Targeting the Peripheral Nerve Tumor Microenvironment

In addition to their role as central nervous system (CNS) transmitters, neurons direct tissue growth, maintenance, function, and differentiation through electrical and chemical signals. This fundamental biological communication regulates many physiological and disease processes during development, including cancer. The presence of peripheral nerves in malignant tumors was discovered more than a century ago. Subsequent studies have shown that neoplastic neurons promote tumor progression, inhibit tumor-associated pro-inflammatory cytokines, promote neovascularization, facilitate metastasis, and regulate immune depletion and evasion.

Creative Biolabs offers the following related services to help accelerate the progress of your program.

Nerves as Tumor Markers

Cancer cells alter normal neurons, and the role of nerves as potential biomarkers of cancer has been extensively studied. Currently, the only neuronal marker in clinical use is polyneuropathy, nerve injury (PNI). PNI is a poorly characterized feature in a wide variety of tumors and serves as a dichotomous variable (present or absent) in the staging system of several cancers. A recent study has shown that the presence of PNI is an important prognostic factor in oral cancer. Furthermore, the distance between the nerve and the tumor is an important prognostic factor even in patients without PNI. In fact, the shorter the distance from the tumor to the nerve, the worse the overall survival.

In addition to PNI, tumor nerve density in the tumor microenvironment (TME), like immune cell levels in the TME, correlates with tumor characteristics and outcomes. This marker was found to be associated with low recurrence-free survival and increased tumor proliferation in prostate cancer, TP53 mutation status in HNSCC, lymph node metastasis in breast cancer, deeper tumor infiltration in gastric cancer, and lower disease-specific survival in colorectal cancer. Increased normalized nerve density was associated with a poorer prognosis even in patients without PNI. These data support the use of nerve fiber density in TME as a prognostic factor.

In addition, the density of specific neural phenotypes has been investigated as a potential biomarker.

Mechanisms of Neural Action in TME

Peripheral nerves in the TME are involved in a continuous crosstalk that generates functional microcirculation between nerves, cancer cells and other TME components. These physiological mechanisms, including PNS regulation of pluripotent cell (e.g., cells in the basal layer of the skin) fate, fibroblast activity, and immune cell infiltration, play a crucial role in TME homeostasis and may be hijacked by cancer.

Targeting PNS in Tumors

Nerves in the tumor TME have distinct functions that affect both cancer cells and cells in the TME by regulating known cancer-related pathways. Targeting upstream neuronal signaling may provide a safer way to simultaneously modulate multiple key cancer pathways than directly targeting intracellular signaling processes in the TME. Such upstream inhibition may not only be safer but also help overcome resistance to targeted therapies.

The understanding of the complex interactions between the nervous and immune systems and cancer is now growing, and scientists have recognized the powerful ability of cancer cells to hijack neuronal signals and suppress the immune system. There is now an urgent need to further unravel the specific interactions between various tumor types and the nervous and immune systems, as well as the important roles played by different branches of the nervous system in cancer biology and various tumor types. This will enable us to discover new ways to develop cancer therapies.

Reference

1. Yaniv, Dan, et al. "Targeting the peripheral neural-tumour microenvironment for cancer therapy." Nature Reviews Drug Discovery (2024): 1-17.