Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within ...cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
This article offers a personal commentary on the influence of Tom O'Regan, my Honours supervisor in the 1990s. Among many other things, he was a major contributor to the 'cultural policy debate' in ...Australia. More than offering an explanation about the subject, O'Regan had warned of the need to strike a balance when debating culture and critiquing cultural policy, and not fall into polemical traps. Making a case for policy independence, he urged academics to participate collaboratively and cooperatively in cultural policy-making processes, instead of primarily engaging in cultural criticisms. I write as well of my firsthand experience of how his cultural policy writings transcended scholarly rationale into the actual policy domain during my time as a media policy professional in Singapore. His ability to apply policy thinking beyond academia underscores why he was - and will remain - a giant of media and cultural studies in Australia and beyond.
The tumor microenvironment plays a critical role in maintaining the immature phenotype of tumor-initiating cells (TIC) to promote cancer. Hepatocellular carcinoma (HCC) is a unique disease in that it ...develops in the setting of fibrosis and cirrhosis. This pathologic state commonly shows an enrichment of stromal myofibroblasts, which constitute the bulk of the tumor microenvironment and contribute to disease progression. Follistatin-like 1 (FSTL1) has been widely reported as a proinflammatory mediator in different fibrosis-related and inflammatory diseases. Here we show FSTL1 expression to be closely correlated with activated fibroblasts and to be elevated in regenerative, fibrotic, and disease liver states in various mouse models. Consistently, FSTL1 lineage cells gave rise to myofibroblasts in a CCL
-induced hepatic fibrosis mouse model. Clinically, high FSTL1 in fibroblast activation protein-positive (FAP
) fibroblasts were significantly correlated with more advanced tumors in patients with HCC. Although FSTL1 was expressed in primary fibroblasts derived from patients with HCC, it was barely detectable in HCC cell lines. Functional investigations revealed that treatment of HCC cells and patient-derived 3D organoids with recombinant FSTL1 or with conditioned medium collected from hepatic stellate cells or from cells overexpressing FSTL1 could promote HCC growth and metastasis. FSTL1 bound to TLR4 receptor, resulting in activation of AKT/mTOR/4EBP1 signaling. In a preclinical mouse model, blockade of FSTL1 mitigated HCC malignancy and metastasis, sensitized HCC tumors to sorafenib, prolonged survival, and eradicated the TIC subset. Collectively, these data suggest that FSTL1 may serve as an important novel diagnostic/prognostic biomarker and therapeutic target in HCC. SIGNIFICANCE: This study shows that FSTL1 secreted by activated fibroblasts in the liver microenvironment augments hepatocellular carcinoma malignancy, providing a potential new strategy to improve treatment of this aggressive disease.
We hypothesized that the known heterogeneity of pancreatic β cells was due to subpopulations of β cells at different stages of their life cycle with different functional capacities and that further ...changes occur with metabolic stress and aging. We identified new markers of aging in β cells, including IGF1R. In β cells IGF1R expression correlated with age, dysfunction, and expression of known age markers p16ink4a, p53BP1, and senescence-associated β-galactosidase. The new markers showed striking heterogeneity both within and between islets in both mouse and human pancreas. Acute induction of insulin resistance with an insulin receptor antagonist or chronic ER stress resulted in increased expression of aging markers, providing insight into how metabolic stress might accelerate dysfunction and decline of β cells. These novel findings about β cell and islet heterogeneity, and how they change with age, open up an entirely new set of questions about the pathogenesis of type 2 diabetes.
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•Subpopulations of pancreatic β cells differ and change proportions with aging•Markers of β cell age show heterogeneity both within islets and between islets•IGF1R-expressing β cells are senescent and have dysfunctional insulin secretion•Insulin resistance accelerated expression of p16Ink4a and aging markers in β cells
Aguayo-Mazzucato et al. show that the heterogeneity of pancreatic β cells is likely due to individual β cells at their respective life cycle stage expressing different markers and functional characteristics. Both age and environmental factors, including metabolic stress, can shift the composition of the β cell population contributing to diabetes.
