Neutrophils Activate Tumoral CORTACTIN to Enhance Progression of Orohypopharynx Carcinoma

Abstract

CORTACTIN is an actin-binding protein critically involved in cellular migration and invasion. Here, we investigated the role of CORTACTIN in the pathophysiology of orohypopharynx carcinoma – one of the major subtypes of head and neck cancer. To this end, we analyzed CORTACTIN expression in tumor tissues from 89 orohypopharynx carcinoma patients in relation to clinical parameters. We found that high tumoral CORTACTIN expression associated with poor survival, higher T-stage, and higher lymph node metastasis (N-stage) in these patients. Next, we combined the prognostic values of tumoral and stromal cell biological parameters in our patient cohort. We determined the potential interaction of tumoral CORTACTIN with tumor-infiltrating neutrophils, which have been previously linked to poor clinical outcome in orohypopharynx carcinoma patients with advanced disease. Interestingly, we found that patients with both high tumoral CORTACTIN expression and high neutrophilic infiltration had significantly worse clinical outcome than all other patients in our cohort. These findings suggest that tumoral CORTACTIN and tumor-infiltrating neutrophils might be functionally linked during progression of orohypopharynx carcinoma. In vitro, we showed that neutrophils released soluble factors which phosphorylated CORTACTIN in the tumor cells and promoted their migration. Furthermore, we demonstrated that strong CORTACTIN phosphorylation significantly correlated with strong neutrophilic infiltration in tumor tissues from orohypopharynx carcinoma patients. Taken together, our findings unravel a novel mechanism of tumor-stroma interaction, which might be relevant for a more accurate prognosis and improved therapeutic strategies in this tumor entity.

Neutrophils Increase Oral Squamous Cell Carcinoma Invasion through an Invadopodia-Dependent Pathway

“…Cortactin is required for invadopodia formation (33), and it converges different pathways leading to cancer invasion. The increase in cortactin phosphorylation reported here is similar to earlier observations by Dumitru and colleagues (16) in oropharyngeal cancers. The changes in matrix degradation induced by neutrophils are not as robust as the overall changes in invasion observed in the Transwell assays or invadopodia formation.…”

“…They also observed an increase in expression of MMP9 and CCL4 by CD66b-positive cells in human tumor sections (15). In a follow-up publication, Dumitru and colleagues (16) have shown that neutrophils increased cortactin phosphorylation in squamous cell carcinomas, promoting cancer migration. This finding is particularly important because metastatic spread is associated with the formation of specialized subcellular structures regulated by cortactin phosphorylation called invadopodia (17,18).…”

“…Maturation of invadopodia requires the phosphorylation of cortactin at residues 421 and 466 by a kinase cascade including Src and Arg tyrosine kinases downstream of EGFR (23). A recent report shows that neutrophils induce cortactin phosphorylation in oropharyngeal carcinoma cells (16). Considering the current evidence and our observation that neutrophils increase the number of invadopodia, we tested the effects of neutrophils on cortactin phosphorylation.…”

Integrated Omic Analysis of Oropharyngeal Carcinomas Reveals Human Papillomavirus (HPV)–dependent Regulation of the Activator Protein 1 (AP-1) Pathway

“…It was not possible to assess the independent prognostic utility of cortactin in a multivariate model for OS or DFS given the small number of events in the present cohort. Nonetheless, our findings validate the reported association of cortactin with OPC patient outcome in a univariate analysis model (37).…”

“…In accordance with our findings, high tumor CTTN expression has been shown to correlate with increased aggressiveness and poor outcome in many cancers, but most frequently in HNSCC (37,45). A recent pre-clinical study reported tumor radiosensitization via abrogation of the ␤1-integrin/FAK/cortactin/JNK1 signaling axis by administration of an anti-␤1-integrin antibody in vitro and in vivo, making this pathway a therapeutically attractive target for investigation in OPC (35).…”