Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer

Abstract

Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p = 0.0003). In invasive breast cancers, the presence of nerve fibers was observed in 15% of lymph node negative tumors and 28% of lymph node positive tumors (p = 0.0031), indicating a relationship with the metastatic potential. In addition, there was an association between the presence of nerve fibers and the expression of nerve growth factor (NGF) in cancer cells (p = 0.0001). In vitro, breast cancer cells were able to induce neurite outgrowth in PC12 cells, and this neurotrophic activity was partially inhibited by anti-NGF blocking antibodies. In conclusion, infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves NGF production by cancer cells. The potential participation of nerve fibers in breast cancer progression needs to be further considered.

How Schwann cells facilitate cancer progression in nerves

“…Many of these molecules are implicated in nerve development or nerve repair, which includes nerve growth, cell differentiation, and neuron guidance. The activation of these mechanisms are consistent with the observations of increased nerve growth in pancreatic, prostate and breast cancers [1, 17, 30, 72]. Importantly, some of these molecules not only target nerve cells, but also directly affect cancer cells to stimulate growth or migration.…”

“…Nerve fibers infiltrate tumors in human specimens of pancreatic cancer [29] and invasive breast cancer in human [30]. The infiltration of nerve fibers in tumor has also been observed in mice model of pancreatic cancer [17], prostate cancer [1] and skin cancer [3].…”

“…NGF and its receptors modulate cancer cell growth and expansion in several cancer types. The implication of NGF in the interactions between the nerve cells and the cancer cells has been reported in pancreatic cancer [17, 72, 80] and other types of cancer such as the breast cancer [30]. NGF stimulates axonal growth during neural development and nerve repair.…”

“…NGF and TrkA levels also correlate with the level of PNI in basal cell and cutaneous squamous cell carcinoma [84], oral squamous cell carcinoma [85] and adenoic cystic carcinoma [86]. A high density of nerve fibers and elevated levels of NGF are also observed in breast cancer and are associated with aggressiveness behavior[30]. The increase of NGF expression in tumor compared to control tissue is observed in cancer cells.…”

Disrupted brain network functional dynamics and hyper‐correlation of structural and functional connectome topology in patients with breast cancer prior to treatment

“…Perhaps these processes are also associated with aspects of cancer pathogenesis. Specifically, breast cancer tumors initiate neurogenesis and release nerve growth factor (Cole, Nagaraja, Lutgendorf, Green, & Sood, 2015; Pundavela et al., 2015; Zhao et al., 2014), which may result in aberrant CNS activity via peripheral innervation. Tumor aggressiveness has been associated with tumor‐related neurogenesis (Zhao et al., 2014).…”