Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly (original) (raw)
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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.
Liver cancer stem cells: implications for a new therapeutic target
Liver International, 2009
Hepatocellular carcinoma (HCC) is an aggressive tumour with a poor prognosis. Current therapeutic strategies against this disease target mostly rapidly growing differentiated tumour cells. However, the result is often dismal due to the chemoresistant nature of this tumour type. Recent research efforts on stem cells and cancer biology have shed light on new directions for the eradication of cancer stem cells (CSCs) in HCC. The liver is a distinctive organ with the ability of tissue renewal in response to injury. Based on the hypothesis that cancer development is derived from the hierarchy of the stem cell system, we will briefly discuss the origin of liver stem cells and its relation to HCC development. We will also summarize the current CSC markers in HCC and discuss their relevance to the treatment of this deadly disease.
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.
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 ...
Annals of hepatology
BACKGROUND. The liver possesses two distinct mechanisms for healing. Wound healing via hepatic stem cells recapitulates early development (hepatoblast proliferation), while liver regeneration resembles late embryonic growth (hepatocyte proliferation). Loss of control over both of these processes have been proposed as mechanisms that may contribute to poor outcomes in HCC. MATERIAL AND METHODS. We used microarray gene expression profiles to examine the involvement of hepatic stem cell and hepatocyte proliferation markers and regulators in HCV-induced cirrhosis and HCC. We compared 30 cirrhosis and 49 HCC samples to 12 disease-free control livers. RESULTS. Cirrhosis and HCC expressed markers of stem cell. Inhibitors of hepatocyte proliferation (HP) were highly expressed in cirrhosis. Loss of these HP inhibitors in HCC patients was associated poor prognosis (94 vs. 38% 2-year recurrence- free survival, p = 0.0003). Principal Components Analysis discriminated cirrhotic and HCC tissues, ...
Hepatic “Stem” Cells: Coming Full Circle
Blood Cells, Molecules, and Diseases, 2001
Activation, proliferation, and differentiation of a distinct phenotype of cells, called oval cells, are observed after severe hepatic injuries in which the proliferation of existing hepatocytes is inhibited. Under those conditions, oval cells can act as bipotential progenitors of the two types of epithelial cells within the liver, hepatocytes and bile ductular cells. Oval cells are also believed to play a role in the hepatocellular carcinoma and cholangiocarcinoma development; although circumstantial data are available, no direct evidence exists to support this theory. Oval cells have usually been thought to be the progeny of an hepatic stem cell, native to the liver. Recently, however, we, as well as others, have obtained clear evidence that in the rodents, hepatic oval cells, or at least a fraction of them, can derive from a precursor cell of bone marrow origin. The rodent data have been supported by recent findings that human bone marrow cells are capable of becoming hepatocytes and cholangiocytes as well. Having shown that oval cells can be derived from an extrahepatic source, we now have the technology to address many unanswered questions in oval cell origin, fate, and physiology through the use of sex-mismatched bone marrow transplants.
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.