Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype

Abstract Background: The translational interest in the intratumoral heterogeneity of hepatocellular carcinoma (HCC) has been increasing. The dismal prognosis of this pathology is linked to the features of the HCC harbouring cancer stem cell (CSC), represented by EpCAM-expression. However, the extent of the impact of intratumoral distribution of CSC-features both on the recurrence after curative resection, and on clinical outcome remains unknown. To address this, we investigated the spatial heterogeneity of CSC-features with the aim of identifying the unique HCC patient subgroups amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients who had received liver resection between 2011 and 2017. Tumor specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: (i) negative (E-/-); (ii) heterogeneous (E-/+); and (iii) homogeneous (E+/+). The groups were further analysed with regard to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 314 tumor spots from 69 patients (76.8% male, median age 66 years, liver cirrhosis/fibrosis 75.8). The risk factors were alcohol abuse (26.2%), NASH (13.1%), HBV (15.5%), HCV (17.9%) and others (27.4%), representative of a typical Western cohort. E+/+ patients experienced significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.022; RFS 5 vs. 14 vs. 21 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.031).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present in the cohort. Of note, only homogeneous EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. We identified a unique HCC subtype associated with a high risk of tumor recurrence.

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Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype

10.21203/rs.3.rs-54971/v3 ◽

2020 ◽

Author(s):

Jenny Krause ◽

Johann von Felden ◽

Christian Casar ◽

Thorben W. Fründt ◽

Johanna Galaski ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Spatial Heterogeneity ◽

Early Recurrence ◽

Epcam Expression ◽

Clinical Endpoints ◽

Time To Recurrence ◽

Dismal Prognosis ◽

The Impact ◽

Intratumoral Distribution

Abstract Background: The translational interest in the intratumoral heterogeneity of hepatocellular carcinoma (HCC) has been increasing. The dismal prognosis of this pathology is linked to the features of the HCC harbouring cancer stem cells (CSC), represented by EpCAM-expression. However, the extent of the impact of intratumoral distribution of CSC-features, both on the recurrence after curative resection and on clinical outcome, remains unknown. To address this, we investigated the spatial heterogeneity of CSC-features with the aim of identifying the unique HCC patient subgroups amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients who had received liver resection between 2011 and 2017. Tumor specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: (i) negative (E-/-); (ii) heterogeneous (E-/+); and (iii) homogeneous (E+/+). The groups were further analysed with regard to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 314 tumor spots from 69 patients (76.8% male, median age 66 years, liver cirrhosis/fibrosis 75.8). The risk factors were alcohol abuse (26.2%), NASH (13.1%), HBV (15.5%), HCV (17.9%) and others (27.4%), representative of a typical Western cohort. E+/+ patients experienced significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.022; RFS 5 vs. 14 vs. 21 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.031).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present in the cohort. Of note, only homogeneous EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. We identified a unique HCC subtype associated with a high risk of tumor recurrence.

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Clinical Impact of Intratumoral EpCAM-Positive Cancer Stem Cell Heterogeneity in Patients with Hepatocellular Carcinoma

10.21203/rs.3.rs-54971/v1 ◽

2020 ◽

Author(s):

Jenny Krause ◽

Johann von Felden ◽

Christian Casar ◽

Thorben W. Fründt ◽

Johanna Galaski ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Spatial Heterogeneity ◽

