Vitamin D supplementation improves the prognosis of patients with colorectal cancer liver metastases

Colorectal cancer liver metastasis (CRCLM) is one of the deadliest cancers. CRCLM tumours have two distinct histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours are angiogenic, while their RHGP counterparts are vessel co-opting. The patients with DHGP tumours have a better response to anti-angiogenic agents and chemotherapy, as well as the prognosis. To determine the influence of vitamin D supplementation in CRCLM, we analyzed the HGPs and the 5-year OS of CRCLM patients (n=106). Interestingly, we found an inverse correlation between vitamin D supplementation and the presence of RHGP tumours in CRCLM patients. Additionally, the 5-year OS of the patients that administered vitamin D was significantly higher. The cancer cells in RHGP lesions are characterized by direct contact with the hepatocytes, and this phenomenon enhances the motility of the cancer cells and facilitates their infiltration through liver parenchyma to co-opt the pre-existing vessels. Significantly, our in vitro data demonstrated the downregulation of motility markers in the co-cultured cancer cells with hepatocytes upon exposure to vitamin D. Altogether, this study highlights the role of vitamin D in CRCLM and provides a rationale to investigate the contribution of vitamin D supplementation to the prognosis of CRCLM patients. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Dana Massaro and Ken Verdoni Liver Metastases Research Fellowship ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the McGill University Health Centre Institutional Review Board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors All data produced in the present study are available upon reasonable request to the authors