Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization

Rhee, Hyungjin; Nahm, Ji Hae; Kim, Haeryoung; Choi, Gi Hong; Yoo, Jeong Eun; Lee, Hye Sun; Koh, Myoung Ju; Park, Young Nyun

doi:10.1038/modpathol.2016.111

Cited by 61 publications

(50 citation statements)

References 32 publications

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“…We found that the histopathologic features of IRE-HCCs included sinusoid-like microvascular pattern, macrotrabecular pattern, a high proportion of tumor necrosis and fibrous stroma, and expression of stemness markers, which have been reported as characteristics of aggressive and poor prognostic HCCs [20,21,23,25,43]. Therefore, IRE might be a promising noninvasive biomarker for poor prognostic HCCs showing distinct pathologic features.…”

Section: Discussionmentioning

confidence: 87%

“…HCCs expressing stemness markers, such as K19 and EpCAM, are reportedly associated with poor prognosis and molecular signatures of aggressive biological behavior such as S2 (Hoshida et al [34]) and G1 (Boyault et al [35]) compared to HCCs that do not express these markers [18,19,[34][35][36][37][38]. Rhee et al [23] also recently reported a close association between the expression of the hypoxia marker CAIX and stemness markers including K19 and EpCAM in HCCs. In the present study, IRE-HCCs, which showed histopathologic characteristics indicative of a hypoxic microenvironment, expressed higher K19 and EpCAM levels, despite the lack of statistical significance for K19 level (p = 0.055 after Bonferroni correction).…”

Section: Discussionmentioning

confidence: 94%

“…In addition, we studied the expression of stemness markers which are known to be associated with hypoxic microenvironment and aggressive biologic behavior of HCC: keratin 19 (K19; 1: 100; DAKO) and epithelial cell adhesion molecule (EpCAM; 1: 1,000; Calbiochem, Darmstadt, Germany) [23]. Immunohistochemical staining was performed using an automated staining system (Discovery XT; Ventana Medical Systems, AZ, USA), and the slides were counterstained with hematoxylin.…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

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Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Rhee

An²,

Kim

et al. 2018

Liver Cancer

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Background and Aims: The purpose of our study was to examine the histopathologic characteristics of hepatocellular carcinoma (HCC) with irregular rim-like arterial phase enhancement (IRE), which has been reported to be associated with more aggressive tumor behavior. Methods: We investigated 84 pathologically confirmed HCCs in 84 patients who underwent curative hepatic resection after gadoxetate-enhanced magnetic resonance imaging between January 2008 and February 2013. Two abdominal radiologists independently reviewed these images and classified HCCs into two categories: HCC showing IRE (IRE-HCC) and HCC showing hypoenhancement or diffuse arterial enhancement (non-IRE-HCC). Twenty-two HCCs were classified as IRE-HCCs, and 51 were classified as non-IRE-HCCs concordantly by both reviewers. The remaining 11 HCCs, on whose radiologic classifications the reviewers disagreed, were classified as HCCs with intermediate enhancement patterns. The HCC clinicopathologic characteristics and patient outcomes were then compared. Results: IRE-HCCs showed more frequent microvascular invasion (91 vs. 35%), lower microvascular density (246.5 vs. 426.5/mm²), higher proportions of sinusoid-like microvascular pattern (55 vs. 0%) and macrotrabecular pattern (45 vs. 0%), and larger areas of tumor necrosis (15 vs. 0%) and fibrous stroma (8.3 vs. 2.1%) than non-IRE-HCCs. IRE-HCCs also expressed higher levels of immunomarkers of hypoxia (carbonic anhydrase IX, 64 vs. 8%) and stemness (EpCAM, 50 vs. 20%). p values were < 0.001 for all comparisons except for EpCAM (p = 0.026). HCCs with intermediate enhancement patterns showed mixed/intermediate pathologic features from both IRE- and non-IRE-HCCs. IRE-HCC patients showed poorer 5-year disease-free survival after curative resection than non-IRE-HCC patients (p = 0.005). Conclusions: IRE-HCCs demonstrate aggressive histopathologic features, including more hypoxic and fibrotic tumor microenvironments and increased stemness, compared to non-IRE-HCCs. IRE might therefore serve as a noninvasive imaging biomarker for aggressive HCC.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 94%

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

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Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Rhee