Adjuvant Treatment ◽

Early Recurrence ◽

Epcam Expression ◽

Clinical Endpoints ◽

Time To Recurrence ◽

Dismal Prognosis

Abstract Backgrounds & Aims: Intratumoural heterogeneity of hepatocellular carcinoma (HCC) is of increasing translational interest. Dismal prognosis is frequently linked to HCC harbouring cancer stem cell (CSC)-features, represented by EpCAM-expression. However, to what extent intratumoural distribution of CSC-features impacts on recurrence after curative resection remains unknown. Hence, we aimed to investigate the spatial heterogeneity of CSC-features and its impact on clinical outcome, identifying high-risk patients amenable to adjuvant treatment.Methods: We designed a tissue microarray (TMA) from patients, who received liver resection between 2011 and 2017. Tumour specimens were sampled at multiple locations (n=3-8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: negative (E-/-), heterogeneous-positive (E-/+), homogeneous-positive (E+/+). The groups were further analysed with respect to time-to-recurrence (TTR) and recurrence-free-survival (RFS).Results: We included 341 tumour spots from 75 patients (77% male, median age 66 years, liver cirrhosis/fibrosis 74.6%). Risk factors were alcohol abuse in 23.9%, NASH 16.3%, HBV 14.1%, HCV 17.4% and others 28.3%, representing a typical Western cohort. E+/+ patients experienced a significantly shorter TTR and RFS compared to E+/- (and E-/-) patients (TTR 5 vs. 19 months, p=0.017; RFS 5 vs. 14 vs. 18 months, p=0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (>400 ng/ml, p=0.024).Conclusions: Spatial heterogeneity of EpCAM-expression was markedly present. Only homogeneously positive EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. Similar to colorectal cancer, high or low risk features for recurrence could be decisive for adjuvant treatment.

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Hepatocellular carcinoma: Intratumoral EpCAM-positive cancer stem cell heterogeneity identifies high-risk tumor subtype

BMC Cancer ◽

10.1186/s12885-020-07580-z ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Jenny Krause ◽

Johann von Felden ◽

Christian Casar ◽

Thorben W. Fründt ◽

Johanna Galaski ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Spatial Heterogeneity ◽

Early Recurrence ◽

Epcam Expression ◽

Clinical Endpoints ◽

Time To Recurrence ◽

Dismal Prognosis ◽

The Impact ◽

Intratumoral Distribution

Abstract Background The translational interest in the intratumoral heterogeneity of hepatocellular carcinoma (HCC) has been increasing. The dismal prognosis of this pathology is linked to the features of the HCC harbouring cancer stem cells (CSC), represented by EpCAM-expression. However, the extent of the impact of intratumoral distribution of CSC-features, both on the recurrence after curative resection and on clinical outcome, remains unknown. To address this, we investigated the spatial heterogeneity of CSC-features with the aim of identifying the unique HCC patient subgroups amenable to adjuvant treatment. Methods We designed a tissue microarray (TMA) from patients who had received liver resection between 2011 and 2017. Tumor specimens were sampled at multiple locations (n = 3–8). EpCAM-positivity was assessed for intensity and proportion by applying a score dividing three groups: (i) negative (E−/−); (ii) heterogeneous (E−/+); and (iii) homogeneous (E+/+). The groups were further analysed with regard to time-to-recurrence (TTR) and recurrence-free-survival (RFS). Results We included 314 tumor spots from 69 patients (76.8% male, median age 66, liver cirrhosis/fibrosis 75.8%). The risk factors were alcohol abuse (26.2%), NASH (13.1%), HBV (15.5%), HCV (17.9%) and others (27.4%), representative of a typical Western cohort. E+/+ patients experienced significantly shorter TTR and RFS compared to E+/− and E−/− patients (TTR 5 vs. 19 months, p = 0.022; RFS 5 vs. 14 vs. 21 months, p = 0.016). Only homogeneous EpCAM-positivity correlated with higher AFP levels (> 400 ng/ml, p = 0.031). Conclusions Spatial heterogeneity of EpCAM-expression was markedly present in the cohort. Of note, only homogeneous EpCAM-expression correlated significantly with early recurrence, whereas heterogeneous EpCAM-expression was associated with clinical endpoints comparable to EpCAM-negativity. We identified a unique HCC subtype associated with a high risk of tumor recurrence.

