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Investigation on the functional mechanisms of the prognostic factor RHAMM (CD168) in colorectal cancer: A novel potential target for therapeutic intervention?

English title Investigation on the functional mechanisms of the prognostic factor RHAMM (CD168) in colorectal cancer: A novel potential target for therapeutic intervention?
Applicant Lugli Alessandro
Number 133114
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Cancer Research
Start/End 01.04.2011 - 31.12.2014
Approved amount 216'000.00
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Keywords (4)

colorectal cancer; RHAMM; Ras signalling pathway; Prognosis

Lay Summary (English)

Lead
Lay summary
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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer.
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.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
26th European Congress of Pathology Talk given at a conference EMT-like cancer cells over-express hyaluronan acid mediator motility (RHAMM, CD168) and promote colorectal cancer progression 30.08.2014 London, Great Britain and Northern Ireland Terracciano Luigi Maria; Zlobec Inti; Lugli Alessandro; Iezzi Giandomenica; Mele Valentina;
Annual Meeting of the American Association for Cancer Research (AACR) Poster The receptor for hyaluronic acid mediator motility (RHAMM, CD168) expression in EMT-like cancer cells is a predictor of tumor progression in colorectal cancer 05.04.2014 San Diego, CA, United States of America Iezzi Giandomenica; Terracciano Luigi Maria; Zlobec Inti; Mele Valentina; Lugli Alessandro;


Awards

Title Year
George Tiniakos Award 2014 for the best scientific contribution in gastrointestinal, liver and pancreas pathology. 26th European Congress of Pathology, 30th August – 3rd September 2014, London, United Kingdom 2014

Abstract

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.
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