Low Transforming Growth Factor-beta Pathway Activity in Cervical Adenocarcinomas

Cervical cancer is the fourth most common cancer in women worldwide. Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the most common histological types, with AC patients having worse prognosis. Over the last two decades, incidence rates of AC have increased, highlighting the importance of further understanding AC tumorigenesis, and the need to investigate new treatment options. The cytokine TGF-beta functions as a tumour suppressor in healthy tissue. However, in tumour cells this suppressive function can be overcome. Therefore there is an increasing interest in using TGF-beta inhibitors in the treatment of cancer. Here, we hypothesize that TGF-beta plays a different role in SCC and AC. Analysis of RNA-seq data from the TCGA, using a TGF-beta response signature, resulted in separate clustering of the two subtypes. We further investigated the expression of TGF-beta-signalling related proteins (T beta R1/2, SMAD4, pSMAD2, PAI-1, alpha v beta 6 and MMP2/9) in a cohort of 62 AC patients. Low T beta R2 and SMAD4 expression was associated with worse survival in AC patients and interestingly, high PAI-1 and alpha v beta 6 expression was also correlated with worse survival. Similar correlations of T beta R2, PAI-1 and alpha v beta 6 with clinical parameters were found in previously reported SCC analyses. However, when comparing expression levels between SCC and AC patient samples, pSMAD2, SMAD4, PAI-1 and alpha v beta 6 showed lower expression in AC compared to SCC. Because of the low expression of core T beta R1/2, (p-)SMAD2 and SMAD4 proteins and the correlation with worse prognosis, TGF-beta pathway most likely leads to tumour inhibitory effects in AC and therefore the use of TGF-beta inhibitors would not be recommended. However, given the correlation of PAI-1 and alpha v beta 6 with poor prognosis, the use of TGF- beta inhibitors might be of interest in SCC and in the subsets of AC patients with high expression of these TGF-beta associated proteins.