VGF and Its Receptors in Human Cancers: Molecular Mechanisms, Oncogenic Functions and Clinical Perspectives

Abstract

VGF (nerve growth factor‑inducible; also secretogranin VII/SCG7/SgVII) is a secreted neuroendocrine polyprotein that is induced by nerve growth factor (NGF), brain‑derived neurotrophic factor (BDNF), and other stress and injury signals, then processed by prohormone convertases into multiple bioactive peptides, including TLQP-21, TLQP-62, NERP‑1/2, and others. Although historically studied for energy homeostasis, pain, depression, and neurodegeneration, VGF is increasingly implicated in human malignancies. Functionally, VGF acts through a family of peptide fragments rather than a single VGF receptor: its activity is mediated predominantly by peptide fragments engaging distinct receptors and binding partners - best characterized being TLQP-21 acting on C3AR1-positive myeloid cells, with C1QBP /gC1qR and HSPA8 as candidates, TrkB for TLQP-62, and TGFBR2 in uveal melanoma. Notably, receptor expression is as divergent as receptor identity: across single-cell and pan-cancer analyses, C3AR1 is confined to the myeloid compartment, exemplified by prostate tumors, where it is undetectable in malignant epithelial cells, whereas C1QBP is broadly expressed in tumor, stromal, and immune cells, implying that TLQP-21-based strategies reprogram the myeloid microenvironment rather than target tumor cells directly. In cancer, VGF expression is upregulated in many lineages and associates with neuroendocrine differentiation, EGFR-TKI resistance, epithelial‑mesenchymal transition (EMT), chemoresistance, brain and liver metastatic niche formation, macrophage polarization, and immune infiltration. This review synthesizes VGF molecular biology, its receptor/binding landscape, tumor-specific evidence, prognostic value, and therapeutic strategies including anti-VGF antibodies, TLQP mimetics/antagonists, receptor modulation, and combination targeting with TGF‑β/MAPK/PI3K pathways.