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

Signal Transduction and Targeted Therapy 2020年第1期5卷 1584-1606页

作者： Rodolfo Daniel Cervantes-Villagrana Damaris Albores-garcía Alberto Rafael Cervantes-Villagrana sara judit garcía-acevez Department of Pharmacology Center for Research and Advanced Studies of the National Polytechnic Institute(CINVESTAV-IPN)07360 Mexico CityMexico Department of Environmental Health Sciences Florida International University(FIU)MiamiFlorida 33199USA Laboratorio de investigación en Terapéutica Experimental Unidad Académica de Ciencias QuímicasÁrea de Ciencias de la SaludUniversidad Autónoma de Zacatecas(UAZ)ZacatecasMéxico Dirección de Proyectos e Investigación Grupo Diagnóstico Médico Proa06400 CDMX CuauhtémocMéxico

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.

关键词： PD1 therapies invasion

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