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Review
. 2020 Jun 18;5(1):99.
doi: 10.1038/s41392-020-0205-z.

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Rodolfo Daniel Cervantes-Villagrana  1 , Damaris Albores-García  2 , Alberto Rafael Cervantes-Villagrana  3 , Sara Judit García-Acevez  4
Affiliations
Review

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

Rodolfo Daniel Cervantes-Villagrana et al. Signal Transduct Target Ther. .

Abstract

Normal cells are hijacked by cancer cells forming together heterogeneous tumor masses immersed in aberrant communication circuits that facilitate tumor growth and dissemination. Besides the well characterized angiogenic effect of some tumor-derived factors; others, such as BDNF, recruit peripheral nerves and leukocytes. The neurogenic switch, activated by tumor-derived neurotrophins and extracellular vesicles, attracts adjacent peripheral fibers (autonomic/sensorial) and neural progenitor cells. Strikingly, tumor-associated nerve fibers can guide cancer cell dissemination. Moreover, IL-1β, CCL2, PGE2, among other chemotactic factors, attract natural immunosuppressive cells, including T regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, to the tumor microenvironment. These leukocytes further exacerbate the aberrant communication circuit releasing factors with neurogenic effect. Furthermore, cancer cells directly evade immune surveillance and the antitumoral actions of natural killer cells by activating immunosuppressive mechanisms elicited by heterophilic complexes, joining cancer and immune cells, formed by PD-L1/PD1 and CD80/CTLA-4 plasma membrane proteins. Altogether, nervous and immune cells, together with fibroblasts, endothelial, and bone-marrow-derived cells, promote tumor growth and enhance the metastatic properties of cancer cells. Inspired by the demonstrated, but restricted, power of anti-angiogenic and immune cell-based therapies, preclinical studies are focusing on strategies aimed to inhibit tumor-induced neurogenesis. Here we discuss the potential of anti-neurogenesis and, considering the interplay between nervous and immune systems, we also focus on anti-immunosuppression-based therapies. Small molecules, antibodies and immune cells are being considered as therapeutic agents, aimed to prevent cancer cell communication with neurons and leukocytes, targeting chemotactic and neurotransmitter signaling pathways linked to perineural invasion and metastasis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Oncogenic communication networks link tumor cells with the neuro-immune-vascular systems. Representative communication networks among tumor-associated stroma cells including fibroblasts, immune cells, vascular cells, and neuron fibers. Cell communication is either direct or mediated by cytokines, chemokines, growth factors, and fatty-acid-derived agonists. Tumor cells are positively regulated by the immune system and exhibit mechanisms to evade the antitumoral immune response. Additional communication networks, relevant for tumor vascularization, involve the contribution of fibroblasts, endothelial cells, pericytes and bone-marrow-derived cells including endothelial progenitor cells and Tie2-expressing monocyte/macrophages. Several populations of BMDC are recruited to the tumor microenvironment and niches, where they can differentiate to pro-tumor population as EPC, MDSCs, and macrophage-like cells, among others. Tumor-derived angiogenic factors promote migration and proliferation of adjacent vascular cells and BMDCs to create new vessels, growing with tumors. Central and peripheral nervous systems promote tumor growth, neurons release neurotransmitters with proliferative and migration/invasion properties on stroma and cancer cells. Peripheral nervous fibers (autonomic and sensorial) are attracted by the tumor microenvironment via axonogenesis. Tumor-derived factors recruit neural progenitor cells (NPC) to promote intratumor neurogenesis. The direction/effect arrows indicate potential targets that might be modulated by specific antagonists or agonists. Intratumor sympathetic fibers are associated in early phases of cancer triggering an angiogenic switch via adrenergic signaling. In later phases, parasympathetic fibers contribute to stimulating cancer cells to invasion and metastasis. BMDC bone-marrow-derived cell
Fig. 2
Fig. 2
Oncogenic communication between cancer cells and tumor-associated stroma cells: immunosuppressive and proangiogenic switches. Tumor cells secrete a wide variety of factors that promote the recruitment of different cell types. The immune response evasion occurs by cell–cell interaction through transmembrane proteins as PD-L1/PD-1 and B7/CTLA-4, inhibiting cytotoxic activity. Tumor-derived factors recruit immunosuppressive cells (M2 macrophages, MDSCs, and Tregs) and promote the transition from anti-tumor to pro-tumor cells including M1 to M2 macrophages. Autonomic and sensorial fibers release neurotransmitters and neuropeptides that regulate the immune response. Parasympathetic fibers release acetylcholine, thus inhibiting immune response via nicotinic receptors, while sensorial fibers release substance P and CGRP to activate mast cells and blood vessels. To provide nutrients to the tumor, pro-angiogenic cell communication is required. Release of factors as VEGF, ANG2, CXCL12, and S1P by tumor cells, leukocytes (macrophages and mast cells), and tumor-associated fibroblasts provides an enriched microenvironment proper for tumor vascularization. The insert shows the immunosuppressor switch where in early phase of tumor development cells with anti-tumor functions are recruited, including M1 macrophages and cytotoxic T lymphocyte (CTL); yet they are progressively transformed and attract immunosuppressor and pro-tumor cells. In late phases of cancer these pro-tumor populations are enriched, correlating with high aggressiveness and low survival
