colorectal cancer; RHAMM; Ras signalling pathway; Prognosis
Mele Valentina, Sokol Lena, Kölzer Viktor Hendrik, Pfaff Dennis, Muraro Manuele Giuseppe, Keller Irene, Stefan Zahnd, Centeno Irene, Terracciano Luigi Maria, Dawson Heather, Zlobec Inti, Iezzi Giandomenica, Lugli Alessandro (2017), The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer., in Oncotarget
, 8(41), 70617-70629.
Colorectal cancer (CRC) is one of the most common malignancies in the Western world with an incidence and mortality rate in the European Union of 58/100 000 and 30/100 000 per year, respectively. In Switzerland, the average number of new cases per year is reported at 3768, making CRC the 3rd and 2nd most common malignancy in men and women, respectively Despite improvements in surgical techniques and the implementation of targeted therapies for patients with metastatic disease, individualized treatment options for patients with CRC, particularly in the non-metastatic setting are limited. The American Joint Committee on Cancer and International Union against Cancer (AJCC/UICC) strongly advocate research leading to the identification of novel potential biomarkers which can be translated into clinical practice. In 1992, the molecular cloning of the Receptor for Hyaluronic Acid Mediated Motility RHAMM (CD168) was described and found to have malignant and metastatic potential. Among the first to consolidate the clinical relevance of RHAMM in CRC, our research group has identified the over-expression of this biomarker as a strong, independent and highly adverse prognostic factor in both microsatellite stable (MSS) and microsatellite instability-high (MSI-H) CRC and in early rectal tumours. These studies provide evidence suggesting that this co-receptor of CD44 in addition to its critical involvement in RAS/MAP kinase signaling, and significant impact on prognosis, may be an ideal candidate for therapeutic targeting in CRC. Therefore, the functionality of RHAMM in vitro and in vivo warrants further investigation. The aims of this research project are to: (1) Determine the correlation between the intra- and extra-cellular localisations of RHAMM and their possible differential functional properties; (2) Determine the effect of RHAMM over-expression and silencing on proliferation, cell cycle, migration, and invasion potential in vitro and in vivo; (3) Identify genes and specific exons which are up- or down-regulated in RHAMM over-expressed and silenced cell lines and in fresh frozen CRC specimens by exon arrays.This project is a translation research effort between clinically-orientated researchers and basic scientists each contributing specific expertises not only in different aspects of CRC research (pathology, immunology, prognostic and predictive biomarkers) but also in technical aspects which will be shared between the Institute for Pathology and the Institute of Surgical Research. The successful implementation of this project may have significant implications not only towards the understanding of CRC progression and metastasis formation but could lead to the future development of humanized monoclonal antibodies with possible applications in clinical trials.