Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

Tang, Yi; Kitisin, Krit; Jogunoori, Wilma; Li, Cuiling; Deng, Chu Xia; Mueller, Susette C.; Ressom, Habtom W.; Rashid, Asif; He, Aiwu Ruth; Mendelson, Jonathan; Jessup, J. Milburn; Shetty, Kirti; Zasloff, Michael; Mishra, Bibhuti; Reddy, E. Premkumar; Johnson, Lynt B.; Mishra, Lopa

doi:10.1073/pnas.0705395105

Cited by 300 publications

(272 citation statements)

References 44 publications

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“…It is not clear if the latter cells correspond to the peribiliary Sca-1 + cells, also found in the murine liver [27]. In human liver as well, rare putative stem cells that strongly express STAT3 and the embryonic stem cell-associated pluripotency-associated factors Oct4 and nanog are apparently also located near portal tracts [28].…”

Section: Hepatocytesmentioning

confidence: 99%

“…Mishra and colleagues [28] have suggested that HCC CSCs are descendents of normal parenchymal stem cells that have lost sensitivity to the inhibitory growth effects of TGFβ, while cell selection based on Thy-1 (CD90), a disputed marker of oval cells (see Table 2), in combination with CD44, has also produced cells with aggressive tumorigenic potential [160,161]. It remains to be seen how much overlap there is between these various markers, or whether there is a 'one-fits-all' marker for CSCs in HCC and indeed in other tumour types as well.…”

Section: Mr Alison Et Almentioning

confidence: 99%

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Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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Section: Hepatocytesmentioning

confidence: 99%

Section: Mr Alison Et Almentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

201

149

View full text Add to dashboard Cite

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“…In mouse liver, the location of LRCs has suggested a parenchymal stem cell niche close to the portal area [109], and in human liver, rare putative stem cells strongly expressing STAT3 and the embryonic stem cell-associated pluripotency-associated factors Oct4 and Nanog are also located near portal tracts [110].…”

Section: Digestive Tractmentioning

confidence: 99%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

153

115

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While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organspecific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts.

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“…Human periportal cells also label for octamer 3/4 (Oct3/4), β2 spectrin (β2SP), and TBRII in both human and mouse liver regeneration 27, 28, 32. Through previous studies in human liver donor and liver transplant specimens that represent human liver regeneration, as well as fulminant hepatic failure, putative liver progenitor/stem cell expansion has been observed during massive hepatic necrosis with fibrosis as well as submassive hepatic necrosis with hepatocytic lineage.…”

Section: Liver Stem Cells and Tgf‐β: Evidence From Mouse Knockout LImentioning

confidence: 99%

“…Among numerous proinflammatory factors, interleukin‐6 (IL‐6) is the most prominently elevated in almost 40% of liver cancer patients, suggesting that IL‐6 is associated with HCC progression 81, 82, 83, 84, 85, 86, 87. The TGF‐β pathway induced IL‐6 secretion may confer chemotherapeutic resistance in HCC 32. IL‐6 is required for the priming of hepatocytes to leave their quiescent state (G0) and enter a prereplicative phase (G1), and transcriptionally up‐regulates an array of genes during liver growth 88.…”

Section: Tgf‐β In An Invasive Cancer Stem Cell Modelmentioning

confidence: 99%

Transforming growth factor‐β in liver cancer stem cells and regeneration

Rao

Zaidi

Banerjee

et al. 2017

Hepatology Communications

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Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem‐like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF‐β) pathway, loss of p53 and/or activation of β‐catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF‐β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF‐β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477–493)

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Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

Cited by 300 publications

References 44 publications

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Attributes of adult stem cells

Transforming growth factor‐β in liver cancer stem cells and regeneration

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