ABSTRACT
INDUCTION: chemotherapy (IC) followed by chemoradiation (CRT) is an attractive approach in high-risk locally advanced rectal cancer. Additionally, ASA has shown potential to improve outcomes alongside CRT in rectal cancer. The ICAR trial aimed to evaluate the safety and efficacy of IC followed by CRT with or without ASA on MRI tumor response. METHODS: Single-center, double-blind, randomized phase II trial to evaluate induction treatment with CAPOX, followed by capecitabine-based chemoradiotherapy with ASA (arm 1) or placebo (arm 2) in high-risk stage II-III rectal adenocarcinoma staged by MRI. The primary endpoint was MRI tumor regression grade (mrTRG). Secondary endpoints were pathological response, surgical outcomes, postoperative complications, treatment tolerance, DFS, and OS. RESULTS: Between January 2018 and August 2019, 27 patients were eligible, 25 (92.5%) completed IC, and 23 patients were randomly assigned (12 to ASA group; 11 to placebo group). In the ASA arm, 3 pts (25%) presented distant disease progression at restaging. Seven patients (30.4%) had cCR after neoadjuvant treatment. All 13 patients submitted to surgery after neoadjuvant treatment underwent R0 resections except for 1 patient with positive CRM, and 12 patients (92.3%) had sphincter preservation. After a median follow-up of 34.9 months, the 2-year DFS was 83.1% and 3-year OS was 81.5%. CONCLUSION: There was good compliance in both treatment arms and encouraging cCR rate. ASA during CRT was safe but failed to improve on MRI tumor response. The study was closed due to the absence of benefits.
Subject(s)
Induction Chemotherapy , Rectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/methods , Double-Blind Method , Humans , Induction Chemotherapy/methods , Neoadjuvant Therapy/methods , Neoplasm Staging , Rectal Neoplasms/pathology , Treatment OutcomeABSTRACT
Changes in protein levels in different components of the apical junctional complex occur in colorectal cancer (CRC). Claudin3 is one of the main constituents of tight junctions, and its overexpression can increase the paracellular flux of macromolecules, as well as the malignant potential of CRC cells. The aim of this study was to investigate the molecular mechanisms involved in the regulation of claudin3 and its prognostic value in CRC. In silico evaluation in each of the CRC consensus molecular subtypes (CMSs) revealed that high expression levels of CLDN3 (gene encoding claudin3) in CMS2 and CMS3 worsened the patients' longterm survival, whereas a decrease in claudin3 levels concomitant with a reduction in phosphorylation levels of epidermal growth factor receptor (EGFR) and insulinlike growth factor 1 receptor (IGF1R) could be achieved by inhibiting Nglycan biosynthesis in CRC cells. We also observed that specific inactivation of these receptor tyrosine kinases (RTKs) led to a decrease in claudin3 levels, and this regulation seems to be mediated by phospholipase C (PLC) and signal transducer and activator of transcription 3 (STAT3) in CRC cells. RTKs are modulated by their Nlinked glycans, and inhibition of Nglycan biosynthesis decreased the claudin3 levels; therefore, we evaluated the correlation between Nglycogenes and CLDN3 expression levels in each of the CRC molecular subtypes. The CMS1 (MSI immune) subtype concomitantly exhibited low expression levels of CLDN3 and Nglycogenes (MGAT5, ST6GAL1, and B3GNT8), whereas CMS2 (canonical) exhibited high gene expression levels of CLDN3 and Nglycogenes (ST6GAL1 and B3GNT8). A robust positive correlation was also observed between CLDN3 and B3GNT8 expression levels in all CMSs. These results support the hypothesis of a mechanism integrating RTK signaling and Nglycosylation for the regulation of claudin3 levels in CRC, and they suggest that CLDN3 expression can be used to predict the prognosis of patients identified as CMS2 or CMS3.
Subject(s)
Antigens, CD/genetics , Claudin-3/genetics , Colorectal Neoplasms/genetics , N-Acetylglucosaminyltransferases/genetics , Sialyltransferases/genetics , Colorectal Neoplasms/pathology , Disease-Free Survival , ErbB Receptors/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Glycosylation , Humans , Male , Middle Aged , Prognosis , Receptor, IGF Type 1/genetics , STAT3 Transcription Factor/genetics , Signal Transduction/geneticsABSTRACT
Annexin A2 (ANXA2) is upregulated in several malignancies, including colorectal cancer (CRC). However, there is little knowledge on the molecular mechanisms involved to its upregulation. The aim of this study was to identify the mechanism through which ANXA2 overexpression leads to CRC progression and evaluate its potential prognostic value. We used human CRC samples to analyse the correlation between ANXA2 levels and tumour staging. ANXA2 expression was increased in CRC tissues compared to normal colon tissues. In addition, we observe increased ANXA2 levels in stage IV tumours and metastasis, when compared to stage I-III. Whereas E-cadherin, an epithelial marker, decreased in stage II-IV and increased in metastasis. We've also shown that TGF-ß, a classic EMT inductor, caused upregulation of ANXA2, and internalization of both E-cadherin and ANXA2 in CRC cells. ANXA2 silencing hindered TGF-ß-induced invasiveness, and inhibitors of the Src/ANXA2/STAT3 pathway reversed the EMT. In silico analysis confirmed overexpression of ANXA2 and association to the consensus moleculars subtypes (CMS) with the worst prognosis. Therefore, ANXA2 overexpression play a pivotal role in CRC invasiveness through Src/ANXA2/STAT3 pathway activation. The association of ANXA2 to distinct CMSs suggests the possible use of ANXA2 as a prognostic marker or directed target therapy.