Biography

Research Interests

Project 1: Osteoblastic-Hematopoietic Interactions

The developmental mechanisms of bone and blood formation have traditionally been viewed as distinct, unrelated processes, but there is compelling evidence to suggest that they are functionally intertwined.  First, both cell populations originate in the bone marrow and come into direct physical contact with each other.  Indeed, in situ observations confirm that hematopoietic precursors reside in close proximity to endosteal surfaces in human bone marrow.  Moreover, in vitro studies demonstrate that tight adhesions between these cells are critical for long-term viability and development of primitive human hematopoietic cells.  Second, our in vitro experiments reveal that primary human osteoblasts (OBs) produce growth factors that may be essential for the survival, renewal and maturation of human hematopoietic stem cells (HSCs).  These important observations provide a glimpse of the potential dimensions and ramifications of HSC-OB interactions.  More research is required to secure a broader grasp of the cellular and molecular mechanisms that govern blood and bone biology.

We postulate that HSCs may be dependent on OBs for their survival in vivo and that HSCs influence OB behavior in intact animals.  We are currently in the process of trying to identify those osteoblast-derived factor(s) and the mechanisms that are used by osteoblasts to support hematopoiesis either through cell culture techniques or molecular/biochemical means.  Identifying the mechanisms used by osteoblasts to support hematopoiesis will ultimately reduce the morbidity/mortality associated with bone marrow transplantation for several of the bone marrow failure syndromes. These include, but not limited, the leukemia or any clinical condition requiring bone marrow transplantation.  The results will impact our understanding of the interactive biology of blood and bone cells in health and disease, lead to new strategies for the treatment of hematopoietic and osseous disorders and, one day this may be useful for gene therapy of hematopoietic disorders.

Project 2: Chemokines and Prostate Cancer Metastasis to Bone.

Prostate cancer is a common neoplasm and the second leading cause of cancer deaths in American males. Despite numerous advances, once the tumors metastasize, prostate cancer is almost invariably fatal.  The high mortality rate is principally due to the spread of malignant cells to many tissues including bone.  Because of these facts, there is a growing interest in the early detection and screening of men for prostate cancer, and for a greater understanding of the mechanisms that lead to metastasis. 

The development of metastasis is a complicated, multi-step process.  Briefly, malignant cells initially "escape" from the primary tumor, invade into surrounding tissues and enter into the vascular circulation.  If they are able to survive in the blood stream, they need to arrest at a secondary target site, cross the vascular barrier and migrate into the extravascular connective tissues.  Subsequently, the tumor cells must proliferate or grow, thereby establishing a secondary (or metastatic) tumor.  These events involve numerous cell-cell and cell-extracellular matrix adhesive interactions, which are mediated by many cell surface adhesion molecules. 

The metastasis of circulating prostate carcinoma cells is functionally akin to the behavior of blood cells which also home to bone marrow. There is now compelling evidence that suggests that stromal derived growth factor-1 or SDF-1 and its receptor CXCR4 play a pivotal role in blood cell homing to the marrow. As people working in bone biology often consider issues relating to bone metastasis, these recent findings have caused us to hypothesize that metastatic carcinomas utilized SDF-1 and CXCR4 to localize to bone. Our rationale being: if blood cells use this pathway, why should tumors develop a new pathway?

In our ongoing investigations we are focus on the fundamental mechanisms relating to the bone metastasis of prostate cancer.  We want to determine if prostate cancers express the CXCR4 receptors,  whether the expressed receptor is functional, and if we can limit the metastasis of prostate carcinomas to lodge and grow in the bone marrow using antibodies against CXCR4 and SDF-1.  We are confident that such observations are relevant to a more complete molecular understanding of the behavior of prostate cancer cells and that the new insights derived will lead to the development of innovative strategies to minimize the malignant spread of these cells to bone.

Selected Publications

Taichman RS, Reilly MJ, Matthews LS. Human osteoblast-like cells and osteosarcoma cell lines synthesize macrophage inhibitory protein-1a in response to interleukin-1ß and tumour necrosis factor-a stimulation in vitro. British Journal of Haematology. 108:275-283. 2000.

Hullinger TG, Taichman RS, Somerman MJ. Secretory products from PC-3 and MCF-7 tumor cell lines up-regulate osteopontin in MC3T3-E1 cells J. Cell Biochem 78:607-616. 2000.

Eipers PG, Skale S, Taichman RS, Pipia GG, Swords NA, Mann KG, Long MW. Bone marrow accessory cells regulate human bone precursor cell development. Experimental Hematology 28:815-825. 2000.

Taichman RS, Reilly MJ, Verma RS, Ehrenman K, Emerson SG. Hepatocyte growth factor is secreted by osteogenic cells and cooperatively supports hematopoiesis. British Journal of Haematology. 112:1-12, 2000

Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J, Arenzana-Seisdedos G, Nagler A, Lahav M, Szyper-Kravitz M, Zipori D, Lapidot T. Increased Production of SDF-1 Following Treatment with DNA Damaging Agents: Relevance for Human Stem Cell Homing and Repopulation of NOD/SCID Mice. Journal of Clinical Investigation. 106(11):1331-1339, 2000