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Increased Expression of Circulating Cancer Stem Cell Markers During the Perioperative Period Predicts Early Recurrence After Curative Resection of Hepatocellular Carcinoma

Annals of Surgical Oncology ◽

10.1245/s10434-015-4480-9 ◽

2015 ◽

Vol 22 (S3) ◽

pp. 1444-1452 ◽

Cited By ~ 17

Author(s):

Gi Hong Choi ◽

Gwang Il Kim ◽

Jeong Eun Yoo ◽

Deuk Chae Na ◽

Dai Hoon Han ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Curative Resection ◽

Perioperative Period ◽

Early Recurrence ◽

Stem Cell Markers ◽

Cell Markers ◽

Cancer Stem Cell Markers

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Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma

World Journal of Gastroenterology ◽

10.3748/wjg.v20.i8.2098 ◽

2014 ◽

Vol 20 (8) ◽

pp. 2098 ◽

Cited By ~ 56

Author(s):

Zhe Guo

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Early Recurrence ◽

Stem Cell Markers ◽

Cell Markers ◽

Cancer Stem Cell Markers

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PTK2 Promotes Hepatocellular Carcinoma Cancer Stem Cell Traits and Tumorigenicity by Activating Wnt/β-Catenin Signaling

SSRN Electronic Journal ◽

10.2139/ssrn.3247872 ◽

2018 ◽

Author(s):

Zhongyi Fan ◽

Jingjing Duan ◽

Lingxiong Wang ◽

Saisong Xiao ◽

Lingling Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell

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An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell–like Behaviors Contributing to Disease Progression

Cancer Research ◽

10.1158/0008-5472.can-15-0291 ◽

2015 ◽

Vol 75 (22) ◽

pp. 4985-4997 ◽

Cited By ~ 62

Author(s):

Hiromitsu Hayashi ◽

Takaaki Higashi ◽

Naomi Yokoyama ◽

Takayoshi Kaida ◽

Keita Sakamoto ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cancer Stem Cell ◽

Disease Progression

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Contrast-enhanced ultrasound–based ultrasomics score: a potential biomarker for predicting early recurrence of hepatocellular carcinoma after resection or ablation

British Journal of Radiology ◽

10.1259/bjr.20210748 ◽

2021 ◽

Author(s):

Hui Huang ◽

Si-min Ruan ◽

Meng-fei Xian ◽

Ming-de Li ◽

Mei-qing Cheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

High Risk ◽

Risk Group ◽

Early Recurrence ◽

High Risk Group ◽

Low Risk ◽

Primary Hepatocellular Carcinoma ◽

Contrast Enhanced Ultrasound ◽

Combined Model ◽

Contrast Enhanced

Objectives: This study aimed to construct a prediction model based on contrast-enhanced ultrasound (CEUS) ultrasomics features and investigate its efficacy in predicting early recurrence (ER) of primary hepatocellular carcinoma (HCC) after resection or ablation. Methods: This study retrospectively included 215 patients with primary HCC, who were divided into a developmental cohort (n = 139) and a test cohort (n = 76). Four representative images—grayscale ultrasound, arterial phase, portal venous phase and delayed phase —were extracted from each CEUS video. Ultrasomics features were extracted from tumoral and peritumoral area inside the region of interest. Logistic-regression was used to establish models, including a tumoral model, a peritumoral model and a combined model with additional clinical risk factors. The performance of the three models in predicting recurrence within 2 years was verified. Results: The combined model performed best in predicting recurrence within 2 years, with an area under the curve (AUC) of 0.845, while the tumoral model had an AUC of 0.810 and the peritumoral model one of 0.808. For prediction of recurrence-free survival, the 2 year cumulative recurrence rate was significant higher in the high-risk group (76.5%) than in the low-risk group (9.5%; p < 0.0001). Conclusion: These CEUS ultrasomics models, especially the combined model, had good efficacy in predicting early recurrence of HCC. The combined model has potential for individual survival assessment for HCC patients undergoing resection or ablation. Advances in knowledge: CEUS ultrasomics had high sensitivity, specificity and PPV in diagnosing early recurrence of HCC, and high efficacy in predicting early recurrence of HCC (AUC > 0.8). The combined model performed better than the tumoral ultrasomics model and peritumoral ultrasomics model in predicting recurrence within 2 years. Recurrence was more likely to occur in the high-risk group than in the low-risk group, with 2-year cumulative recurrence rates respectively 76.5% and 9.5% (p < 0.0001).

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