Serum midkine levels for the diagnosis and assessment of response to interventional therapy in patients with hepatocellular carcinoma

Lin, Zheng; Li, Hailiang; Huang, Jinhua; Shin, Jihoon; Luo, Suxia; Guo, Cheng; Zhao, Yan; Li, Fangkun

doi:10.1016/j.jimed.2020.10.009

Cited by 4 publications

(3 citation statements)

References 22 publications

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“…MDK was also shown to monitor disease progression and response to therapy, as it remains elevated in patients with incompletely treated or recurrent HCC while it drops after curative surgery [9]. Most importantly, though, MDK levels can be used to diagnose early-stage HCC and can even diagnose HCC in patients who have tested negative for AFP [11,42,[44][45][46] (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, MDK was proven to have superior performance compared with AFP in differentiating HCC patients from individuals with liver cirrhosis. Correspondingly, Zheng et al [46] evaluated the clinical importance of serum MDK levels both for HCC diagnosis and the monitoring of treatment efficacy in samples from 84 HCC patients undergoing minimally invasive interventional therapy. Results showed a correlation between MDK and several clinical characteristics, such as tumor number and size, vascular invasion, and clinical stage, specifically evident in midto-late-stage HCC.…”

Section: Mdk's Potential As a Biomarker For Hcc Diagnosis And Progres...mentioning

confidence: 99%

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Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

Christou,

Stylianou,

Gkretsi

2024

Cells

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Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.

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Section: Discussionmentioning

confidence: 99%

Section: Mdk's Potential As a Biomarker For Hcc Diagnosis And Progres...mentioning

confidence: 99%

Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

Christou,

Stylianou,

Gkretsi

2024

Cells

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“…Nevertheless, its expression has not been demonstrated in the developing human cerebellum. On the other hand, alterations in PTN are related to tumor cell proliferation and prognosis of neoplasms, such as glioblastoma, testicular germ cell neoplasms, and hepatocellular carcinoma [ 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Pleiotrophin and the Expression of Its Receptors during Development of the Human Cerebellar Cortex

Santana-Bejarano,

Grosso-Martínez,

Puebla-Mora

et al. 2023

Cells

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During embryonic and fetal development, the cerebellum undergoes several histological changes that require a specific microenvironment. Pleiotrophin (PTN) has been related to cerebral and cerebellar cortex ontogenesis in different species. PTN signaling includes PTPRZ1, ALK, and NRP-1 receptors, which are implicated in cell differentiation, migration, and proliferation. However, its involvement in human cerebellar development has not been described so far. Therefore, we investigated whether PTN and its receptors were expressed in the human cerebellar cortex during fetal and early neonatal development. The expression profile of PTN and its receptors was analyzed using an immunohistochemical method. PTN, PTPRZ1, and NRP-1 were expressed from week 17 to the postnatal stage, with variable expression among granule cell precursors, glial cells, and Purkinje cells. ALK was only expressed during week 31. These results suggest that, in the fetal and neonatal human cerebellum, PTN is involved in cell communication through granule cell precursors, Bergmann glia, and Purkinje cells via PTPRZ1, NRP-1, and ALK signaling. This communication could be involved in cell proliferation and cellular migration. Overall, the present study represents the first characterization of PTN, PTPRZ1, ALK, and NRP-1 expression in human tissues, suggesting their involvement in cerebellar cortex development.

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Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration

Ding

Wang

et al. 2023

Cell Death Discov.

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Sorafenib, a multiple-target tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but provides limited benefits. Emerging evidences suggest that prolonged sorafenib treatment induces an immunosuppressive HCC microenvironment, but the underling mechanism is undetermined. In the present study, the potential function of midkine, a heparin-binding growth factor/cytokine, was evaluated in sorafenib-treated HCC tumors. Infiltrating immune cells of orthotopic HCC tumors were measured by flow cytometry. Differentially expressed genes in sorafenib-treated HCC tumors were evaluated by transcriptome RNA sequencing. The potential function of midkine were evaluated by western blot, T cell suppression assay, immunohistochemistry (IHC) staining and tumor xenograft model. We found that sorafenib treatment increased intratumoral hypoxia and altered HCC microenvironment towards an immune-resistant state in orthotopic HCC tumors. Sorafenib treatment promoted midkine expression and secretion by HCC cells. Moreover, forced midkine expression stimulated immunosuppressive myeloid-derived suppressor cells (MDSCs) accumulation in HCC microenvironment, while knockdown of midkine exhibited opposite effects. Furthermore, midkine overexpression promoted CD11b+CD33+HLA-DR− MDSCs expansion from human PBMCs, while midkine depletion suppressed this effect. PD-1 blockade showed no obvious inhibition on tumor growth of sorafenib-treated HCC tumors, but the inhibitory effect was greatly enhanced by midkine knockdown. Besides, midkine overexpression promoted multiple pathways activation and IL-10 production by MDSCs. Our data elucidated a novel role of midkine in the immunosuppressive microenvironment of sorafenib-treated HCC tumors. Mikdine might be a potential target for the combination of anti-PD-1 immunotherapy in HCC patients.

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Serum midkine levels for the diagnosis and assessment of response to interventional therapy in patients with hepatocellular carcinoma

Cited by 4 publications

References 22 publications

Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker

Pleiotrophin and the Expression of Its Receptors during Development of the Human Cerebellar Cortex

Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration

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