Toll-like receptors (TLRs) mediate interactions between environmental stimuli and innate immunity. TLRs play a major role in the development of numerous pancreatic diseases, making these molecules attractive as potential therapeutic targets. TLR2, TLR7 and TLR9 are involved in the initiation of type 1 diabetes mellitus (T1DM), whereas TLR2 and TLR4 play a major role in the onset of type 2 diabetes mellitus (T2DM). Furthermore, TLRs cause derangements in several tumor suppressor proteins (such as p16, p21, p27, p53 and pRb), induce STAT3 activation and promote epithelial-mesenchymal transition as well as oncogene-induced senescence. In this review we will focus on the contribution of TLRs in pancreatic disease including cancer and we describe recent progress in TLR-modulation for the treatment of these patients.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in women (7%) and the sixth in men (5%) in Italy, with a life expectancy of around 5% at 5 years. From 2010, the Italian Association of Medical Oncology (AIOM) developed national guidelines for several cancers. In this report, we report a summary of clinical recommendations of diagnosis, treatment and follow-up of PDAC, which may guide physicians in their current practice. A panel of AIOM experts in upper gastrointestinal cancer malignancies discussed the available scientific evidence supporting the clinical recommendations.

Clinical observations suggested that a non negligible proportion of patients, ranging from 40% to 70%, does not seem to benefit from the use of anti-EGFR targeted antibodies even in the absence of a mutation of the K- RAS gene. The EGFR pathway activation via the Ras-Raf-MAP-kinase and the protein-serine/threonine kinase AKT could determine resistance to anti-EGFR treatment. We tested the interaction between phosphorylated AKT and MAPK expression in colorectal tumours and corresponding metastases and global outcome in K-RAS wild type patients receiving irinotecan-cetuximab. Seventy-two patients with histologically proven metastatic colorectal cancer, treated with Irinotecan and Cetuximab based chemotherapy, were eligible for our analysis. In metastases pAKT correlated with RR (9% vs. 58%, p = 0.004), PFS (2.3 months vs.9.2 months p < 0.0001) and OS (6.1 months vs.26.7 months p < 0.0001) and pMAPK correlated with RR (10% vs., 47%, p = 0.002), PFS (2.3 months vs.8.6 months p < 0.0001) and OS (7.8 months vs.26 months p = 0.0004). At multivariate analysis pAKT and pMAPK in metastases were able to independently predict PFS. pAKT in metastases independently correlated with RR as well pAKT and pMAPK expression in metastases may modulate the activity of EGFR-targeted antibodies. We could speculate that in patients with pAKT and pMAPK metastases expression targeting these factors may be crucial.

Background: HER family receptors play a key role in tumor progression in several malignancies, such as colorectal, lung or breast cancer. The aims of this study were to investigate expression of HER-1, HER-2 and HER-3 in pancreatic cancer (PC) samples and evaluate the association between HER-family receptor expression and patients’ clinical outcomes. Methods: Tissue samples from 91 PC patients were subjected to immunohistochemical staining to assess the expression of HER-1, HER-2 and HER-3. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+ or 3+ were assigned to each sample based on the intensity of staining for HER receptors. Scores of 2+ or 3+ were defined as positive staining. Results: HER-1 overexpression was observed in 41 out of 91 samples (45.1%), while HER-2 was not overexpressed in any of the analyzed samples. HER-3 was overexpressed in 37 samples (40.7%) and was found to be associated with advanced TNM stage. In particular, HER-3 was overexpressed in 12 out of 16 stage IV patients (75%) compared with only 33.3% of stage I-III patients (p = 0.02). Among 79 patients with available survival data, the 6 patients with strong HER-3 expression (score 3+) had a shorter survival compared with remaining patients (median overall survival 6.9 months vs. 12.3 months, respectively). Conclusions: HER-1 and HER-3 were found to be expressed in a significant proportion of PC patients. Strong HER-3 expression represents an indicator of poor prognosis in PC patients, being associated with advanced stage and shorter survival.