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Serum Protein Kinase C Delta: New Kid on the Block for Early Detection of Hepatocellular Carcinoma

  • Jaideep Behari
    Correspondence
    Correspondence: Address correspondence to: Jaideep Behari, MD, PhD, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Kaufmann Medical Building; Suite 201, Pittsburgh, PA 15213.
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

    Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania

    Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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Open AccessPublished:November 03, 2022DOI:https://doi.org/10.1016/j.gastha.2022.10.014
      Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths in the world.
      • Mortality G.B.D.
      Causes of Death C. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      Age-standardized incidence rates of HCC are highest in Asia and Africa; however, both incidence and mortality are rapidly rising in the United States and Europe due to a shift in epidemiology of HCC from viral hepatitis to nonalcoholic fatty liver disease–related cancer.
      • Singal A.G.
      • Lampertico P.
      • Nahon P.
      Epidemiology and surveillance for hepatocellular carcinoma: New trends.
      Given the dual clinical challenges of detection at late stages and the high incidence-to-mortality ratio of HCC,
      • Akinyemiju T.
      • Abera S.
      • et al.
      Global Burden of Disease Liver Cancer Collaboration
      The Burden of primary liver cancer and Underlying Etiologies from 1990 to 2015 at the Global, regional, and national level: Results from the Global Burden of disease study 2015.
      major hepatology societies have recommended abdominal ultrasound with or without alpha fetoprotein (AFP) as the primary HCC surveillance strategy for at-risk patients.
      • Kim T.H.
      • Kim S.Y.
      • Tang A.
      • et al.
      Comparison of international guidelines for noninvasive diagnosis of hepatocellular carcinoma: 2018 update.
      However, ultrasound suffers from low sensitivity for detecting early-stage HCC, with factors such as operator experience and patient factors, such as obesity, decreasing its diagnostic accuracy.
      • Tzartzeva K.
      • Obi J.
      • Rich N.E.
      • et al.
      Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a Meta-analysis.
      • Del Poggio P.
      • Olmi S.
      • Ciccarese F.
      • et al.
      Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis.
      • Simmons O.
      • Fetzer D.T.
      • Yokoo T.
      • et al.
      Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.
      At present, only limited data exist on the cost-effectiveness of other imaging modalities, such as computed tomography and magnetic resonance imaging.
      • Pocha C.
      • Dieperink E.
      • McMaken K.A.
      • et al.
      Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography -- a randomised study.
      ,
      • Kim S.Y.
      • An J.
      • Lim Y.S.
      • et al.
      MRI with liver-specific Contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma.
      Given the limitations of imaging-based strategies, serum-based biomarkers have an important role in HCC surveillance. AFP has been widely used in combination with ultrasound for HCC surveillance. AFP has significant limitations as a biomarker for the detection of HCC due to low specificity when used alone, but combining it with ultrasound improves sensitivity from 45% with ultrasound alone to 63% with ultrasound plus AFP.
      • Tzartzeva K.
      • Obi J.
      • Rich N.E.
      • et al.
      Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a Meta-analysis.
      However, it is obvious that no single serum biomarker may be sufficient due to HCC tumor heterogeneity and the need to predict response to therapy.
      • Johnson P.
      • Zhou Q.
      • Dao D.Y.
      • et al.
      Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma.
      Thus, other serum biomarkers such as des-γ-carboxy prothrombin (DCP), GALAD (gender, age, AFP-L3, AFP, and DCP), and methylated DNA markers panel are being investigated in HCC surveillance strategies.
      • Johnson P.
      • Zhou Q.
      • Dao D.Y.
      • et al.
      Circulating biomarkers in the diagnosis and management of hepatocellular carcinoma.
      • Tayob N.
      • Kanwal F.
      • Alsarraj A.
      • et al.
      The performance of AFP, AFP-3, DCP as biomarkers for detection of hepatocellular carcinoma (HCC): a Phase 3 biomarker study in the United States.
