Roles of Tumor Microenvironment in Hepatocelluar Carcinoma

Seo, Haeng Ran

doi:10.2174/1573394711666151022203313

Cited by 22 publications

(11 citation statements)

References 61 publications

(65 reference statements)

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“…Studies have shown that CD133-positive liver CSCs can induce aberrant signaling pathways different from those in CD133-negative cells, such as the Akt/PKB pathway, JNK, mTOR, ERK, and β-catenin etc. [9, 39, 40]. However, the specific mechanism of action by which CD133 CSCs are able to avoid conventional therapies in HCC remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Song

Jang

Shin

et al. 2017

J Exp Clin Cancer Res

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BackgroundCD133-positive cells in hepatocellular carcinoma (HCC) exhibit cancer stem cell (CSC)-like properties as well as resistance to chemotherapeutic agents and ionizing radiation; however, their function remains unknown. In this paper, we identified a hitherto unknown mechanism to overcome CD133-induced resistance to anticancer therapy.MethodsWe applied an alternative approach to enrich the CD133-positive HCC population by manipulating 3D culture conditions. Defense mechanisms against reactive oxygen species (ROS) in CSC spheroids were evaluated by fluorescence image-based phenotypic screening system. Further, we studied the effect of sulfasalazine on ROS defense system and synergistic therapeutic efficacy of anticancer therapies both in culture and in vivo HCC xenograft mouse model.ResultsHere, we found that oxidative stress increase CD133 expression in HCC and increased CD133 expression enhanced the capacity of the defense system against ROS, and thereby play a central role in resistance to liver cancer therapy. Moreover, ablation of CD133 attenuated not only the capacity for defense against ROS, but also chemoresistance, in HCC through decreasing glutathione (GSH) levels in vitro. Sulfasalazine, a potent xCT inhibitor that plays an important role in maintaining GSH levels, impaired the ROS defense system and increased the therapeutic efficacy of anticancer therapies in CD133-positive HCC but not CD133-negative HCC in vivo and in vitro.ConclusionThese results strongly indicate functional roles for CD133 in ROS defense and in evading anticancer therapies in HCC, and suggest that sulfasalazine, administered in combination with conventional chemotherapy, might be an effective strategy against CD133-positive HCC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0511-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Song

Jang

Shin

et al. 2017

J Exp Clin Cancer Res

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“…Hepatocellular carcinoma (HCC) is one of the most common solid tumors and the leading cause of cancer-related mortality worldwide 1,2 . Because most patients with HCC lose the opportunity for radical treatment (operation or liver transplantation) due to the advanced stage at which the cancer is detected, the long-term outcome of HCC is poor 3 . To date, sorafenib is the only approved systemic therapy for the treatment of advanced and recurrent HCC 4 , but its therapeutic effect is less than satisfactory, largely due to hypoxia-mediated sorafenib resistance 5–7 .…”

Section: Introductionmentioning

confidence: 99%

Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

et al. 2019

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Sorafenib resistance is one of the main obstacles to the treatment of advanced/recurrent hepatocellular carcinoma (HCC). Here, sorafenib-resistant HCC cells and xenografts in nude mice were used as experimental models. A cohort of patients with advanced recurrent HCC who were receiving sorafenib therapy was used to assess the clinical significance of this therapy. Our data showed that 14-3-3η maintained sorafenib resistance in HCC. An analysis of the underlying molecular mechanisms revealed that 14-3-3η stabilizes hypoxia-inducible factor 1α (HIF-1α) through the inhibition of ubiquitin-dependent proteasome protein degradation, which leads to the maintenance of cancer stem cell (CSC) properties. We further found that microRNA-16 (miR-16) is a competent miRNA that reverses sorafenib resistance by targeting the 3′-UTR of 14-3-3η and thereby inhibits 14-3-3η/HIF-1α/CSC properties. In HCC patients, significant negative correlations were found between the expression of miR-16 and 14-3-3η, HIF-1α, or CSC properties. Further analysis showed that low miR-16 expression but high 14-3-3η expression can prognosticate sorafenib resistance and poor survival. Collectively, our present study indicated that miR-16/14-3-3η is involved in sorafenib resistance in HCC and that these two factors could be potential therapeutic targets and biomarkers for predicting the response to sorafenib treatment.

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“…In order to recapitulate the interplay between HCC and its microenvironment, the multicellular tumor spheroid model (MCTS) has emerged as a powerful method for mirroring tumor complexity and heterogeneity enhancement in anticancer research24. In vitro , MCTS has been used in cancer research as an intermediate model between an in vitro cancer cell line culture system and an in vivo tumor, because MCTS can closely mirror the three-dimensional (3D) cellular context and therapeutically relevant pathophysiological gradients of in vivo tumors, such as pH and oxygen gradients, penetration rate of growth factors, and the distribution of proliferating/necrotic cells252627.…”

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confidence: 99%

Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids

Song

Kim

et al. 2016

Sci Rep

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Worldwide, hepatocellular carcinoma (HCC) is one of the human cancers with a high mortality rate despite its early diagnosis in patients and improvements in therapeutic technology. HCC accounts for up to 90% of all primary liver cancers and represents a major health problem 1,2 . Chronic infection by hepatitis B and C and chronic alcohol consumption are major causes, as well as metastasis from tumors elsewhere in the body. Because only 10-20% of liver cancers can be surgically removed, the prognosis for the disease is very poor 3 . The cumulative 3-year recurrence rate remains high, approximately 80% after resection with a curative aim, and usually results in a high rate of mortality 4 . Moreover, most HCC exhibit resistance to conventional chemotherapeutic agents. Therefore, the development of an effective HCC treatment strategy remains an unmet medical need 5 . Accordingly, researchers have aimed to derive target genes and drug candidates for HCC; however, the development of targeted drugs has not yet significantly improved outcomes 5,6 . Lately, the paradigm in cancer biology has shifted from the study of the genetics of tumor cells alone to the complicated crosstalk between cancer and the tumor microenvironment (TME) [7][8][9] . The TME is the cellular environment in which the tumor exists, including the surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix (ECM). Recent studies have shown that the stromal cells in HCC have a dynamic and flexible function in

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Roles of Tumor Microenvironment in Hepatocelluar Carcinoma

Cited by 22 publications

References 61 publications

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Sulfasalazine attenuates evading anticancer response of CD133-positive hepatocellular carcinoma cells

Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α

Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids

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