HIF-1α and CXCR4/CXCL12 have crucial roles in the metastatic process of colorectal cancer. Our aim was to study the significance of targeting HIF-1α and the CXCR4/CXCL12 axis in colorectal cancer to prevent the dissemination process in vitro.

Gastric cancer (GC) remains a health issue due to the low efficiency of therapies, such as cisplatin. This unsatisfactory situation highlights the necessity of finding factors impacting GC sensibility to therapies. We analyzed the cisplatin pangenomic response in cancer cells and found HDAC4 as a major epigenetic regulator being inhibited. HDAC4 mRNA repression was partly mediated by the cisplatin-induced expression of miR-140. At a functional level, HDAC4 inhibition favored cisplatin cytotoxicity and reduced tumor growth. Inversely, overexpression of HDAC4 inhibits cisplatin cytotoxicity. Importantly, HDAC4 expression was found to be elevated in gastric tumors compared to healthy tissues, and in particular in specific molecular subgroups. Furthermore, mutations in HDAC4 correlate with good prognosis. Pathway analysis of genes whose expression in patients correlated strongly with HDAC4 highlighted DNA damage, p53 stabilization, and apoptosis as processes downregulated by HDAC4. This was further confirmed by silencing of HDAC4, which favored cisplatin-induced apoptosis characterized by cleavage of caspase 3 and induction of proapoptotic genes, such as BIK, in part via a p53-dependent mechanism. Altogether, these results reveal HDAC4 as a resistance factor for cisplatin in GC cells that impacts on patients’ survival.

Surgical procedures that combine both complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved the survival of patients with peritoneal carcinomatosis (PC). Current imaging and laboratory investigations are not very useful to diagnose PC. This prospective study sought to determine the usefulness of routine second-look surgery (RSLS) combined with HIPEC in the diagnosis and treatment of patients with PC at high-risk for recurrence.From 2007 to 2011, RSLS was performed on 14 patients who had undergone a complete initial oncological resection for synchronous colonic PC and/or ovarian metastasis with PC discovered during primary colon cancer surgery after a course of 12 cycles of intravenous chemotherapy, eventually associated with HIPEC.Pathology confirmed PC in 71% of patients during RSLS, with a median peritoneal carcinomatosis index (PCI) of 10. There was no post-operative mortality, while 7% of patients exhibited Dindo Grade III-IV complications. The 2-year overall survival and disease-free survival rates were 91% and 38%, respectively. Following RSLS and CCRS, peritoneal recurrence was observed in only 8% of patients who had undergone HIPEC.RSLS combined with HIPEC after initial resection of synchronous colonic PC allows diagnosis and treatment of low-score PC, with limited post-operative complications and increased overall survival rates.