Metastasis of tumors to parenchymal organs is not solely dependent on the characteristics of the malignant cells. It is also influenced by the parenchymal cells of the organ being invaded. The question addressed in this proposal is: why leukemia/lymphoma cells reside in the bone marrow at diagnosis and when the disease relapses? Based on in vitro and in vivo data it is proposed that the marrow stromal cells interact with the leukemia/lymphoma cells in vivo to provide a growth stimulation to the leukemia/lymphoma cells. Normal hematopoiesis is dependent in vitro and in vivo on cellular elements of the marrow microenvironment. The marrow stromal elements are composed of endothelial cells, macrophages and mesenchymal fibroblastic cells. The distribution in vivo of the fibroblastic colony forming cells and hematopoietic stem cells in non-random. In long-term marrow cultures in vitro the hematopoietic stem cells with a greater regenerating potential are present in the association with marrow stromal cells in the adherent layer. Observations by us and others suggest that human and murine marrow stromal cells provide an inductive (or inhbitory) microenvironment for leukemia/lymphoma cells in vitro. We propose that the marrow stromal cells are associated with the leukemia/lymphoma cells in vivo as well and regulate growth of lymphoma/leukemia cells. We have developed an in vivo and in vitro mouse model to address these questions. We propose that the heterotypic adherence between the leukemia/lymphoma cells and marrow stromal cells is mediated by a family of leukemia cell adherence proteins. We will develop monoclonal antibodies to the leukemia cell adherence proteins and test their ability of the monoclonal antibodies to interfere with the interaction between marrow stromal cells and leukemia/lymphoma cells in vitro. Effect of the monoclonal antibodies on the metastasis of leukemia/lymphoma in vivo after intraveneous injection will also be evaluated.
| Patrick Jr, C W; Smith, T W; McIntire, L V et al. (1996) Cellular interactions among marrow stromal and normal/neoplastic pre-B- and B-lymphoblastic cells. Leuk Lymphoma 22:205-19 |
| Patrick Jr, C W; Juneja, H S; Lee, S et al. (1995) Heterotypic adherence between human B-lymphoblastic and pre-B-lymphoblastic cells and marrow stromal cells is a biphasic event: integrin very late antigen-4 alpha mediates only the early phase of the heterotypic adhesion. Blood 85:168-78 |
| Juneja, H S; Rajaraman, S; Gay, R E et al. (1992) Characterization of heterotypic adherence between transformed human lymphoblastic cells and marrow stromal cells: VCAM-1 is a ligand for one of the leukemia cell adhesion proteins. Exp Hematol 20:1263-70 |
