Journal Article
Neuroinflammation and RAMP1: the Role of the Peripheral and Central Nervous System in Tumor Progression
Pedro Daniel Moumesso Cavalcante; Jonas Lucas Dias da Silva; Laryssa Rosy Santos Oliveira; Rikelly Barbosa da Silva; Juliana Acioli Costa Lima; Guilherme de Brito Souza; Davi Ramon da Silva Santos; Júllia Victória Nascimento de Abrantes; Mateus Lima de Farias; Sofia Amancio de Almeida Oliveira; João Paulo Emiliano da Silva; Rafael de Oliveira Calaça Farias; Leonardo Prudêncio Coutinho de Almeida; Salomão Belfort Sparapan de Melo; Sandra Taveiros de Araújo; Raimundo Rodrigues de França-Júnior; José Emerson Xavier; Carlos Alberto de Carvalho Fraga
Cell Biochemistry and Biophysics · Vol. 84, Issue 2 · pp. 1725-1743 · 2026
Abstract
Calcitonin gene-related peptide (CGRP) and receptor activity modifier protein 1 (RAMP1) form a critical neuroimmunoendocrine axis in the modulation of neuroinflammation, pain, and tumor progression. CGRP, released by sensory and sympathetic fibers, is a potent vasodilator and nociceptive modulator; its action depends on the receptor composed of CALCRL and RAMP1. In the central nervous system, the activation of microglia and astrocytes and the induction of pathways such as NF-κB and MAPK culminate in the production of proinflammatory cytokines (TNF-α, IL-6), differing from systemic inflammation due to the presence of the blood-brain barrier and the glial microenvironment. Preclinical evidence demonstrates RAMP1 expression in neurons, glial cells, endothelium, and macrophages; CGRP/RAMP1 signaling promotes vascular permeability, cytokine release, and angiogenesis, potentially synergizing with VEGF. In animal models and cell cultures, genetic or pharmacological manipulations of the axis reduce tumor angiogenesis, pro-tumor immune infiltration, tumor growth, and nociceptive behavior. Given the clinical availability of CGRP antagonists and monoclonal antibodies, blocking the CGRP/RAMP1 axis is a promising translational strategy for modulating tumor progression and cancer pain. This review summarizes preclinical evidence on mechanisms and therapeutic feasibility. The article includes preclinical and clinical safety and biomarker studies.