Bone marrow cells: The source of hepatocellular carcinoma?

doi:10.1016/j.mehy.2006.10.064

Medical Hypotheses

Volume 69, Issue 1, 2007, Pages 36-42

https://doi.org/10.1016/j.mehy.2006.10.064 Get rights and content

Summary

Whether the stem cells or the mature cells are the origination of hepatocellular carcinoma is uncertain. Recently, researches have shown that some cancer stem cells could derive from adult stem cells. Moreover, gastric cancer could originate from bone marrow stem cells. Hematopoiesis and the hepatic environment are known to have a close relationship at the time of hepatic development and systemic diseases. Here we propose a new carcinogenetic model of hepatocellular carcinoma. Chronic liver injury could recruit bone marrow stem cells to the liver. Bone marrow cells take part in liver regeneration by differentiating to oval cells and hepatocytes. Persistent regeneration results in hyperproliferation, an increased rate of transforming mutations. Extracellular matrix remodeling triggers a cascade of events that inhibits the transactivation potential of liver-specific transcription factors, blocks the maturation of stem cells, and then results in hepatocellular carcinoma.

Introduction

A role for cancer stem cells has been demonstrated for some cancers, such as the hematopoietic system, breast and brain [1], [2], [3], [4], [5], [6], [7], [8]. Recently, the clear similarities between stem cell and cancer stem cell genetic programs are the basis of a proposal that some cancer stem cells could derive from adult stem cells. Adult mesenchymal stem cells (MSCs) may be targets for malignant transformation and undergo spontaneous transformation following long-term in vitro culture, supporting the hypothesis of cancer stem cell origin [9], [10], [11]. However, the origin of the cancer stem cell remains elusive. Wang et al. reported that chronic infection of C57BL/6 mice with Helicobacter pylori induced repopulation of the stomach with bone marrow-derived cells, which progressed through metaplasia and dysplasia to intraepithelial cancer subsequently [12]. This discovery suggested that intraepithelial cancer could arise from bone marrow cells.

Hematopoiesis and the hepatic environment are known to have a close relationship at the time of hepatic development and systemic diseases. Hepatic oval cells, the liver stem cells involved in some forms of liver regeneration, express many markers, such as c-kit, CD₃₄ and Thy-1, also found on hematopoietic stem cells (HSCs) [13], [14], [15], [16], [17], [18]. Recently, some research reported that bone marrow stem cells could differentiate into oval cells and hepatocytes [19], [20], [21], [22], [23], [24], [25], [26], [27]. Now that bone marrow cells and oval cells have a close relationship, does hepatocellular carcinoma (HCC) originates from bone marrow stem cells?

Section snippets

Chronic inflammation and hepatocarcinogenesis

The long known association between cancer and chronic tissue injury strongly suggested that cancer growth may represent the continuous operation of an unregulated state of tissue repair [28]. The appreciated roles of Hedgehog and Wnt signaling pathways in tissue regeneration, stem cell renewal and cancer growth together suggest that carcinogenesis proceeds by misappropriating homeostatic mechanisms that govern tissue repair and stem cell self-renewal [29]. Malignant transformation of

Niche and hepatocarcinogenesis

Stem cells reside in a physical niche, a particular microenvironment. The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation, maintenance and regeneration. During development, blood cell formation moves from extraembryonic regions to the aorto-gonadalmesonephros in the embryo and then to the liver in the first trimester. Liver provides a more conducive microenvironment to support HSCs [57]. HSCs could be detected in the fetal and

Differentiation and cellular origination of HCC

Hepatic oval cells, the liver stem cells involved in some forms of liver regeneration, express many markers, such as c-kit, CD₃₄ and Thy-1, also found on HSCs [13], [14], [15], [16], [17], [18]. CK19 (a marker of oval cell) positivity was significantly correlated with poor survival outcome and poor histological differentiation [80]. Hepatoma cells could produce erythropoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony-stimulating factor (GM-CSF) and macrophage

Conclusions

Malignant transformation of hepatocytes may occur in the context of chronic liver injury, regeneration and cirrhosis. Cirrhosis is caused by ECM remodeling which demolishes normal liver blood system, resulting in hypoxia. Here we propose a new carcinogenetic model of HCC. Chronic liver injury and hypoxia could recruit bone marrow stem cells to liver. Bone marrow cells take part in liver regeneration by differentiating to oval cells and hepatocytes. Persistent regeneration results in

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