Identification of a novel therapeutic target for head and neck squamous cell carcinomas: A role for the neurotensin‐neurotensin receptor 1 oncogenic signaling pathway

Abstract

Distant metastasis is a major factor associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), but little is known of its molecular mechanisms. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Based on a genomewide gene expression analysis using clinical specimens of HNSCC, we narrowed our focus to the analysis of the neurotensin (NTS) and neurotensin receptor 1 (NTSR1) oncogenic signal pathways. Kaplan-Meier curves and log rank tests revealed that high mRNA expression levels of NTS and NTSR1 had a significant adverse effect on metastasis-free survival rate, suggesting a contribution of this pathway in HNSCC cancer progression. In HNSCC cells, which expressed NTSR1, a NTS agonist promoted cellular invasion, migration and induction of several mRNAs, such as interleukin 8 and matrix metalloproteinase 1 transcripts. In addition, knock down of NTSR1 expression with small interfering RNAs resulted in reduction of cellular invasion and migration in HNSCC cell lines. Our findings suggest a critical role for the NTS and NTSR1 oncogenic pathways in invasion and migration of HNSCC cells during the metastatic process. Our study raises the possibility that NTS and NTSR1 could be a useful predictive marker of poor prognosis in patients with HNSCC and a molecular therapeutic target in antimetastatic strategies for HNSCCs. ' 2008 Wiley-Liss, Inc.Key words: head and neck squamous cell carcinomas; microarray; neurotensin; neurotensin receptor 1 Head and neck squamous cell carcinomas (HNSCC) represent 6% of all cancers. 1 Despite of considerable advances in surgery, radiotherapy and chemotherapy, the overall 5-year survival rate for patients with this type of cancer is among the lowest of all major cancer types and has not improved dramatically during the last decade. Local tumor recurrence and distant metastasis after conventional therapy appear to be major contributing factors for restricted survival of HNSCC patients. 1 In particular, distant metastasis represents a major challenge in the therapeutic management of cancer patients. About 60% of patients have microscopic or clinically evident metastases at the time of diagnosis of primary tumors. 2 It is likely that the metastatic rate will be higher in HNSCC because many patients are at an advanced stage of the disease by the time of diagnosis and treatment. Currently, systemic chemotherapy is the major mode of treatment of metastatic diseases. However, this treatment is usually palliative, but not curative in part due to the poor response of metastatic tumors to chemotherapy. 3,4 Thus, identification of prognostic markers and effective treatment regimens for metastasis are urgently needed. Over the past decade, research effort on metastatic disease has been focused on the biological processes that influence establishment of metastases. It has been well established that tumor metastasis is a complex, multistep process that requires migration, invasion and angiogenes...

Neurotensin Receptor 1 Determines the Outcome of Non–Small Cell Lung Cancer

“…We had previously shown the presence of a chronic self-activation loop between neurotensin and NTSR1, as one mechanism responsible for the constitutive activation of the mitogen-activated protein kinase mitogenic signaling pathways along with sustained target gene activation (17)(18)(19)(20). More recently, NTSR1 expression level was associated with poor prognosis in patients with ductal breast cancer, and similar results have been found in head and neck squamous cell carcinomas (21,22).…”

Targeting Neuropeptide Receptors for Cancer Imaging and Therapy: Perspectives with Bombesin, Neurotensin, and Neuropeptide-Y Receptors

“…This high expression in ductal pancreatic adenocarcinomas offers the molecular basis for neurotensin receptor scintigraphy for early tumor diagnosis, as well as a rationale for treatment strategies with neurotensin receptor antagonists and radiolabeled neurotensin analogs (42). In head and neck squamous cell carcinomas, high messenger RNA expression levels of neurotensin and NTSR 1 are associated with a poor metastasis-free survival rate (43). In vitro, neurotensin agonists have been shown to promote cellular invasion, migration, and induction of interleukin 8 and matrix metalloproteinase 1 transcripts (43).…”

“…In head and neck squamous cell carcinomas, high messenger RNA expression levels of neurotensin and NTSR 1 are associated with a poor metastasis-free survival rate (43). In vitro, neurotensin agonists have been shown to promote cellular invasion, migration, and induction of interleukin 8 and matrix metalloproteinase 1 transcripts (43). NTSR 1 is also overexpressed in colorectal carcinoma (44).…”

NTSR1 (neurotensin receptor 1 (high affinity))

“…NTSR1 contributed to cancer cell invasion and migration and is highly expressed in patients with metastasis (Shimizu et al, 2008).…”