An²,

Kim

et al. 2018

Liver Cancer

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“…TACE has been suggested as a treatment option for chemoresistant unresectable cases for which liver transplantation is not an option or as 'bridging' treatment for those patients awaiting liver transplantation (40). However, the TACE procedure may increase the risk of resistance to chemotherapy by occluding the blood flow and inducing hypoxia with a concomitant risk of invasion and recurrence through EMT due to changes in the tumor microenvironment (41). Our current results suggested that low-dose metformin (1 mM) may reduce resistance to cisplatin in hypoxic conditions that result from TACE.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

et al. 2018

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Hepatoblastoma is the most commonly occurring liver tumor in children. Preoperative chemotherapy and surgery have improved treatment outcomes; however, further improvements are required in the treatment of advanced cases. Recently, the efficacy of transarterial chemoembolization (TACE) has garnered attention. TACE increases the local concentration of drugs by transcatheterically administering antitumor agents, and induces necrosis in the tumor by embolizing the feeding artery. However, studies have revealed that tumors exhibit resistance to anticancer drugs in hypoxic environments. Metformin is a drug used to treat type 2 diabetes; however, recent reports have indicated that it may also exhibit antitumor effects in various cancer cell lines. These effects are hypothesized to be mediated by the activation of adenosine monophosphate-activated protein kinase and reduction of mammalian target of rapamycin signaling, but these effects occur at high concentrations that are not suitable for use in a clinical setting. The potential efficacy of metformin at increased physiological concentrations has not been evaluated. The present study investigated the therapeutic effect of low concentrations of metformin in combination with cisplatin on liver cancer HepG2 cells in hypoxic conditions. HepG2 cells were treated with cisplatin alone, metformin alone, or a combination of these two drugs and cultured in normoxia or hypoxia. Treatment with either 5 µM cisplatin or 1 mM metformin alone did not significantly affect cell proliferation or apoptosis in hypoxic conditions. However, when 5 µM cisplatin was combined with 1 mM metformin, a significant inhibition of cell proliferation and induction of apoptosis was observed in hypoxic HepG2 cells. In conclusion, a low concentration of metformin attenuates hypoxia-induced resistance to cisplatin in HepG2 cells. Selective delivery of an effective dose of metformin to a hepatoblastoma tumor may be achievable and clinically useful with TACE.

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“…This implies a relationship where increased tumor cell death indicates a more aggressive cancer. Tumor microvessels are fragile and susceptible to hypoxia, which suggests that the degree of tumor necrosis re ects the level of intratumoral hypoxia [13,14,27,28]. Measured experimentally with a polarographic needle, intratumoral hypoxia correlates with poor prognosis and sensitivity to radiotherapy and chemotherapy in solid tumors [13].…”

Section: Discussionmentioning

confidence: 99%

Tumor necrosis as a poor prognostic predictor on postoperative survival of patients with solitary small hepatocellular carcinoma

Ling

Chen

Wen

et al. 2020

Preprint

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Abstract Background: Small hepatocellular carcinoma (sHCC) is a special subtype of HCC with the maximum tumor diameter ≤ 3 cm and favorable long-term outcomes. Surgical resection or radiofrequency ablation offer the greatest chance for cure; however, many patients still undergo tumor recurrence after primary treatment. So far, there is no clinical applicable method to assess biological aggressiveness in solitary sHCC. Methods: In the present study, we retrospectively evaluated tumor necrosis of 335 patients with solitary sHCC treated with hepatectomy between December 1998 and 2010 from Sun Yat-sen University Cancer Center. Results: In the current study, the presence of tumor necrosis was observed in 157 of 335 (46.9%). Further correlation analysis showed that the presence of tumor necrosis in sHCC was significantly correlated with tumor size and vascular invasion (P = 0.026, 0.003, respectively). The presence of tumor necrosis was associated closely with poorer cancer-specific overall survival (OS) and recurrence-free survival (RFS) as evidenced by univariate (P < 0.001;hazard ratio, 2.821; 95% CI, 1.643-4.842) and multivariate analysis (P = 0.005; hazard ratio, 2.208; 95% CI, 1.272-3.833). More importantly, the combined model by tumor necrosis, vascular invasion and tumor size can significantly stratify the risk for RFS and OS and improve the ability to discriminate sHCC patients’ outcomes (P < 0.0001 for both). Conclusions: Our findings provide evidence that tumor necrosis has the potential to be a parameter for cancer aggressiveness in solitary sHCC. The combined prognostic model may be a useful tool for identifying solitary sHCC patients with worse outcomes.

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Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization

Cited by 61 publications

References 32 publications

Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Metformin attenuates hypoxia‑induced resistance to cisplatin in the HepG2 cell line

Tumor necrosis as a poor prognostic predictor on postoperative survival of patients with solitary small hepatocellular carcinoma

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