Nerve Dependence: From Regeneration to Cancer Benoni Boilly, Sam Faulkner, Phillip Jobling, Hubert Hondermarck  Cancer Cell  Volume 31, Issue 3, Pages 342-354 (March 2017) DOI: 10.1016/j.ccell.2017.02.005 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Nerve Dependence in Regeneration and Cancer (A) Many examples of animal regeneration, including but not limited to body and head regeneration in annelid worms, fin and barbel regeneration in fish, and appendage (limb and tail) regeneration in Urodele amphibians are dependent on the presence of nerves. (B) In Urodele amphibians, after a period of about 2 months post amputation, the limb is completely reconstituted and functional (redrawn from Goss, 1969). This regeneration process takes place only if the stump is innervated. (C) After limb amputation, the epidermal cells migrate over the amputation plane and multiply to constitute the epidermal cap. Underneath, mesenchymal cells proliferate to form the blastema. Early on, growing nerve fibers infiltrate the blastema and there are reciprocal interactions between nerves and the blastema. As indicated by the red arrows, surgical denervation of the stump completely prevents regeneration (nerve dependence). (D) In cancer, as demonstrated in prostate and gastric cancer, the innervation of the tumor participates in tumor growth and metastasis. Similarly to the blastema, there are reciprocal interactions between nerves and the tumor, and as indicated by the red arrows, the denervation of the tumor suppresses its growth and metastasis. Cancer Cell 2017 31, 342-354DOI: (10.1016/j.ccell.2017.02.005) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Molecular Mechanisms of Nerve Dependence in Regeneration Versus Cancer (A) In regeneration, nerve infiltration (axonogenesis) in the blastema is driven by the secretion of neurotrophic growth factors (such as FGFs) by mesenchymal progenitor/stem cells and cells from the epidermal cap. Conversely, nerves (including axons and surrounding Schwann cells) liberate mitogenic growth factors (such as nAG and FGFs), morphogens (such as BMP2), and neurotransmitters (such as SP) in the microenvironment of the blastema, resulting in the stimulation of proliferation of both mesenchymal and epidermal cells. Macrophages have also been identified to be necessary to regeneration and the mechanism may involve the release of neurotrophic growth factors to stimulate axonogenesis. Together, the crosstalk between nerves and blastema cells results in the stimulation of growth and morphogenesis. (B) In cancer, nerve infiltration (axonogenesis) in the tumor microenvironment is stimulated by the release of neurotrophic growth factors by cancer cells. Conversely, nerve endings (including axons and surrounding Schwann cells) release neurotransmitters (catecholamines and acetylcholine have mostly been described so far) that can activate the growth of both cancer and stromal cells through the stimulation of specific membrane receptors. Neurotrophic growth factors and neurotransmitters liberated in the tumor microenvironment can also activate stromal, endothelial, and immune cells, and therefore have a stimulatory impact on tumor neo-angiogenesis and inflammation. The crosstalk between nerves, and cancer/stromal cells contributes to tumor growth and metastasis. Cancer Cell 2017 31, 342-354DOI: (10.1016/j.ccell.2017.02.005) Copyright © 2017 Elsevier Inc. Terms and Conditions