Tumor innervation: peripheral nerves take control of the tumor microenvironment
Stefan M. Gysler, Ronny Drapkin
Stefan M. Gysler, Ronny Drapkin
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Review

Tumor innervation: peripheral nerves take control of the tumor microenvironment

Abstract

In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic intervention.

Authors

Stefan M. Gysler, Ronny Drapkin

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Figure 3

Exosomes as intercellular messengers between nerves and the TME.

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Exosomes as intercellular messengers between nerves and the TME. Exosome...
Exosomes are capable of local and distant signaling. They can induce axonogenesis of nerve fibers into the TME and modulate tumor growth. Tumor-derived exosomes (TEX) also influence T cell function within the TME, leading to an immune-suppressive environment. Nerves are also capable of both exosome release and internalization, and thus may also participate in exosome-mediated communication within the TME. TEX have been implicated in developing the metastatic niche; however, it is not yet known whether altered neural signaling, either locally or via the central nervous system, is in part responsible for promoting the growth of seeded cells into metastatic tumors. Identification of exosome-mediated signaling may lead to novel treatments to limit angiogenesis, tumor immunity, metastasis, and cancer pain.