Chemotherapeutic alteration of β-catenin and c-kit expression by imatinib in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro

Abstract

Abstract.The most common neoplasm arising in the upper aerodigestive tract is head and neck squamous cell carcinoma (HNSCC). Tumor growth, invasion and systemic dissemination is a multistep process of dysregulated cellular signaling pathways and an altered cell-cell and cell-matrix interaction. Aberrant Wnt/β-catenin signaling is linked to tumor development and dissemination in several tumor entities. β-catenin is a multifunctional protein within the canonical Wnt pathway, which is an important factor for reducing cell-cell adhesion in malignant tissue and for triggering cell cycle progression and unscheduled proliferation. Another pivotal factor in carcinogenesis is the tyrosine kinase receptor c-kit, which in the case of dysregulated expression is associated with neoplastic transformation in epithelial tissue. This study evaluates the expression pattern of secreted and nuclear β-catenin and c-kit in p16-positive and HPV-negative squamous cell carcinomas (SCC) and the vulnerability of therapy with the tyrosine kinase inhibitor imatinib as a potential targeted treatment modality compared to platinum-based chemotherapeutic drugs. The different squamous tumor cell lines were incubated with increasing concentrations of carboplatin (3 or 7.5 µmol/ml) and imatinib (18 or 30 µmol/ml). ELISA and immunohistochemical methods were carried out after 48, 72, 120, 192 and 240 h. We detected a reliable trend towards significantly decreased cytosolic and nuclear β-catenin and c-kit expression levels in p16-positive SCC and non-HPV HNSCC cells induced by imatinib exposure for an extended incubation period, whereas platinum-based agents had no or, at best, a slight influence. Virus-transformed squamous cell carcinoma (CERV196) cells were characterized by a reduced susceptibility to an imatinibaltered β-catenin expression. Further studies are planned to investigate this observance in HPV-positive HNSCC in vitro. The implementation of a selective molecular therapy in established chemotherapeutic regimes may enhance the efficacy of platinum-based chemotherapy without increased toxicity and could thus improve the clinical outcome in HNSCC, irrespective of the HPV status. IntroductionWith a global annual incidence of ~644,000 cases and 352,000 associated deaths, head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide (1,2). HNSCC is a heterogeneous group, consisting of various tumor entities, which differ greatly in tumor aggressiveness and response to treatment. HNSCC is characterized by local invasiveness and a propensity for dissemination to cervical lymph nodes and systemic metastasis. The poor five-year survival rate has remained unchanged in the last decades despite improved techniques in diagnostics and treatment modalities in surgery, radiation and chemotherapy (3). Therefore, it is urgently necessary to identify new molecular determinants in order to develop innovative therapeutic approaches in HNSCC.Recently there has been increasing awareness about a subset of squamous cell carcinomas (SCCs)...

Targeting Wnt/Beta-Catenin Signaling in HPV-Positive Head and Neck Squamous Cell Carcinoma

“…In the study by Schultz et al [ 29 ], the expression of the Beta-Catenin as well as of the c-kit was assessed in p16-positive, and HPV-negative HNSCC treated with imatinib. However, this study lacks in vitro analyses of the therapeutic potential of the Wnt/Beta-Catenin signaling blockade.…”

Lapatinib-induced mesenchymal-epithelial transition in squamous cell carcinoma cells correlates with unexpected alteration of β-catenin expression

“…In addition, HNSCC presents a high propensity to develop local recurrence following treatment ( 40 ). Concomitant CTR treatment has been previously demonstrated to increase the overall and five-year survival rate of patients with HNSCC at advanced stages, and offer better locoregional control rate ( 29 ). To further improve the survival rates for patients with HNSCC, particularly those presenting with unresectable HNSCC, innovative strategies and targeted therapies must be explored ( 41 ).…”

“…Previous studies have suggested that the multifunctional protein β-catenin is one of the most important factors for reducing cell-cell interactions in malignant epithelial cells ( 28 , 29 ). However, previous studies have reported that β-catenin participates in the development of HN cancer via a nuclear downstream effector of the canonical wingless-related integration site (WNT)-signalling cascade ( 15 ).…”

Imatinib-associated matrix metalloproteinase suppression in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro

“…The epidemiological, genetic, molecular and clinical profile of HPV-associated HNSCC cells appears to differ from that of tobacco and alcohol-induced HNSCC (non-HPV). HPV-positive oropharyngeal carcinomas are characterized by young age at onset, male predominance, and strong association with sexual behaviour (11,12). Kreimer and colleagues (13) analysed study locations and found that HPV prevalence of oral SCCs was similar in Europe (16.0%) and North America (16.1%) but significantly greater in Asia (33.0%).…”

“…The expression of E6 and E7 inhibits two tumoursuppressor proteins: p53 and retinoblastoma protein (pRb). The loss of several key regulative proteins activates dedifferentiation, proliferation and cell cycle progression of HPV-infected epithelial cells and facilitates induction of the transformed phenotype (12,16). Loss of cell adhesion and transformation of epithelial cells to a mesenchymal phenotype is described as epithelialmesenchymal transition (EMT).…”