Intratumor Heterogeneity in Hepatocellular Carcinoma

Friemel, Juliane; Rechsteiner, Markus; Frick, Lukas; Böhm, Friederike; Struckmann, Kirsten; Egger, Michèle; Moch, Holger; Heikenwälder, Mathias; Weber, Achim

doi:10.1158/1078-0432.ccr-14-0122

Cited by 264 publications

(217 citation statements)

References 42 publications

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“…Results indicated that heterogeneity of PTPRS expression within individual tumor was 16.7% (2 of 12), similar to the low heterogeneity status of TP53 mutation in HCC. 29 …”

Section: Heterogeneity Of Ptprs Expression In Hccmentioning

confidence: 99%

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

et al. 2015

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Hepatocellular carcinoma (HCC) is the third-most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly down-regulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, such as larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type, but not mutant, PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, whereas knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition (EMT). Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis-inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways reinhibits EMT and metastasis caused by PTPRS down-regulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a demethylation agent, 5-aza-2 0 -deoxycytidine, recovers PTPRS expression in a dose-dependent manner. Conclusions: Epigenetic inactivation of PTPRS may increase phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC. (HEPATOLOGY 2015;62:1201-1214 H epatocellular carcinoma (HCC), epidemic to Asia and Africa with an increasing incidence in Western countries, is the third-leading cause of cancer-related deaths worldwide.1 Less than 30% of HCCs are diagnosed at an early stage and are amenable for resection, liver transplantation, or local ablation.2 In advanced cases, the only effective systemic therapy is the multikinase inhibitor, sorafenib, with a partial response of only 2.2% and median overall survival (OS) of 9.2 months.3 Apart from sorafenib, several novel targeted agents or regimens have been tested; however, none of them showed any positive results, mandating alternative effective treatments.4 Therefore, understanding of the driving events of HCC progression and metastasis is of

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“…Results indicated that heterogeneity of PTPRS expression within individual tumor was 16.7% (2 of 12), similar to the low heterogeneity status of TP53 mutation in HCC. 29 …”

Section: Heterogeneity Of Ptprs Expression In Hccmentioning

confidence: 99%

Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor–induced epithelial‐mesenchymal transition

et al. 2015

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“…Further research into tumor biology and biochemistry might provide clues as to why some tumors might respond better than others, and coupled with continued treatment development might make more significant breakthroughs for the treatment of HCC. Intratumoral heterogeneity of HCC has already been described, particularly in large HCCs and is implicated with tumor behavior such as an early tumor recurrence in certain subgroup [15,16]. Improved targeted therapies, combined with effective viral suppression with antiviral therapy, might significantly affect the prognosis of patients with HCC associated with chronic hepatitis B.…”

Section: Discussionmentioning

confidence: 99%

A case of advanced hepatocellular carcinoma cured with antiviral therapy and sorafenib

Krawitz¹,

Guglielmo²,

Hann³

2016

Integr Cancer Sci Therap

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Hepatocellular carcinoma (HCC) continues to be a devastating complication of chronic hepatitis B virus (HBV) infection. Local ablative therapies for small HCC are successful, but treatment of advanced HCC is severely lacking. Sorafenib is the only current therapy for advanced HCC. However its benefit is limited to a short gain in survival. Recently, studies have shown survival benefit of antiviral therapy for HBV associated HCC. We present a case where a large advanced HCC achieved a cure following combined therapy with sorafenib and anti-HBV drugs. It appears that in addition to sorafenib, continuous suppression/elimination of the virus with anti-HBV therapy prevented new/recurrent HCC while the remaining tumor was locally ablated.Core tip: In addition to sorafenib to control the existing tumor, antiviral drugs can prevent the development of new or recurrent cancer by suppressing the viral (the hepatocarcinogen) replication. Another point is the patient's attitude and compliance. This patient was determined to receive maximum sorafenib treatment and tolerated the severe side effects and was able to achieve this favorable result.

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“…It is expected that improved patient stratification, as well as combinatorial treatments, might enhance the efficacy of sorafenib. Another challenge for the development of HCC treatment is the substantial degree of tumor heterogeneity, present not only within the tissue, but also on an intra-tumoral level (8).…”

Section: Discussionmentioning

confidence: 99%