Figure 2: Sketch diagram showing interaction between the nerve fibers and tumor cells in the pathogenesis of perineural invasion. Molecules involved in this interaction include the chemokine Fractalkine/Neurotactin (CX3CL1) expressed by neurons and its receptor CX3CR1 on tumor cells and membranebound glycoproteins (SIGLEC-4a) binding to tumor mucins (MUC-1). Neurotropins secreted by neural and tumor cells sustain growth and survival of both intratumoral nerves and cancer cells. Colony stimulating factors (G and GM-CSF) secreted by tumor cells sensitize neural cells expressing their receptors (CSFR), affecting pain perception.