      • Choi J.
      • Kim G.A.
      • Han S.
      • et al.
      Longitudinal Assessment of three serum biomarkers to detect very early-stage hepatocellular carcinoma.
      In this issue of Gastro Hep Advances, Oikawa et al report on the potential of serum protein kinase C delta (PKC-δ) as a novel biomarker for HCC complementary to biomarkers currently used in clinical practice.
      • Oikawa T.
      • Yamada K.
      • Tsubota A.
      • et al.
      Protein kinase C delta is a novel biomarker for hepatocellular carcinoma.
      These investigators previously reported that while PKC-δ is an intracellular serine/threonine kinase, HCC cells secrete PKC-δ into the extracellular space, where it acts as a growth factor for HCC progression, while neither normal hepatocytes nor non-HCC gastrointestinal cancer cells secrete PKC-δ.
      • Yamada K.
      • Oikawa T.
      • Kizawa R.
      • et al.
      Unconventional secretion of PKCdelta Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in liver cancer.
      They also demonstrated that HCC patients had higher serum PKC-δ than patients with a chronic liver disease or healthy controls. Here, they extend their observations on serum PKC-δ in a larger group of patients with a chronic liver disease with or without HCC.
      Serum PKC-δ levels were found to be higher in chronic liver disease patients with HCC than in those without HCC. They also report that in their cohort, the diagnostic performance of PKC-δ was comparable to that of AFP and DCP. However, a particularly intriguing observation is that serum PKC-δ levels were elevated in a subset of patients that were double-negative for AFP/DCP, and serum PKC-δ levels were not correlated with AFP/DCP levels. This finding suggests that serum PKC-δ may detect tumors with distinct biology and serve as a complementary biomarker to the GALAD, which includes both AFP and DCP.
      • Johnson P.J.
      • Pirrie S.J.
      • Cox T.F.
      • et al.
      The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers.
      A second observation that deserves further investigation is that serum PKC-δ performed better than AFP/DCP in detecting very early-stage (solitary and small) tumors.
      Despite the promise serum PKC-δ holds as a biomarker of early-stage HCC, several questions need to be addressed before it can be adopted in clinical practice. First, this study will need to be replicated in a larger, more diverse group of patients. Second, given the rapidly changing epidemiology of HCC from a viral hepatitis-related to nonalcoholic fatty liver disease-related cancer, diagnostic performance of PKC-δ will need validation in subjects with and without coexisting obesity. Third, the role of serum PKC-δ as a complementary test to conventional biomarkers will need validation. Fourth, determining the diagnostic performance of serum PKC-δ levels in combination with abdominal ultrasound will be needed and compared with other emerging biomarker panels such as the GALAD score and circulating cell-free DNA. Fifth, the ability of PKC-δ to identify tumors with distinct biology and/or response to specific treatments will need additional exploration.
      In summary, there is an urgent need to improve surveillance strategies for HCC, a common cancer with increasing incidence and high mortality, as the current strategy consisting of ultrasound with or without AFP has significant limitations. Serum PKC-δ represents a novel biomarker for HCC detection that may prove to be complementary to other serum biomarkers, particularly in cases of AFP/DCP double-negative tumors and in detection of small, early-stage HCC.

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      Linked Article

      • Protein Kinase C Delta Is a Novel Biomarker for Hepatocellular Carcinoma
        Gastro Hep AdvancesVol. 2Issue 1
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          Hepatocellular carcinoma (HCC) is the most common cancer with a poor prognosis. Identification of an alternative biomarker that can detect early-stage and conventional tumor marker-negative HCC is urgently needed. We found that protein kinase C delta (PKCδ) is specifically secreted from HCC cell lines into extracellular space and contributes to tumor development and that its serum levels were elevated in HCC patients. This study aimed to assess the practical usefulness of serum PKCδ for detecting HCC in chronic liver disease (CLD) patients.
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