Fig. 3
Fig. 3
Axonogenesis is induced by oncogenic communication between cancer cells and adjacent sensorial/autonomic fibers. Tumor-derived neurotrophins (as NGF and BDNF) promote the axonogenic switch of sensorial afferent and autonomic efferent fibers derived of tumor-adjacent nerves. Then, nerve fibers innervating the tumors release factors allowing survival, proliferation, and migration of cancer cells. The autonomic fibers innervating the tumor release noradrenaline and acetylcholine, providing a direct stimulus to receptors expressed in cancer cells. Tumor-derived factors stimulate sensory fibers triggering pain, and the antidromic signals promote neuropeptides release (as SP) into the tumor, activating NK1 in cancer cells and leading to growth factor receptor transactivation via Src (EGFR, HER2). The insert shows the contribution of sympathetic and parasympathetic fibers during cancer progression. Sympathetic neurons contribute highly in early phases, the sympathetic fiber-derived noradrenaline activates an angiogenic switch in endothelial cells, promoting neoplastic development. As the contribution of sympathetic signaling decreases, there is a robust contribution of parasympathetic fibers in late phases inducing proliferation, invasion, and metastasis
Fig. 4
Fig. 4
Tumor neurogenesis and perineural invasion, close and distant communication between cancer cells and neurons. In perineural invasion, cancer cells migrate in response to different mediators released by autonomic and sensory fibers. Also, tumor cells secrete CCL2 and CSF-1 to accumulate endoneurial macrophages and, at the same time, release factors that stimulate perineural invasion. Cancer stem cells have the faculty to differentiate and acquire an autonomic neuron-like phenotype generating tumor-derived neurogenesis. Also, neurons and Schwann cells release GRFα1 and GDNF (secreted by the endoneurial macrophages), activating RET in tumor cells. Besides, Schwann cells release TGFβ, increasing the aggressiveness of cancer cells through TGFβ-RI. Schwann cells drive perineural invasion, cancer cells interact directly with Schwann cells via NCAM1 to invade and migrate along nerves. Tumor-derived neurogenesis occurs when cancer stem cells differentiate to neuron-like cells, particularly to autonomic neurons that release neurotransmitters to enrich the tumor microenvironment. Tumor-induced neurogenesis is characterized by the recruitment of neural progenitor cells (NPC)-derived from the central nervous system (CNS), particularly from the subventricular zone (SVZ). NPCs travel through the bloodstream attracted by tumor-derived factors, once they infiltrate and colonize the tumor, they differentiate into functional autonomic neurons that stimulate tumor growth. DRG dorsal root ganglion, SVZ subventricular zone, CNS central nervous system, NCAM1 neural cell adhesion molecule 1, ACh acetylcholine, NA noradrenaline, SDF-1 stromal derived factor, TH tyrosine hydroxylase, VAChT vesicular acetylcholine transporter, BDNF brain-derived neurotrophic factor, CCL2 chemokine (C–C motif) ligand 2, CSC cancer stem cell, NPC neural progenitor cell
Fig. 5
Fig. 5
Glutamate, GABA, and dopamine contribution to cancer progression. a Glutamate stimulates tumor cell proliferation and survival via metabotropic (mGluR3, mGluR1) and ionotropic (NMDAR and AMPAR) receptors; particularly, mGluR1 overexpression drives melanoma. Direct effects of dopamine and GABA on cancer cells promote survival and proliferation via D1/5 and GABAB receptors, respectively. Glutamate release is increased in glioma cells. Dopamine induces survival and proliferation of cancer stem cells (CSC) via D2 receptor, anti-psychotic drugs decrease the CSC population. b Metastatic brain cells from breast cancer acquire GABAergic properties to take advantage of GABA and glutamate neurotransmitters sustaining their metabolism and survival. GABA and glutamate are uptaken by GAT and EAAT2, respectively, in metastatic cells; the neurotransmitters are metabolized. In addition, GABA receptor activation in cancer cells promotes metastasis. Blockers for GABA (GAT) and glutamate (EAAT2) transporters and GABA antagonist could inhibit the survival and proliferation of metastatic cancer cells
Fig. 6
Fig. 6
Positive regulation among cancer cells, leukocytes, and neurons to cancer progression. Cancer cells release neurotrophins and extracellular vesicles to activate the neurogenic/axonogenic switch and release chemotactic factors while expressing ligands in the membrane to recruit and activate the immunosuppressor switch in the tumor microenvironment for reciprocally stimulate the cancer cells and the angiogenic process. Cancer-associated nerves release peptides (sensorial fibers) and neurotransmitter as NA or ACh (autonomic fibers) stimulating proliferation and migration of cancer cells, but they also recruit and activate immunosuppressor leukocytes as M2-macrophages and MDSCs. Leukocytes release pain mediators and stimulate to nerves, but also release neurotrophins, inducing tumor innervation. Protumor factors are released by leukocyte populations promoting cancer cell proliferation, migration, and metastasis. Joint of cells activate the angiogenic switch, via angiogenic growth factors released by cancer cells and leukocytes as mast cells or M2 macrophages, and by sympathetic-derived noradrenaline. NA noradrenaline, ACh acetylcholine, VEGF vascular endothelial growth factor, BDNF brain-derived neurotrophic factor, SDF-1 Sema4D: semaphorin 4D, Sema4F semaphorin 4F, PGE2 prostaglandin E2. EV extracellular vesicles
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