ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.
ABSTRACT
BACKGROUND: Inverted papillomas are primarily benign neoplasms that occur in the nasal cavity and paranasal sinuses. Many aspects of sinonasal inverted papillomas are still controversial and active fields of research. Inverted papillomas generate considerable interest because they are locally aggressive, have a propensity to recur and are associated with malignancy. However, neither the etiology and pathogenesis of these tumors nor the putative role as a precursor to carcinoma and the factors responsible for associated malignancy have been clarified. Whether carcinomas in inverted papillomas arise meta- or synchronous is also still unknown. PATIENTS AND METHODS: In a retrospective study we reviewed the charts of 93 patients with sinonasal inverted papillomas who were treated at our department between 1990 and 2007. Comparison was made between the group of patients with inverted papillomas and associated squamous cell carcinomas and the group of patients with benign inverted papillomas. We undertook a critical analysis of our results compared with the international medical literature. RESULTS: Associated malignancy was found in 11 patients (11.8 %). In each one case a metachronous carcinoma with and without recurrent inverted papilloma was diagnosed, the remaining 9 carcinomas were determined to be synchronous malignancies. Our data suggest, that the association between carcinoma and inverted papilloma is indirect and that the gradual progression from inverted papilloma to a malignant neoplasm is if at all infrequent. Male gender, advanced age and recurrent inverted papilloma do not per se present risk factors for the development of associated malignancies. CONCLUSIONS: Sinonasal carcinomas arise in about 10 % of patients with inverted papillomas, but the ratio of metachronous carcinomas has possibly been overrated up to now. Nevertheless, regular follow-up investigations after surgical resection of inverted papillomas are mandatory. The assumption, that carcinomas in inverted papillomas are less aggressive than carcinomas alone and the definition of high-risk groups for the development of carcinomas seems hazardous.
