< Back to previous page
Project
Tumor-microenvoronment interactions in multiple myeloma: regulation by epigenetic modifications and hypoxia. (FWOAL554)
Multiple myeloma (MM) is a B cell malignancy characterized by an excess of monotypic plasma cells. The MM cells are mostly localized in the bone marrow (BM), although a small number of MM cells can be encountered in the peripheral blood circulation. MM comprises about 10% of hematological malignancies (1). The BM microenvironment provides an appropriate "soil" for the MM cells towards which the MM cells actively home (2), and communicate, through soluble and adhesive interactions with different stromal cell types (3-5) resulting in a protection against apoptosis and induction of proliferation of the MM cells (3). Moreover, activation of osteoclasts and inhibition of osteoblasts, lead to enhanced bone resorption and further activation of the MM cells. BM endothelial cells (BMEC) lining BM sinusoids, are activated during the development of the MM disease, leading to enhanced angiogenesis of the BM of MM patients (6,7).
Next to human cells, the murine 5TMM models (8) will be used in this project. These 5TMM models originated spontaneously in ageing C57BlKaLwRij mice (9-11) and mimic the human disease closely, the major characteristics are: presence of MM cells in the BM (12), serum paraprotein concentration correlated to the development of the disease, induction of bone lesions and angiogenesis (12-15). Analysis of expression of adhesion molecules (12,16,17), chemokine receptors (18-24), proteases (25-27) and their in vitro stroma dependency also demonstrate great similarity to human MM cells. One of the great advantages of these syngeneic immunocompetent models is that in vivo experiments can be combined with in vitro experiments. By using these in vivo models we previously identi?ed a heterogeneity within the MM cells (28-30). The 5TMM models can be used to target a speci?c process in vivo. In our previous FWO project we focused on the tumor-host interactions in MM and the 5TMM models have been used in multiple "pre-clinical" studies evaluating the effects of inhibiting particular pathways on tumor development and associated changes in the microenvironment (angiogenesis and bone disease) (31-34). We have identi?ed IGF-1 as a major survival and growth factor (35,36) and were able to block the IGF-1/IGF-1R interactions with the selective RTK inhibitor picropodophylin (37-39). Targeting the cell cycle proteins cdk4/6 with a small molecule inhibitor appeared to be a successful approach not only by arresting MM cells (40) but also by inhibiting MM associated bone disease (79). We could interfere with the homing of the MM cells by targeting different CCR (19,24), CXCR4 (20) and CD9 (41). The BM also contributed to the survival & proliferation of the MM cells by osteopontin (18) and leptin secreted by adipocytes (42). MMP9 secreted by the MM cells themselves could be targeted (34) or used in the targeting of the MM cells (43). We found epigenetic regulation of these tumor host interactions to be involved. Three of the most common interacting epigenetic modi?cations regulating transcriptional activity are (i) DNA methylation, (ii) posttranscriptional (non)histone modi?cations e.g. acetylation, methylation, phosphorylation and (iii) small noncoding miRNA. Not only the interaction between these three major epigenetic modi?cations, but also the dynamic interplay between these post-transcriptional modi?cations (PMT) has profound impacts on transcriptional regulation (cfr 'histone code' or 'PMT code hypothesis) (44,45). While DNA methylation maintains long term silencing of genes, PMTs have been demonstrated to be more dynamic modi?cations able to respond to the microenvironment according to the needs (46). Aberrant transcriptional silencing of genes via these epigenetic mechanisms is a hallmark of cancer cells (47). Importantly, transcriptional gene silencing is reversible by epigenetic therapies like histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi). We demonstrated that HDACi not only showed speci?city towards the MM cells (80), in vitro they regulated CD9 expression (48) and when used in vivo they dramatically decreased tumor burden (81) and bone disease. Moreover, we showed synergy when combined with the proteosome inhibitor bortezomib (82). In the current project we would like to pursue our work on the tumor-host interaction focusing on the regulation of these interactions. Two major regulatory pathways that we intend to investigate are the A) epigenetic regulations and B) hypoxia induced regulation.
Next to human cells, the murine 5TMM models (8) will be used in this project. These 5TMM models originated spontaneously in ageing C57BlKaLwRij mice (9-11) and mimic the human disease closely, the major characteristics are: presence of MM cells in the BM (12), serum paraprotein concentration correlated to the development of the disease, induction of bone lesions and angiogenesis (12-15). Analysis of expression of adhesion molecules (12,16,17), chemokine receptors (18-24), proteases (25-27) and their in vitro stroma dependency also demonstrate great similarity to human MM cells. One of the great advantages of these syngeneic immunocompetent models is that in vivo experiments can be combined with in vitro experiments. By using these in vivo models we previously identi?ed a heterogeneity within the MM cells (28-30). The 5TMM models can be used to target a speci?c process in vivo. In our previous FWO project we focused on the tumor-host interactions in MM and the 5TMM models have been used in multiple "pre-clinical" studies evaluating the effects of inhibiting particular pathways on tumor development and associated changes in the microenvironment (angiogenesis and bone disease) (31-34). We have identi?ed IGF-1 as a major survival and growth factor (35,36) and were able to block the IGF-1/IGF-1R interactions with the selective RTK inhibitor picropodophylin (37-39). Targeting the cell cycle proteins cdk4/6 with a small molecule inhibitor appeared to be a successful approach not only by arresting MM cells (40) but also by inhibiting MM associated bone disease (79). We could interfere with the homing of the MM cells by targeting different CCR (19,24), CXCR4 (20) and CD9 (41). The BM also contributed to the survival & proliferation of the MM cells by osteopontin (18) and leptin secreted by adipocytes (42). MMP9 secreted by the MM cells themselves could be targeted (34) or used in the targeting of the MM cells (43). We found epigenetic regulation of these tumor host interactions to be involved. Three of the most common interacting epigenetic modi?cations regulating transcriptional activity are (i) DNA methylation, (ii) posttranscriptional (non)histone modi?cations e.g. acetylation, methylation, phosphorylation and (iii) small noncoding miRNA. Not only the interaction between these three major epigenetic modi?cations, but also the dynamic interplay between these post-transcriptional modi?cations (PMT) has profound impacts on transcriptional regulation (cfr 'histone code' or 'PMT code hypothesis) (44,45). While DNA methylation maintains long term silencing of genes, PMTs have been demonstrated to be more dynamic modi?cations able to respond to the microenvironment according to the needs (46). Aberrant transcriptional silencing of genes via these epigenetic mechanisms is a hallmark of cancer cells (47). Importantly, transcriptional gene silencing is reversible by epigenetic therapies like histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi). We demonstrated that HDACi not only showed speci?city towards the MM cells (80), in vitro they regulated CD9 expression (48) and when used in vivo they dramatically decreased tumor burden (81) and bone disease. Moreover, we showed synergy when combined with the proteosome inhibitor bortezomib (82). In the current project we would like to pursue our work on the tumor-host interaction focusing on the regulation of these interactions. Two major regulatory pathways that we intend to investigate are the A) epigenetic regulations and B) hypoxia induced regulation.
Date:1 Jan 2010 → 31 Dec 2013
Keywords:Stem Cell, Blood, Coagulation, Myeloma, Immunology, Microbiology, HLA, Hematology, Lymphoma, cancer, Bone Marrow Transplantation
Disciplines:Basic sciences, Biological sciences