Identification of therapeutic targets against tumor‐initiating cells (TICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched a TIC population capable of tumor ...initiation and self‐renewal by serial passages of hepatospheres with chemotherapeutic agents. In chemoresistant hepatospheres, CD47 was found to be up‐regulated, when compared with differentiated progenies. CD47 is preferentially expressed in liver TICs, which contributed to tumor initiation, self‐renewal, and metastasis and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed stem/progenitor cell characteristics. CD47+ hepatocellular carcinoma (HCC) cells preferentially secreted cathepsin S (CTSS), which regulates liver TICs through the CTSS/protease‐activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino approach suppressed growth of HCC in vivo and exerted a chemosensitization effect through blockade of CTSS/PAR2 signaling. Conclusion: These data suggest that CD47 may be an attractive therapeutic target for HCC therapy. (Hepatology 2014;60:179–191)
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•ANXA3 confers HCC cells with the ability to resist sorafenib.•ANXA3 is enriched in sorafenib-resistant HCC.•ANXA3 activates autophagy and attenuates PKCδ/p38 dependent ...apoptosis.•ANXA3 is a useful predictive biomarker to stratify patients for sorafenib treatment.•Anti-ANXA3 therapy with sorafenib/regorafenib a potential treatment strategy for HCC.
Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA-approved first-line targeted drug for advanced HCC, but its effect on patient survival is limited. Further, patients ultimately present with disease progression. A better understanding of the causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC.
The functional effects of ANXA3 in conferring sorafenib resistance to HCC cells were analyzed in apoptotic and tumorigenicity assays. The role of ANXA3/PKCδ-mediated p38 signaling, and subsequently altered autophagic and apoptotic events, was assessed by immunoprecipitation, immunoblotting, immunofluorescence and transmission electron microscopy assays. The prognostic value of ANXA3 in predicting response to sorafenib was evaluated by immunohistochemistry. The therapeutic value of targeting ANXA3 to combat HCC with anti-ANXA3 monoclonal antibody alone or in combination with sorafenib/regorafenib was investigated ex vivo and in vivo.
ANXA3 conferred HCC cells with resistance to sorafenib. ANXA3 was found enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, overexpression of ANXA3 in sorafenib-resistant HCC cells suppressed PKCδ/p38 associated apoptosis and activated autophagy for cell survival. Clinically, ANXA3 expression correlated positively with the autophagic marker LC3B in HCC and was associated with a worse overall survival in patients who went on to receive sorafenib treatment. Anti-ANXA3 monoclonal antibody therapy combined with sorafenib/regorafenib impaired tumor growth in vivo and significantly increased survival.
Anti-ANXA3 therapy in combination with sorafenib/regorafenib represents a novel therapeutic strategy for HCC treatment. ANXA3 represents a useful predictive biomarker to stratify patients with HCC for sorafenib treatment.
This study represents the most extensive pre-clinical characterization of anti-ANXA3 monoclonal antibodies for the treatment of hepatocellular carcinoma to date. These results support the clinical trial development of anti-ANXA3 antibodies in combination with sorafenib/regorafenib. Further studies will optimize patient target selection and identify the best treatment combinations.
Although social movements and media can help destabilize authoritarian governments, not all social protest is effective or culminates in the toppling of dictatorships. Frequently, the military’s ...response determines the outcome.
In Defect or Defend, Terence Lee uses four case studies from Asia to provide insight into the military’s role during the transitional phase of regime change. Lee compares popular uprisings in the Philippines and Indonesia—both of which successfully engaged military support to bring down authoritarian rule—with protest movements in China and Burma which were violently suppressed by military forces.
Lee’s theory of “high personalism” and power-sharing among the armed forces leadership provides a framework for understanding the critical transitory phases of democratization. He uses this theory to review and assess Eastern Europe’s democratization events in 1989, the Colored Revolutions of the early 2000s, and the protests and revolutions unfolding in the Middle East. This book will appeal to students and scholars of comparative politics, Asian studies, security studies, and international relations, as well as defense policymakers.
