Influence of the tumor microenvironment on the humoral and cellular immune responses : insights for new specific cancer biomarkers and therapeutic targets
(2011)
Files
thèsecomplèteFDefresne.pdf
Open Access - Adobe PDF
- 5.85 MB
Details
- Authors
- Supervisors
- Feron, Olivier
- Abstract
- (en) Cancer is a complex network of tumor cells and host cells. Tumor cells, by secreting and expressing different proteins, permanently communicate with the stroma and the host surrounding tissues, leading to remodeling of the extra-cellular matrix and further invasiveness or humoral immune response against tumor-associated antigens. Acute comprehension of those two aspects of tumor progression is crucially needed in order to dissect metastasis processes and to identify biomarkers, allowing targeted therapies or early diagnosis of this lethal disease. In the first part of our work, we identified circulating autoantibodies as biomarkers of tumor growth and metastasis development. First, we showed the influence of radiotherapeutic and chemotherapeutic treatments on circulating anti-GRP78 antibodies. Indeed, while chemotherapy induces a decrease in the anti-GRP78 antibodies titer, radiotherapy appeared to increase it, drawing the attention to the therapeutic status of cancer patients recruited in studies aiming to identify new autoantibodies as cancer biomarkers. Second, we documented that hypoxia allows to identify new potential biomarkers that would not have been identified otherwise. Hypoxia is one of the most common features of solid tumors. Integrating this characteristic in our conditions of SERPA, we were able to identify six proteins which induce a humoral immune response in tumor-bearing mice. Thus, on a translational research perspective, this part of our work provides new insights to improve the serological proteome analysis but also the interpretation of the data. Our studies also led to the identification of unsuspected mammary tumor-associated antigens and the possible use of corresponding autoantibodies to detect early stages of the disease. The second part of our work was dedicated to the study of the secretome of tumors cells and to the systemic effects it induces in a syngenic model of melanoma tumors. We focused our attention on the endothelial progenitor cells and how tumor cells influence them in metastasis development. We identified SPARC as a key protein involved in the physical interaction between tumor cells and EPC, sustaining the protective role of EPC towards metastasis development. Although we showed that whether tumor cells lead to an increase or a decrease in SPARC expression in EPC, it may either prevent or promote metastases formation (through macrophage-like activity). The mechanism through which tumor cells modulates SPARC expression in EPC warrants further studies. More generally, the plasticity of EPC and the multiple role of SPARC in tumor and host tissues need to be carefully re-evaluated before considering therapeutic modalities based on anti-vasculogenic strategies or SPARC inhibition.
- Affiliations
Citations
Defresne, F. (2011). Influence of the tumor microenvironment on the humoral and cellular immune responses : insights for new specific cancer biomarkers and therapeutic targets. https://hdl.handle.net/2078.5/152056