Midkine: A Promising Target for Cancer Therapy

Midkine (MK) is a heparin-interacting growth factor or cytokine. MK flies through tissues throughout embryonic development of the individual and is downregulated in adults.MK is released in a high concentration during mid-pregnancy and is involved in the growth of pregnancy. MK promotes the growth, survival, migration, cytokine production, differentiation, and more of the target cells. MK is involved in several physiologic functions including development, reproduction, and repair, and it is involved in the onset of inflammatory and malignant disorders.

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Structure of Midkine

MK mainly consists of 2 domains, the N-domain at N-terminus and the C-domain at C-terminus. Both domains are basically three antiparallel -folds. Aside from that, there are short tails on either side of the N-terminus and the C-terminus, and a hinge between the two domains. A dozen membrane proteins have also been referred to as MK receptors: receptor protein tyrosine phosphatase Z1 (PTP), low-density lipoprotein receptor-related protein, integrin, neurocan C, anaplastic lymphoma kinase, and Notch-2.

Fig.1 Schematic diagram of the structure of MK (Takashi M., et al. 2014).

Role of Midkine

MK is also present in a lot of damaged tissues like the brain, blood vessels, kidneys, and heart. Moreover, MK administration also lessens cardiac ischemic injury. MK also takes part in the inflammatory reaction through two functions.

• MK promotes neutrophil and macrophage migration through the direct effects and upregulation of chemokines.
• MK prevents differentiation of regulatory T cells in part by preventing the growth of differentiation-essential tolerogenic dendritic cells.

MK receptors are different and signaling circuitry is multidimensional, and that is what makes MK function different. It can induce the growth, survival, differentiation, and migration of most cell types and also is anti-apoptotic. MK is also antibacterial and one of the members of the natural immune system.

Function of Midkine in Construction and Reproduction

MK functions in development, reproduction, repair, inflammation, innate immunity, hypertension, and angiogenesis. MK is overly expressed during embryogenesis (particularly mid-gestation). MK also becomes heavily expressed at some restricted places in adult tissues. When human tissues are damaged, MK is expressed. MK increases the development and survival of neural progenitor cells, including neural stem cells. MK also encourages embryonic neurons to survive, migrate, and extrude neurites. While it works on neural progenitor cells, MK also boosts primordial germ cell growth and survival.

Cancer Biomarker for Diagnosis and Prognosis

MK is notably high in most diseases (including cancer) and thus can serve as a disease biomarker. Among late-stage tumors, MK is hyperactive and detectable by blood, urine, and tumor test. MK is now a potential molecular target for most conditions, including malignant tumors. As MK is involved in many physiological and pathological processes, MK and drugs that inhibit MK and its signaling system should have utility for a large number of disorders. MK is a potent cancer biomarker because it is present in the most cancerous tissue (eg, for the following cancers).

Fig.2 Implications of MDK in the hallmarks of cancer (Zhang, ZZ., et al. 2021).

Future Perspectives

MK-triggered tumorigenesis relates to cancer cell proliferation, survival, anti-apoptosis, angiogenesis and EMT. MK is a heparin-associated growth factor and cytokine that turned up in many cancers. The greatest clinical value of MK is that it is a soluble cytokine easily detected in the peripheral bloodstream and can be used as a cancer biomarker and a new therapeutic target. MK has already demonstrated that it is an excellent method for cancer detection, control, and treatment, and there are further MDK-based diagnostics on the horizon. Since MDK is abundant in cancer tissues and plays a role in tumourigenesis, it counts as a tumor consensus antigen and looks like a good candidate for cancer vaccines. For patients who have excess MDK in body fluids, MDK vaccines containing peptides, DNA, whole proteins, or viral vectors can be injected.

Clinical Significance of Midkine

We might get better outcomes for patients by someday developing new drugs that disable the newly identified MK signaling pathways or MK-dependent chemoresistance. New MDK inhibitor therapies might work selectively and cytologically, with the greatest efficacy without resistance or relapse.

The clinical value of midkine is not just in cancer prognosticating. Higher midkine levels predict advanced tumor stage, poorer survival, and metastasis in cancer patients. Moreover, midkine expression profiles have promise as diagnostic biomarkers for early cancer surveillance and treatment response monitoring. In short, the complex nature of midkine's involvement in cancer biology makes it a candidate target for treatment and prognostic evaluation.

Conclusion

Midkine is a heparin-responsive growth factor first described as a product of retinoic acid-responsive genes in the womb. Midkine is overexpressed at exogenously high levels in various human cancers, and serves as a mediator of the acquisition of hallmarks of cancer, broadly promising as a cancer biomarker and potential therapeutic target for individualized cancer therapy.

Targeting MK with novel inhibitors is an attractive therapeutic approach, as its inhibition is unlikely to produce systemic deleterious effects. Although further studies are needed, including identification of direct targets of MK, additional structural modifications, and safety validation, MK inhibitors appear to be promising therapeutic targets for the treatment of a variety of cancers. MK may represent a promising molecular target for cancer therapy, and therefore, it is important to explore MK-mediated regulatory mechanisms involved in cancer progression and metastasis.

References

1. Filippou, P., et al. Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target. Oncogene. 2020, 39(10): 2040-2054.
2. Takashi M., et al. Structure and function of midkine as the basis of its pharmacological effects. The British Pharmacological Society. 2014, 171(4): 814-826.
3. Zhang, Z., et al. Midkine: A multifaceted driver of atherosclerosis. Clinica chimica acta. 2021, 521: 251-257.