Background & Aims: Recent efforts in stem cell biology suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability to maintain tumor formation/growth ...specifically resides in a small population of cells called cancer stem cells (CSCs). The aim of this study is to identify, isolate, and characterize the CSC population that drives and maintains hepatocellular carcinoma (HCC) growth and metastasis. Methods: Normal stem cells involved in liver regeneration were identified using a severe partial hepatectomy model. Purified HCC cells, with or without expression of the identified normal stem cell phenotype, were evaluated, based on their tumorigenic potential and exhibition of defined stem/progenitor cell-like properties, to determine whether liver CSCs can be or partly be identified by this surface marker. Results: We report the identification and isolation of a population of CSCs expressing a CD133 surface phenotype from human liver cell lines. CD133+ cells possess a greater colony-forming efficiency, higher proliferative output, and greater ability to form tumor in vivo. These cells are endowed with characteristics similar to those of progenitor cells including the expression of “stemness” genes, the ability to self-renew, and the ability to differentiate into nonhepatocyte-like lineages. Furthermore, CD133 is found to represent only a minority of the tumor cell population in human HCC specimens. Conclusions: We report the identification of a CSC population in HCC characterized by their CD133 phenotype. The identification of tumorigenic liver CSCs could provide new insight into the HCC tumorigenic process and possibly bear great therapeutic implications.
Hepatocellular carcinoma (HCC) is heterogeneous, rendering its current curative treatments ineffective. The emergence of single-cell genomics represents a powerful strategy in delineating the complex ...molecular landscapes of cancers. In this study, we demonstrated the feasibility and merit of using single-cell RNA sequencing to dissect the intra-tumoral heterogeneity and analyze the single-cell transcriptomic landscape to detect rare cell subpopulations of significance. Exploration of the inter-relationship among liver cancer stem cell markers showed two distinct major cell populations according to EPCAM expression, and the EPCAM+ cells had upregulated expression of multiple oncogenes. We also identified a CD24+/CD44+-enriched cell subpopulation within the EPCAM+ cells which had specific signature genes and might indicate a novel stemness-related cell subclone in HCC. Notably, knockdown of signature gene CTSE for CD24+/CD44+ cells significantly reduced self-renewal ability on HCC cells in vitro and the stemness-related role of CTSE was further confirmed by in vivo tumorigenicity assays in nude mice. In summary, single-cell genomics is a useful tool to delineate HCC intratumoral heterogeneity at better resolution. It can identify rare but important cell subpopulations, and may guide better precision medicine in the long run.
•Single-cell transcriptomics dissected the intra-tumoral heterogeneity of hepatocellular carcinoma (HCC).•HCC single cells showed two distinct major cell populations according to EPCAM expression.•CD24+/CD44+-enriched cell subpopulation was identified within the EPCAM+ cells.•CTSE was the most upregulated signature gene in CD24+/CD44+-enriched cells.•Knockdown of CTSE significantly reduced self-renewal ability in vitro and tumorigenicity in vivo.
Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an ...enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1. Using the STAM NASH-HCC mouse model, we find that HGF-induced FRA1 activation is associated with the fibrosis-dependent development of HCC. Thus, targeting the CAF-derived, HGF-mediated c-Met/FRA1/HEY1 cascade may be a therapeutic strategy for the treatment of HCC.
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•The presence of α-SMA(+) CAFs correlates with poor prognosis of HCC•CAFs regulate liver T-ICs through paracrine secretion of HGF•FRA1 is required for HGF/c-Met-mediated T-IC phenotypes•The HGF-mediated c-Met/FRA1/HEY1 cascade represents a therapeutic target for HCC
Similar to normal stem cells, tumor-initiating cells are regulated extrinsically within their microenvironment. Lau et al. find that cancer-associated fibroblasts play a crucial role in the regulation of liver T-ICs through HGF-mediated activation of the c-Met/FRA1/HEY1 cascade. Targeting this pathway may be a promising approach for cancer treatment.
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