cells have been reported in precancerous conditions, such as chronic inflammation (hepatitis B/hepatitis C, alcoholic hepatitis and steatohepatitis). An origin of hepatocellular carcinoma (HCC) from hepatic progenitor cells is currently inferred from the fact that many tumors contain a mixture of mature cells and cells phenotypically similar to hepatic progenitor cells. In our series, there were 42 patients (31 males, 11 females, aged 23e80 years old) with HCC, who accepted liver resection, yielding specimens sufficient for pathological studies. Immunohistochemical studies were made with human monoclonal antibodies against OV-6, CD133, CK-19, CD44, AFP for investigating the HPC. HPC grading was higher in HCC patients with hepatitis B or hepatitis C and lower in those with non-B or non-C hepatitis. As regards the survival of HCC patients based on the grading of cancer stem cells (CSC) within the tumor, the group of Grade 0 showed a more favorable survival rate than that of Grade 1e3. The 1-, 3-, and 5-year survival rates of Grade 0 and Grade 1e3 were 92%, 76%, and 69%, and 63%, 50%, and 50%, respectively (p Z 0.073). These liver CSC would be more resistant to chemotherapeutic agents than tumor cells with limited proliferative potential. In conclusion, we strongly believe that the contributions of HPC warrant research in patients with HCC. Without determining the characteristics of CSC, it is impossible to propose new treatment strategies.