Midkine (MDK) as a central regulator of the tumor microenvironment: From developmental cytokine to therapeutic target

Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK/LTK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor…

• UD
  U.S. Department of Veterans Affairs

  Award: VA 1 I01 BX006280-02
• CP
  Cancer Prevention and Research Institute of Texas

  Awards: RP230420, RP230444
• NC
  National Cancer Center
• TT
  Texas Tech University Health Sciences Center
• NI
  National Institutes of Health
• HT
  Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University

  Awards: RP230444, RP230420
• OO
  Office of Faculty Development, Texas Tech University Health Sciences Center El Paso
• NC
  National Cancer Institute

  Awards: R 01 CA266970, R01 CA266970