Nerve Growth Factor Links Oral Cancer Progression, Pain, and Cachexia

Abstract

Cancers often cause excruciating pain and rapid weight loss, severely reducing quality of life in cancer patients. Cancer-induced pain and cachexia are often studied and treated independently, although both symptoms are strongly linked with chronic inflammation and sustained production of pro-inflammatory cytokines. Since nerve growth factor (NGF) plays a cardinal role in inflammation, and pain, and because it interacts with multiple pro-inflammatory cytokines, we hypothesized that NGF acts as a key endogenous molecule involved in the orchestration of cancer-related inflammation. NGF might be a molecule common to the mechanisms responsible for clinically distinctive cancer symptoms such as pain and cachexia as well as cancer progression. Here we reported that NGF was highly elevated in human oral squamous cell carcinoma tumors and cell cultures. Using two validated mouse cancer models, we further demonstrated that NGF blockade decreased tumor proliferation, nociception, and weight loss by orchestrating pro-inflammatory cytokines and leptin production. NGF blockade also decreased expression levels of nociceptive receptors TRPV1, TRPA1, and PAR-2. Together, these results identified NGF as a common link among proliferation, pain, and cachexia in oral cancer. Anti-NGF could be an important mechanism-based therapy for oral cancer and its related symptoms.

Leptin acts on neoplastic behavior and expression levels of genes related to hypoxia, angiogenesis, and invasiveness in oral squamous cell carcinoma

“…Increased plasma levels of leptin were identified in patients with oral premalignant lesions but not in head and neck squamous cell carcinoma (HNSCC) patients. 14,16 Significant reduction in leptin levels in OSCC patients was previously observed, and it was correlated with weight loss and cachexia status, 15,16,19 but there are controversies about this fact in the literature. 21 Our results suggested a possible involvement of serum leptin as well tissue protein expression and LepR mRNA in OSCC.…”

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review

“…The pain mechanism in oral cancer can be established by association with perineural involvement, with invasion and proliferation of a cancer occurring within a nerve associated with pain. 56,57 Higher NGF levels were found in cancer tissues from oral cancer patients. 57 Angiogenesis is a crucial step in the processes of uncontrolled tumor proliferation and metastasis, and inhibiting angiogenesis is considered to be effective for treating oral cancer.…”

“…56,57 Higher NGF levels were found in cancer tissues from oral cancer patients. 57 Angiogenesis is a crucial step in the processes of uncontrolled tumor proliferation and metastasis, and inhibiting angiogenesis is considered to be effective for treating oral cancer. Vascular endothelial growth factor (VEGF) is thought to be an important angiogenic factor, 58 and studies have shown that OSCC is associated with an elevated VEGF concentration in the serum.…”

Pain Management in Lung Cancer

“…Furthermore, tumors growing in the vicinity of peripheral nerves can compromise the integrity of the nerve, inducing a neuropathic condition accompanied by persistent pain, hyperalgesia, or allodynia [29]. Other mediators that have been studied to be involved in the cancer-related pain are nerve growth hormone [30,31], bradykinin [32−34], endothelin-1 [35,36], proteases-activated receptor 2 (PAR2) [37,38], proton and acid-sensing receptor [39,40]. Carriers of the specific IL-6 (i.e.…”