Chemokines at the heart of oncology research

Researchers in Bordeaux are taking a closer look at chemokines, proteins involved in the mechanisms whereby tumor cells invade tissues. This research has been the subject of several publications, notably in "Nature Communications".

  • 07/12/2017

Les cellules tumorales d'un gliome ne surexprimant pas le récepteur CXCR3 ©LAMC Les cellules tumorales d'un gliome ne surexprimant pas le récepteur CXCR3 ©LAMC

In the 1990s, researchers discovered a major new family of proteins called chemokines. They are referred to as “chemoattractants” as they attract immune system cells in vertebrates to combat infection. Over the years, studies have shown that chemokines are involved in many diseases, particularly cardiovascular, neurodegenerative diseases, HIV, etc. They therefore represent a specific focus of study, along with the receptors that they activate on cells, in order to gain a better understanding of their role and function. A team led by Andreas Bikfalvi at the Angiogenesis and Tumor Microenvironment Laboratory (LAMC, INSERM research unit and University of Bordeaux) has been studying the role of one receptor in particular, called CXCR3, in cancer and tumor invasion.

Research that could be extended to different cancers and diseases

This research project relating to the chemokine receptor has been the subject of several publications, the latest of which appeared very recently in the nature research journal, “Nature Communications”. The study focuses on one of the two forms of this receptor which exhibits pro-tumor properties. A team led by Isabel Alves at the Institute of Membrane and Nano-object Chemistry and Biology (CBMN, CNRS research unit, Bordeaux INP and University of Bordeaux) is also involved and has succeeded in identifying a LRP1 co-receptor to CXCR3-A. When both LRP1 and CXCR3-A receptors form a complex on the membrane, the CXCR3-A receptor can enter the cell and be recycled. In tumor cells, however, the LRP1 co-receptor is inhibited and the CXCR3-A receptor remains more present on the cell membranes, particularly those which are invasive at the periphery of tumors.

This represents a new mechanism whereby tumor cells invade tissues, explains Andreas Bikfalvi, who is also the Director of the LAMC. “The research was conducted on brain tumors but undoubtedly bears a broader significance and can be extended to other types of tumors and diseases”.

Integrated research from the molecule to the patient

These discoveries also follow on from other results obtained by these research teams who work not only on brain tumors but on pancreatic cancer as well, which is also very aggressive and invasive.

The CXCR3 receptor is found in humans in two main forms, A and B. In research published in Cancer Research (Quemener et al, Can Res, 2016), the team demonstrated that the presence of CXCR3-A or CXCR3-B and their activation by chemokines have diametrically opposed functions. CXCR3-A expressed in tumor cells has a pro-tumor and pro-invasive effect, whereas CXCR3-B expressed on a vascular level has the opposite effect. When a receptor is activated by a chemokine, its form changes, resulting in various cellular events. The researchers succeeded in demonstrating differences in form modifications of CXCR3-A or CXCR3-B following activation by their chemokines (Boyé et al, Scientific reports, 2017).

Many pathways remain thus to be explored by researchers in Bordeaux in an integrated research project ranging from the molecule to the patient. These include: improving our knowledge of CXCR3-A, making it a therapeutic target, understanding why the LRP1 is inhibited and trying to prevent it.

An international consortium dedicated to brain tumors

Gliomas, which are the most common form of brain tumors, are divided into high-grade gliomas and low-grade gliomas. The first type is extremely aggressive and highly invasive. Low-grade gliomas exhibit different behaviors: they may progress quickly or very slowly. These cancers particularly affect young people under 30 years of age. A consortium was recently set up with the specific aim of obtaining methods to predict the progression of these low-grade gliomas, incorporating complex data thanks to imaging, genetics, molecular data, etc. This consortium was recently selected within the framework of a European program, TRANSCAN-2 (Translational CancerResearch: "Minimally and non-invasive methods for early detection and/or progression of cancer").

Coordinated by Andreas Bikfalvi, the consortium includes his team at the LAMC, as well as researchers based in Bordeaux: from the Bordeaux Institute of Mathematics and the Monc-Inria oncology modeling team: Olivier Saut and Thierry Colin, from the Bordeaux population health research center and the Translational Medicine Statistics team - SISTM-Inria: Rodolphe Thiebaut, and international partners (Lorenzo Bello, Humanitas, University of Milan; Rolf Bjerkvig, Jebsen Brain Tumor Research Center, University of Bergen, Norway).

References

The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors. Boyé and al.